Comtan (Entacapone) and Stalevo (Carbidopa+Entacapone+Levodopa) Tablets: Wockhardt settled patent dispute with innovator; Review by IP Pharma doc

Indian pharma giant Wockhardt announced (in a press release Here) a settlement and license agreement with innovator Orion Corporation w.r.t it’s pending patent litigation on anti-Parkinson medication Comtan (Entacapone) and Stalevo (Carbidopa+Entacapone+Levodopa) tablets. Following patents are listed in orange book for Comtan (Entacapone) and Stalevo (Carbidopa+Entacapone+Levodopa) tablets:

US4963590 (Expiry: Nov 27, 2007): Claims Pharmaceutical composition and method of use of catechol-O-methyl transferase inhibitor

US5112861 (Expiry: May 12, 2009): Method of use with Entacapone and levodopa


US5135950 (Expiry: Oct 31, 2010): Crystallographically essentially pure polymorphic form A

US5446194 (Expiry: Oct 19, 2013): Covers Entacapone as product

US6500867(Expiry: Jun 29, 2020): Covers An oral solid tablet composition comprising pharmacologically effective amounts of Entacapone, Levodopa, and Carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and a pharmaceutically acceptable excipient, wherein a substantial portion of carbidopa or a pharmaceutically acceptable salt or hydrate thereof is separated from entacapone and levodopa or pharmaceutically acceptable salts or hydrates thereof in the tablet.

US6797732 (Expiry: Jun 29, 2020): A stable oral solid composition comprising pharmacologically effective amounts of active agents consisting of Entacapone, Levodopa, and Carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and comprising at least one pharmaceutically acceptable excipient other than microcrystalline cellulose

US6599530 (Expiry: Sep 14, 2018): Which covers an oral compacted composition in the form of a tablet, which comprises a pharmaceutically effective amount of entacapone, nitecapone, or pharmaceutically acceptable salt of entacapone or nitecapone, and croscarmellose sodium in an amount of at least 6% by weight of the composition.

Earlier, Wockhardt's challenged innovator’s ‘950, ‘194, ‘867, ‘530 and ‘732 patents listed in the Orange Book.

Subsequently, innovator Orion sued Wockhardt for patent infringement in the District Court of Delaware. Additionally, Orion filed the first lawsuit in the US in 2007 and thereafter two additional lawsuits were filed in 2008. The settlement agreement relates to all three suits.


Under the terms of the settlement agreement, Wockhardt will be able to launch generic versions of Comtan and Stalevo on September 30, 2012, or possibly even earlier, subject to certain conditions. Additional terms related to the settlement remain confidential, and the agreement is subject to review by the US Department of Justice and the U.S Federal Trade Commission (FTC).

Wockhardt is first Para IV filer on Entacapone tablets (Comtan) and accordingly, is eligible for 180 days First To File generic exclusivity as per Hatch-Waxman provisions.

Also, another generic player Sun Pharma has filed Para IV on this product and innovator has sued Sun Pharma in District Court of Delaware

USFDA Approvals
USFDA approved Comatan (Entacapone) 200 mg tablets on Oct 19, 1999 and
Stalevo (CARBIDOPA; ENTACAPONE; LEVODOPA) NDA for 12.5MG;200MG;50MG, 25MG;200MG;100MG and 37.5MG;200MG;150MG strength on Jun 11, 2003. Recently, USFDA approved new strengths of Stalevo (CARBIDOPA; ENTACAPONE; LEVODOPA) 50MG;200MG;200MG (approved on Aug 2, 2007), 18.75MG;200MG;75MG (approved on Aug 29, 2008), and 31.25MG;200MG;125MG (approved on Aug 29, 2008)

About Entacapone

Entacapone is a catechol-O-methyl transferase inhibitor for the treatment of Parkinson's disease. When administered in conjunction with dopaminergic agents such as L-DOPA, Entacapone increases the bioavailability of these compounds by facilitating their passage across the blood-brain barrier.

Darifenacin hydrobromide (Enablex) ER 7.5 mg and 15 mg tablets: Watson confirmed patent challenge

Generic player Watson Pharma confirmed (in a press release Here ) that it has filed ANDA with Para IV certification against innovator Novartis’s urinary incontinence medication Darifenacin hydrobromide (Enablex) extended-release 7.5 mg and 15 mg. Darifenacin, which is chemically (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl] pyrrolidin-3-yl] -2,2-diphenyl-acetamide is a M-3 Muscarinic acetylcholine receptor inhibitor.

Following patents are listed in Orange Book for this product:

US5096890 (Assignee; Pfizer, Expiry: Mar 13, 2015): Which covers 3-substituted pyrrolidine derivatives like Darifenacin as product

US6106864 (Assignee; Pfizer, Expiry: Aug 21, 2016): which covers a pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier; characterized in that the dosage form is adapted to release in the lower gastrointestinal tract at least 10% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof.

Earlier, Watson filed it’s ANDA (possibly, on latest ANDA filing date i.e Dec 22, 2008) and sent innovator Para IV notice w.r.t ‘864 patent.

Further, after the receipt of Para IV notice letter, innovator Novartis filed suit against Watson on April 24, 2009 in the U.S. District Court of Delaware seeking to prevent Watson from commercializing its products prior to expiration of ‘864, accordingly, Watson’s ANDA approval process would be delayed by 30 months as per Hatch-Waxman provisions.

Possibly, Watson is first Para IV filer for this product, accordingly, Watson will be eligible for 180 days lucrative exclusivity.

Earlier, innovator got final approval to market this product on Dec 22, 2004.

Sumatriptan 85 mg + Naproxen sodium 500 mg Tablets (Treximet): Innovator sued Teva for filing ANDA with Para IV certification

Innovator Pozen and GlaxoSmithKline (GSK) has filed a lawsuit after they received a Para IV letter from Terva Pharma on April, 2009 w.r.t antimigraine medication Treximet (Sumatriptan 85 mg+Naproxen sodium 500 mg). Teva's letter advised POZEN and GSK that it intended to market a generic version of Treximet tablets before the expiration of following Orange Book listed patents:

US5037845: (Expiry: Aug 6, 2008): Expired patent, which covered sumatriptan as product

US6060499 (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 of said LA-NSAID.

US6586458 (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.

US7332183 (Expiry: Oct 2, 2025): 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

Innovator has sued generic player Teva for the infringement of ‘0499 and ‘458 patents in US district court of Eastern Texas.

Also, innovator has earlier sued generic players like Par, Mylan and Alphapharm in Novemebr, 2008 for filing ANDA with Para IV certification in US district court of Eastern Texas.

Earlier, innovator got approval on this combination on Apr 15, 2008. The New combination exclusivity on this product will expire on Apr 15, 2011.

Enoxaparin (Lovenox): US Supreme refused to hear innovator Sanofi’s appeal against patent invalidation

Refer to our earlier posts on blockbuster blood thinner medicine Enoxaparin litigation Here, the innovator Sanofi’s appeal against May, 2008 ruling of CAFC w.r.t key patent US5389618 (Expiry: Feb 14, 2012) which was later reissued as USRE38743 (Expiry: Feb 14, 2012) covering Enoxaparin, wherein, court declared patent invalid due to inequitable conduct. Subsequently, innovator appealed to US supreme against said decision.

As per latest decision, the appellate court has refused to hear innovator’s appeal without citing any specific comments.

Earlier, generic players like Amphastar and Teva has filed ANDA for this product and successfully challenged innovator’s key patents ‘743.

The inequitable conduct was alleged w.r.t EP40144, which was granted in Europe as patent in 1980 (Which got revoked in 1990). The said patent covers the same invention as disclosed in ‘723. Aventis got ‘618 patent after overcoming 3 rejections by USPTO.

Finally, Aventis demonstrated that pharmacokinetic profile with respect to t1/2 is better in ‘618 patent in comparison to ‘144 patent. The federal court affirmed the ruling by a district court in California that there was an intent to deceive by Sanofi-Aventis in its failing to disclose dosages of the drug in pharmacokinetic studies.

Enoxaparin (6-[5-acetylamino-4,6-dihydroxy-2- (sulfooxymethyl)tetrahydropyran-3-yl] oxy-3- [5-(6-carboxy-4,5-dihydroxy-3- sulfooxy-tetrahydropyran-2-yl)oxy-6-(hydroxymethyl)- 3-sulfoamino-4-sulfooxy-tetrahydropyran-2-yl] oxy-4-hydroxy-5-sulfooxy-tetrahydropyran-2- carboxylicacid ) is a low molecular weight heparin manufactured by Sanofi-Aventis.

Ezetimibe (Zetia) 10 mg tablets: Glenmark got USFDA tentative approval

Glenmark Generics announced (in a press release Here ) that the USFDA has granted tentative approval for the generic version of innovator Schering Plough and MSP Singapore Company LLC's hypercholesterolemia treatment Ezetimibe (Zetia) 10 mg tablets.

Also, innovator shering and MSP has sued Glenmark in New Jersey Disctrict Court for the infringement of following patent:

USRE37721(Expiry: April,25, 2017): which covers Ezetimibe as product

Also, there are two other non-litigated Orange Book listed patents which covers combination of Ezetimibe with other API’s. Earlier, Glenmark filed an Abbreviated New Drug Application (ANDA) on October 25, 2006 for this product.

Possibly, Glenmark is eligible for First Para IV filing 180 days exclusivity for this high margin product which achieved sales of USD 1.5 billion in 2008..

Erlotinib (Tarceva) 25 mg, 100 mg and 150 mg Tablets: Delhi HC dismisses innovator Roche’s plea

An Indian division bench headed by Justice AP Shah and Justice Muralidhar (Delhi high court) dismissed the plea of the Swiss Pharma giant Roche on temporary injunction against Indian generic player Cipla w.r.t manufacturing and selling the generic drug Erlotinib [N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine] 25 mg, 100 mg and 150 mg tablets till the issue of patent rights was decided through litigation. Also, court imposed 5 lakh rupees cost on innovator Roche for suppressing the material facts.

Earlier, In January, 2008, innovator Roche filed a patent infringement suit against Cipla in the Delhi high court for the infringement of Indian patent IN196774 ('which is equivalent patent of orange book listed patent US5747498), following Cipla’s launch of the generic version of Tarceva in December, 2007. Subsequently, Delhi High Court in March, 2008 allowed Indian firm Cipla to manufacture and sell a generic version of the patented drug, Tarceva, in India (link to opinion of court Here).

Also, innovator Roche may appeal against said decision in Supreme court.

The above litigation is one of the most famous patent litigation in India. Two famous indian politician cum attorney's Mr. Arun Jaitley represented Cipla, while Roche was represented by Mr. Abhishek Manu Shanghvi.

Generic player Cipla has alleged that disputed patent is invalid as obvious and is an attempt by innovator Roche on patent evergreening w.r.t already known and patented quinazoline derivative Gefatinib (further, the patent application on Gefetinib was rejected in India due to strong prior art disclosure in EP0566266). Also, generic player alleged that the Erlotinib can not be patented as per indian patent section 3 (d) as it is derivative of Gefetinib.

Furthermore, generic palyers counsel argued that API in their formulation (cipla's Erlocip formulation) contains crystalline Polymorph form B, whereas, innovator's disputed patent IN196774 discloses Erlotinib as mixture of two crystalline polymorphic forms A and B (thermodynamically unstable polymorph mixture, not suitable for formulation development), accordingly, their formulation is non-infringing.

Additionally, patent application on Polymorph Form B (equivalent of Orange Book listed patent US6900221) was already rejected in India due to obviousness and section 3 (d) during prosecution by patent examiner.

Importantly, court in it's decision observed that innovator's marketed product contains crystalline polymorph form B (as confirmed from XRD analysis), which is not covered by '774 patent.

Further, court considered "Public interest" element w.r.t price diffrence, availability and affordability of this product in India.

Other related links
Link to business-standard news Here
Link to livemint news Here

Link to review by Spicy IP team Here

Omega-3-acid Ethyl Esters (Lovaza) 1 g capsules: Innovator Pronova sued Teva

Innovator Pronova BioPharma confirmed (in a press release Here ) that company has filed a lawsuit against Teva Pharma in the United States District Court for the District of Delaware.

Earlier, innovator Pronova received a Paragraph IV Notice Letter dated March 9 2009 from Teva (as reported by us Here ) advising that Teva has submitted an Abbreviated New Drug Application (ANDA) to the US Food and Drug Administration for approval to market a generic version of Omega-3-acid Ethyl Esters 1 g capsules with para IV certification.

Following patents are listed in Orange Book for Omega-3-acid Ethyl Esters (Lovaza) 1 g capsules:

US5502077 (Expiry: Mar 26, 2013): Which covers a method for the treatment or prophylaxis of hypertriglyceridemia in a human patient, which comprises orally administering to the patient a pharmaceutical composition in which the active ingredients consist essentially of a mixture of fatty acids of which at least 80% by weight is comprised of a combination of (all-Z omega-3)-5,8,11,14,17-eicosapentaenoic acid (EPA) and (all-Z omega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio of EPA:DHA of from 1:2 to 2:1, said composition being administered in amounts providing a daily dosage of 1 to 10 grams of said mixture of fatty acids

US5656667 (Expiry: Aug 27, 2018): Which covers a method for elevating the HDL cholesterol level in the serum of a human patient, which comprises administering to the patient a pharmaceutical composition in which the active ingredients consist essentially of a mixture of fatty acids of which at least 80% by weight is comprised of a combination of (all-Z omega-3)-5,8,11,14,17-eicosapentaenoic acid (EPA) and (all-Z omega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio of EPA:DHA of from 1:2 to 2:1, said composition being administered in amounts providing a daily dosage of 1 to 10 grams of said mixture of fatty acids.

US5698594 (Expiry: Aug 4, 2009): Which covers a method for the treatment or prophylaxis of hypertension in an adult human patient, which comprises administering to the patient, on a daily basis, an effective amount of a pharmaceutical composition in which the active ingredients consist essentially of a mixture of fatty acids of which at least 80% by weight is comprised of a combination of (all-Z omega-3)-5,8,11,14,17-eicosapentaenoic acid (EPA) and (all-Z omega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio of EPA:DHA of from 1:2 to 2:1 and of which at least 1% by weight of the mixture of fatty acids is comprised of (all-Z omega-3)-6,9,12,15,18-heneicosapentaenoic acid.

Teva's notice letter states that its ANDA contains a Paragraph IV Certification alleging that the '077 and '667 patents are not valid, unenforceable, or will not be infringed by the commercial manufacture, use or sale of Teva's product.

Innovator in its complaint in the United States District Court for the District of Delaware has asserted US5502077 and US5656667 against Teva.

Also, generic players like Par (as reported by us Here ), Apotex (as reported by us Here)
has filed ANDA with Para IV certification for this product

LOVAZA (Omega-3-acid ethyl esters) is indicated as an adjunct to diet to reduce very high (≥500 mg/dL) triglyceride (TG) levels in adult patients, the approved formulation also contains fish oils. USFDA approved omega-3-acid ethyl esters (Lovaza) on Nov 10, 2004.

Losartan: Paediatric extension denied in UK

An application for a paediatric extension for antihypertensie Losartan potassium of granted certificate SPC/GB/95/010 was filed. The preliminary view of the examiner was that this application did not meet the requirements of Article 8(1)(d)(i) of Regulation (EEC) No. 1768/92 as it did not include a copy of the statement of compliance with an agreed completed paediatric investigation plan as referred to in Article 36(1) of EC Regulation (EC) No. 1901/2006.

Link to full decision Here

Memantine: SPC revocation decision delayed

SPC revocation decision on alzheimer treatment medication Memantine has delayed in UK. The Judge in the UK came to the conclusion that he needed to refer questions on the legal interpretation of the SPC Regulation to the European Court of Justice for clarification of the position. The said decision can further take some time, however, commercially, generic player Synthon (who has opposed the SPC) will have to wait for final decision from court.

Link to court decision Here

New Paragraph IV filings reported by USFDA till April 21, 2009

Pregabalin (Lyrica) Capsules 25, 50, 75, 100, 150, 200, 225, and 300 mg Para IV filed on Dec 30, 2008

Ropinirole (Requip XL) Extended-release Tablets 4 mg and 8 mg Para IV filed on Oct 31, 2008 and Nov 3, 2008

Venlafaxine Hydrochloride (Venlafaxine hydrochloride) Tablets 37.5, 75, and 150 mg Para IV filed on Feb 12, 2009

Omega-3-acid ethyl esters (Lovaza) Capsules 1 g Para IV filed on Nov 10, 2008

Darifenacin (Enablex) Extended-release Tablets 7.5 and 15 mg Para IV filed on Dec 22, 2008

Doxycycline (Doryx) Delayed-release Tablets 150 mg Para IV filed on Dec19, 2008

Levonorgestrel; Ethinyl Estradiol; Ethinyl Estradiol 0.15 mg/0.03 mg/0.01 mg Tablets (Seasonique) Para IV filed on Jan 22, 2008

(Source: USFDA)

Raloxifene Hydrochloride (Evista) 60 mg Tablets: Court issued preliminary injunction against generic launch by Teva

Innovator Eli Lilly announced (in a press release Here) that the U.S. District Court for the Southern District of Indiana has issued a preliminary injunction to prevent “at risk launch” of a generic version of Lilly's medicine Raloxifene Hydrochloride (Evista) 60 mg Tablets by Teva until the Court renders its final ruling.

Earlier, Teva had indicated it was prepared to launch the generic version prior to the resolution of outstanding patent litigation currently being considered by the U.S. District Court for the Southern District of Indiana. Lilly had previously sought and been granted a temporary restraining order to prevent the generic launch.

Also, as per press release from Teva ( Here ), Teva will appeal against said decision.

Detailed patent analsyis of IPPharmdoc on this product Here

Dextromethorphan HBr+ Guaifenesin ER 30 mg+600 mg and 60 mg+1200 mg tablets (Mucinex): Watson confirmed Para IV filing and litigation with innovator

Generic player Watson Pharma confirmed (in a press release Here) that it has filed Abbreviated New Drug Applications (ANDA) with Paragraph IV certification on Dextromethorphan HBr+ Guaifenesin 30 mg+600 mg and 60 mg+1200 mg ER tablets. Watson has challenged innovator Reckitt Benckiser following Orange Book listed patents on Dextromethorphan HBr+ Guaifenesin ER 30 mg+600 mg and 60 mg+1200 mg tablets (Mucinex):

US6372252 (Assignee: Adams Lab): Which covers a modified release tablet having two portions, wherein a first portion comprises a first quantity of guaifenesin in an immediate release form which becomes fully bioavailable in the subject's stomach and a second portion comprises a second quantity of guaifenesin and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer wherein the weight ratio of said hydrophilic polymer to said water-insoluble polymer is in the range of from about 1:1 to about 6.8:1, wherein said tablet demonstrates a Cmax in a human subject equivalent to the Cmax obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period, and wherein said tablet also provides therapeutically effective bioavailability for at least twelve hours after a single dose in a human subject according to serum analysis.
US6955821 (Assignee: Adams Lab): Which covers a modified release drug product comprising a first quantity of guaifenesin in an immediate release formulation wherein the guaifenesin becomes bioavailable in a subject's stomach; a second quantity of guaifenesin in a release-delaying matrix; and at least one additional drug, wherein the release-delaying matrix comprises a hydrophilic polymer and a water-insoluble polymer in a weight ratio of hydrophilic polymer to water-insoluble polymer from about 1:1 to about 9:1, wherein the immediate release formulation guaifenesin has a Cmax in a human subject equivalent to the Cmax obtained when a dose of a standard immediate release formulation having one third the amount of guaifenesin is dosed, and immediately after administration the serum concentration of guaifenesin peaks in about an hour, followed by a gradual serum concentration decrease over twenty-four hours but the serum concentration of guaifenesin never decreases below the minimum concentration of said standard immediate release formulation over twelve hours, and wherein the drug product releases a therapeutically effective bioavailable guaifenesin dose for at least twelve hours after a single dose in the human subject according to serum analysis.

Innovator Reckitt Benckiser has filed suit against Watson on April 20, 2009 in the U.S. District Court for the Southern District of New York seeking to prevent Watson from commercializing its products prior to expiration of ‘821 and ‘252 patents

Dextromethorphan HBr+ Guaifenesin ER tablets are indicated to help loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus and make coughs more productive.

According to IMS Health data for the twelve-months ended December 31, 2008, Dextromethorphan HBr+ Guaifenesin ER tablets 30 mg+600 mg and 60 mg+1200 had total U.S. sales of approximately $106 million and $85 million respectively,.

Carvedilol (Coreg): Teva settled with Glenmark on API process patents

Refer to our earlier post on carvedilol (Coreg) Here and Here, wherein, Teva dropped API process patent infringement charges against Dr. Reddy and Taro, now, Teva has settled with another generic player Glenmark ( also, refer to Livemint news on this litigation) and dropped infringement charges.
The lawsuits concern following patents which covers Carvedilol API manufacturing process:

US6699997 (Assignee: Teva, Date of Grant: March 2, 2004) : Which covers A process for preparing carvedilol comprising a step of reacting a compound of formula II, 4-(oxiran-2-ylmethoxy)-9H-carbazole with a compound of formula III, 2-(2-methoxyphenoxy)ethylamine, wherein, the compound of formula III and the compound of formula II are at a molar ratio of from about 2.8:1 to about 10:1.
US7126008 (Assignee: Teva, Date of Grant: October 24, 2006 ): Which covers a process for preparing carvedilol comprising a step of reacting a compound of formula II, 4-(oxiran-2-ylmethoxy)-9H-carbazole with a compound of formula III, 2-(2-methoxyphenoxy)ethylamine, wherein, the compound of formula III is at a molar excess over the compound of formula II.
Teva filed a notice in the U.S. District Court of New Jersey to dismiss the suit against Glenmark without prejudice.
After innovator GSK’s product patent on Carvedilol expired in 2007, more than dozen generic companies have developed their generic product and got USFDA approval. Further, Teva has aggressively asserted its patent on process to snub other generic players to continually monopolize market on this product.

Carvedilol is a non-selective beta blocker indicated in the treatment of mild to moderate Congestive Heart failure(CHF). It is marketed under various Trade names like Coreg (GSK), Dilatrend (Roche) and Eucardic (Roche). Carvedilol is the only bata blocker which is(which reduce cardiomyopathy of heart muscle) used in CHF therapy.

Propafenone ER capsules (Rythmol) 225, 325, and 425mg: innovator settled with generic player Par; generic version delayed till Jan, 2011

Generic player Par Pharma announced (in a press release Here) that Par has entered into a settlement agreement with innovator Reliant Pharmac to resolves patent litigation related to Reliant’s Propafenone ER capsules (Rythmol) 225, 325, and 425 mg.

Following patent is listed in Orange Book for this product:

US5681588 (Assignee: Knoll, Expiry: Oct 28, 2014): Which covers a cylindrical delayed release microtablet with a convex or flat upper side and lower side of Propafenone a) the height and diameter are, independently of one another, 1-3 mm, b) the active ingredient content is in the range from 81 to 99.9% of the weight of the microtablet, c) the active ingredient density is greater than 1, d) the release of active ingredient in the USP paddle method at 50 rpm is 80% as a maximum after 3 hours and as a minimum after 24 hours, e) the release rate is virtually independent of the pressure when compressing the tablets, and f) the tablet contains no release-delaying ancillary substance but 0.1-5% by weight of a lubricant and 0-18.9% by weight of other conventional ancillary substances.

Earlier, innovator Reliant sued generic player Par in Delaware District Court in Dec, 2006 for filing ANDA on Propafenone ER capsules (Rythmol) 225, 325 and 425 mg with Para IV certification against ‘588 patent.

Under the terms of the settlement, Par will have the right to introduce a generic version of Rythmol® SR on January 1, 2011, or earlier under certain circumstances. Propafenone extended release capsules are indicated to prolong the time to recurrence of symptomatic atrial fibrillation in patients without structural heart disease.

Propafenone ER capsules (Rythmol) 225, 325, and 425 mg had combined U.S. sales of approximately $119 million for the twelve months ended September 2008, according to IMS Health.

Racemic O-Desmethylvenlafaxine (ODMV) succinate (Pristiq): Sepracor Announced Patent Interference Proceedings

In a battle of Pharma giant like Sepracor and Wyeth on patent priority date dispute w.r.t O-desmethylvenlafaxine (ODMV) succinate, Sepracor announced (in a press release Here) that the Board of Patent Appeals and Interferences (BPAI) of the USPTO has combined three patent interferences into a single interference and set a date for oral arguments. The interference seeks to determine the priority of inventorship of claims directed to racemic O-desmethylvenlafaxine (ODMV) succinate. Wyeth markets racemic ODMV succinate in the U.S. under the brand name PRISTIQ® for the treatment of major depressive disorder in adults.
The interference is between Wyeth's following Orange Book listed patents:
US6673838 (Assignee: Wyeth, Date of grant: January 6, 2004): Which covers O-desmethyl venlafaxine succinate as product. The said patent also covers polymorphs, pharmaceutical compositions, dosage forms, and methods of use with the same.
US7291347 (Assignee: Wyeth, Date of grant: November 6, 2007): Which covers oral dosage form comprising O-desmethyl venlafaxine succinate, wherein the oral dosage form is a tablet and capsule.
Sepracor claims that they discovered the drug first and filed an application for a patent in April 1999, almost two years before Wyeth made its first filing in February 2001.

The earliest application filing date asserted by Sepracor (April 6, 1999) is approximately 22 months earlier than the earliest application filing date asserted by Wyeth for its patents (February 12, 2001).

Sepracor claims that they discovered the drug first and filed an application for a patent in April 1999, almost two years before Wyeth made its first filing in February 2001.

BPAI of the U.S. Patent and Trademark Office plans to hear arguments from the two companies on January 6, 2010.

Budesonide Respules (Pulmicort) inhalation suspension: US court bars Apotex from generic launch till final decision on permanent injunction

In continuation of our earlier post on Budesonide Here, Here, wherein, Innovator Astra filed a lawsuit in the US District Court for the District of New Jersey against Apotex (Apotex) filed a motion for Interim Relief seeking to prohibit sales of Apotex’s generic product until the patent infringement case has concluded.

The District Court for the District of New Jersey gave the drugmaker a restraining order (as reported by Astra in press release Here) that bars Apotex from selling a copycat version of AstraZeneca's top-selling asthma medicine Budesonide Respules (Pulmicort) inhalation suspension. Also, Court will decide by month end on permanent injunction.

Earlier, innovator was sucessful against generic launch by Teva. Later on, Teva settled with innovator and agreed to launch generic version in Dec, 2009 under licensing agreement.

Zoledronic acid (ZOMETA) lyophilized powder for injection: USFDA confirmed that drug was not withdrawn due to safety issues

The USFDA has determined after review of citizen petition (filed on Spetember, 2007) by generic player Sun Pharma (through Kendle international) that ZOMETA (zoledronic acid for injection), equivalent to (EQ) 4 milligrams (mg) base/vial, lyophilized powder for injection, was not withdrawn from sale for reasons of safety or effectiveness.

Eralier, Innovator Novartis discontinued manufacturing and marketing this product in May, 2003. This decision will allow USFDA to approve ANDA's for this product

For more details:
http://edocket.access.gpo.gov/2009/pdf/E9-8524.pdf

Venlafaxine HCl (Effexor ER) 37.5, 75 and 150 mg Capsules: Innovator sued Zydus Cadilla for filing Paragraph IV

Innovator Wyeth has sued generic competitor Zydus Cadilla for filing ANDA no. 90-174 with Paragraph IV certification against Orange Book listed patents of Wyeth's anti-depression drug Effexor ER Capsules 37.5, 75 and 150 mg (venlafaxine HCl).

Following patents are listed in Orange Book w.r.t Venlafexine XR capsules:

US6274171 (Expiry: September 20, 2017): Link
US6403120 (Expiry: September 20, 2017) link
US6419958 (Expiry: September 20, 2017) Link
US4535186 (Expiry: June 13, 2008) Link
US5916923 (Expiry: December 28, 2013) Link
US6444708 (Expiry: December 28, 2013) Link

Innovator has sued Zydus Cadilla for the infringement of ‘171, ‘120 and ‘958 patents in the US District Court for the District of Delaware.

Following generic players are in litigation with innovator:

Anchen Pharmaceuticals

Lupin

Sandoz

Mylan

Wockhardt

Biovail

Apotex

Also, innovator has settled with generic players like Impax , Sun pharma and Teva on this product.
Earlier news of pharmadoc Here

Capecitabine (Xeloda) Tablets, 150 mg and 500 mg: Mylan confirmed patent challenge

Generic player Mylan confirmed (in a pess release Here) that Mylan have been sued by innovator Hoffmann-La Roche Inc. in connection with the filing of an Abbreviated New Drug Application (ANDA) with the U.S. Food and Drug Administration (FDA) for Capecitabine Tablets, 150 mg and 500 mg, the generic version of Xeloda® Tablets, a chemotherapy treatment for breast and colorectal cancer.

Mylan believes it is the first company to have filed a substantially complete ANDA containing a Paragraph IV certification for the product and expects to qualify for 180 days of sole marketing exclusivity once final FDA approval is obtained.

Following patent are listed in Orange Book: for this product

US4966891 (Expiry: Jan 13, 2011): which covers Fluorocytidine derivatives like Capecitabine as product

US5472949 (Expiry: Dec 14, 2013): Which covers N4 -(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine compounds as product

Innovator Hoffmann-La Roche filed a lawsuit on April 8, 2009 in the U.S. District Court for the District of New Jersey alleging infringement of ‘949 patent. Possibly, Mylan may have filed Para III against ‘891 patent.

Xeloda Tablets, 150 mg and 500 mg, had approximately $447 million in sales for the 12 months ending Dec. 31, 2008, according to IMS Health. Currently, Mylan has 117 ANDAs pending FDA approval, 33 of which are potential first-to-file opportunities.

Innovator got approval to market this drug in US on Apr 30, 1998

Fluvastatin Sustained Release 80 mg tablets: Actavis launched generic version in UK, Holland after favorable patent litigation outcome

Generic player Actavis has launched Fluvastatin SR in the UK and the Netherlands (as reported by Actavis in press release Here). Actavis was first to market in both countries.

Fluvastatin SR extended release tablets from Actavis are the generic equivalent of Novartis‘ Luvinsta® SR / Lescol® XL and are available in 80mg tablets in both markets. Fluvastatin SR is used to treat high cholesterol levels in the blood.

Fluvastatin SR tablets are manufactured by Actavis Malta and developed by Actavis‘ R&D in Iceland.

This launch was possible after Actavis won a court case in January 2009 in the UK, whereby Novartis’ following formulation patent was revoked:

EP0948320 (Assignee: Novartis): Following independent claims were litigated in the trial

Claim1 which covers a pharmaceutical composition for sustained release, said composition comprising a water soluble salt of fluvastatin as active ingredient and being selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.

Claim2 which covers use of a water soluble salt of fluvastatin for the manufacture of a pharmaceutical composition for sustained release, for the treatment of hypercholesterolemia.

The said patent was revoked (otherwise, the patent would have prevented the launch of the product until 2017) on obviousness grounds, in the light of following prior art:

(1) British National Formulary (March 1996 )
(2) US4739073
(3) WO199506470

The formulation patent has also been revoked in the Netherlands.

Fluvastatin was the first fully synthetic HMG-CO-A analogue; The compound was patented as product patent EP114720 in the the early 1980s (now, expired). A Supplementary Protection Certificate (SPC) in respect of the patent covering Fluvastatin (EP114720) expired on 22 August 2008.

The compound received marketing approval for use in humans at the end of 1993 and was first marketed in 1994. At the priority date of EP0948320 (which, 8 October 1996), the drug was available in the form of capsules containing 20 mg or 40 mg of Fluvastatin sodium (a water-soluble salt of the active ingredient).

Link to court decision Here

Lanthanum Carbonate (Fosrenol) Chewable tablets 500 mg, 750 mg and 1gm: Natco and Lupin to jointly commercialize generic version

This post is in continuation to our earlier post Here, the first Para IV filer Natco has collaborated with M/S Lupin, to jointly commercialize generic version of Lanthanum Carbonate (Fosrenol) Chewable tablets 500 mg, 750 mg and 1gm

Link to business-standard news Here

Budesonide Respules (Pulmicort) inhalation suspension: AstraZeneca sued Apotex to seek a declaration of patent infringement

In continuation of our earlier post on Budesonide Here, Innovator Astra announced ( in a press release Here) that Astra has filed a lawsuit in the US District Court for the District of New Jersey against Apotex (Apotex) seeking a declaration of patent infringement
Also, Innovator has filed a motion for Interim Relief seeking to prohibit sales of Apotex’s generic product until the patent infringement case has concluded. The Court has indicated that it will hear oral arguments regarding the motion on 16 April 2009.

Desloratadine 5 mg Tablets (Clarinex): Mylan Announced Settlement With Innovator

Generic player Mylan announced ( announced in a press release Here) the settlement of all patent litigation relating to the generic version of Schering- Plough's Desloratadine 5 mg Tablets (Clarinex).

Earlier, innovator had sued various generic players like Zydus, Sandoz, Mylan, Orchid, Perrigo, Glenmark, GeoPharma, Lupin, Ranbaxy, Sun, Watson, Dr. Reddy's who filed ANDA to market this product. Importantly, Innovator has patents listed in orange Book with expiries in 2020.

Apart from Mylan, innovator had settled with Geopharm, Perrigo, Watson Pharma and Ranbaxy, Dr. Reddy, Lupin.

Possibly, all generic players are in licensing agreement with Innovator and would launch generic around July, 2012.

Our Earlier post on this product Here, Here , Here, Here, Here and Here

Efavirenz (600 mg) + Emtricitabine (200 mg) + Tenofovir Disoproxil Fumarate (300 mg) (Atripla):Innovator Gilead Confirmed Receipt of Para IV Letter

Innovator Gilead Sciences confirmed (in a press release Here ) the receipt of a Paragraph IV Certification Notice Letter from generic player Teva Pharma on Efavirenz (600 mg) + Emtricitabine (200 mg) + Tenofovir Disoproxil Fumarate (300) mg (Atripla). The antiviral combination is currently sold in the United States through a joint venture between Bristol-Myers Squibb (BMS) and Gilead.
In the Notice Letter, Teva alleges that following two Orange Book listed patents associated with Emtricitabine are invalid, unenforceable and/or will not be infringed by Teva's manufacture, use or sale of the product described in its ANDA submission:

US6642245 (Expiry: May 4, 2021): which covers A method for treating HIV infection in humans comprising administering an effective amount of (-)-.beta.-L-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable salt, optionally in a pharmaceutically acceptable carrier.

US6703396 (Expiry: Sep 9, 2021): The (-)-enantiomer of cis-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolane-5-yl)-(1H)-pyrimid in-2-one that is at least 95% free of the corresponding (+)-enantiomer

Earlier, Teva challenged the validity of these same two Emtricitabine patents with an ANDA filing for Truvada® (Emtricitabine and Tenofovir disoproxil fumarate) as reported by us Here. Subsequently, Innovator Gilead sued Teva in District Court in New York.

Earlier news of IPPharmadoc on this product Here

Sevelamer Carbonate (Renvela) 800 mg tablets: Impax Confirms Patent Challenge

Impax Lab announced (in a press release Here ) that it has initiated a challenge of the patents listed by Genzyme Corporation in connection with its Renvela® (sevelamer carbonate) 800 mg tablets.
Earlier, innovator sued generic companies like Impax (as reported by us Here) and Lupin (as reported by us Here) for filing ANDA for Sevelamer Hydrochloride.

Evista (Raloxifene ) & Xigris (Drotrecogin alfa): U.S. Appeals Court Issued ruling in favor of innovator Lilly

The US Court of Appeals for the Federal Circuit (CAFC) in Washington, D.C. overturned a lower court decision and ruled in favor of innovator Eli Lilly (as reported by Lilly in press release Here) in the case between Ariad Pharma v. Eli Lilly.

An earlier jury decision in the U.S. District Court of Massachusetts, and a subsequent bench trial ruling, had deemed that a patent owned by Harvard University, the Massachusetts Institute of Technology and the Whitehead Institute, and licensed to Ariad, was valid and infringed by Lilly's sales of Evista(R) and Xigris(R). Today's ruling by the Court of Appeals overturned that prior decision, concluding that Ariad's patent claims are invalid for failing to meet the written description requirement.

US Court CAFC opinion Here

Earlier news of IP Pharma Doc on this product Here and Here

Budesonide Respules (Pulmicort) inhalation suspension (0.25mg/2ml, 0.5mg /2ml): AstraZeneca sued Apotex

Innovator AstraZeneca has filed a patent infringement lawsuit against Canadian generic player Apotex to block a generic version of Astra's lucrative Budesonide Respules (Pulmicort) inhalation suspension (0.25mg/2ml, 0.5mg /2ml) anti-asthma formulation.

Innovator has listed the following patents in Orange Book for this product:

US6598603 (Expiry: Jun 23, 2019): which covers a method of treating a patient suffering from a respiratory disease, the method comprising administering to the patient a nebulized dose of a budesonide composition in a continuing regimen at a frequency of not more than once per day.

US6899099 (Expiry: Jun 23, 2019): which covers a method of treating a patient suffering from a respiratory disease, the method comprising administering to the patient a nebulized dose of a budesonide composition in a continuing regimen at a frequency of not more than once per day, wherein the administration is in the evening.

Earlier, innovator sued Ivax (Teva) in 2005 and Breath pharma in 2008 for filing ANDA with Para IV against orange book listed patents.

Also, in November 2008 innovator settled with first para IV filer Ivax (Teva) after later launched its product ‘at risk’ in US market in Novemeber, 2008. Subsequently, Teva agreed to settle with innovator (as reported by IPPharmadoc Here ) and delayed generic launch till December, 2009, however, Teva would pay royalty based on sale of this product to innovator.

As per USFDA records, two generic players Ivax (approved on November 18, 2008) and Apotex (approved on March 30, 2009) has approved ANDA for this product.

Further, innovator Astra has not disclosed whether it was seeking a preliminary injunction or restraining order against Apotex.

Although, Ivax (Teva) is first Para IV filer for this product, however, due to failure to market drug product with in stipulated time of final approval from USFDA (as per Medicare Modernization act provisions on gneneric exclusivity), Teva has forfeited its 180 days generic exclusivity.

Furthermore, if Apotex agreed to launch this product in US market, the said launch would be "at risk" launch, wherein, generic company can face triple damages, in case of adverse court ruling against generic company.

In the past, some generic players have succesfully launched their generic product 'at risk' in US market. The launch of Fexofenadine and Pentoprazole was 'at risk' launch by Teva. From patent damages perspective, the pharma sector is a quite safe sector and there are hardly any triple damages award against any generic player, thetherefore, many generic players are opting for this lucarative but risky route. Also, innovator companies tries to settle with generic players to stop early generic erosion.

Budesonide inhalation suspension (0.25mg/2ml, 0.5mg /2ml, 1mg /2ml) was approved by USFDA on Aug 8, 2000.

IP Pharma doc’s earlier post on this product Here and Here

Reuters news Here and Here

Lanthanum Carbonate (Fosrenol) Chewable tablets 500 mg, 750 mg and 1gm: Innovator sued Natco

Innovator Shire has filed lawsuit (as confirmed by press release Here ) in the U.S. District Court for the Southern District of New York against Hyderabad based Natco Pharma Limited for infringement of Orange Book listed patents US5968976 and US7381428, listed for Lanthanum Carbonate (Fosrenol) Chewable tablets 500 mg, 750 mg and 1 gm
Earlier, Ippharmadoc reported Here that innovator confirmed receipt of Paragraph IV notice letter from Barr and Mylan. Innovator has already sued Barr and Mylan in District Court of the Southern District of New York as reported by us here. And Here

Oxycotin (Oxycontin) ER tablets: U.K. appeals court opined Infringement of controlled release formulation patents by generic players

A U.K. appeals court comprising bench of LORD JUSTICE JACOBLORD NEUBERGER and LORD JUSTICE LAWRENCE COLLINS has determined that generic players Sandoz and Ratiopharm GmbH have infringed the patents of Purdue Pharma LP affiliate Napp Pharmaceutical Holdings Ltd. for the painkiller Oxycontin.

The Litigated patents are owned by innovator Napp Pharma, disputed patents are EP722730 and EP1258246. The Judge held both patents valid but not infringed by the tablets which Ratiopharm and Sandoz wish to sell, a product made by Cimex AG (now Acino AG).

The patents relate to controlled release formulations of a painkiller called Oxycodone. Napp sells such a formulation under the trademark Oxycotin. Its importance is shown by its sales figures – of the order of £32 million per annum in the UK alone.

In the final decision court dismissed generic players Ratiopharm and Sandoz’ s appeal concerning validity and allow Napp's appeal concerning infringement.

The decision of court is well written and particularly useful for the Pharma scientists working in formulation or novel drug delivery system.

Link to court decision Here

Methylphenidate hydrochloride extended-release 18 mg, 27 mg, 36 mg and 54 mg tablets (Concerta): disputed patent declared invalid

In a major victory to generic player Watson Pharma, the United States District Court for the District of Delaware has ruled that Watson's generic version of Concerta (methylphenidate hydrochloride extended-release tablets) does not infringe following Orange Book listed patent:

US6919373 (Expiry: Jan 31, 2018): the patent covers a method for treating ADD or ADHD comprising administering a dosage form comprising methylphenidate that provides a release of methylphenidate at an ascending release rate over an extended period of time.

Court opined that the '373 Patent is invalid. The opinion, dated March 30, 2009, was issued by Judge Joseph Farnan, Jr., and applies to Watson's generic versions of Concerta(R) in the 18 mg, 27 mg, 36 mg and 54 mg strengths.

Also, following patent is listed for this product in Orange Book:

US6930129 (Expiry: Jan 31, 2018): Which covers a method for treating Attention-Deficit Disorder or Attention-Deficit Hyperactivity Disorder in a patient, wherein the method comprises administering a pharmaceutically acceptable composition comprising methylphenidate and a pharmaceutically acceptable carrier to said patient in a manner that achieves a substantially ascending methylphenidate plasma drug concentration over a time period of about 8 hours following said administration.

Prior to the commencement of the trial, the plaintiffs offered Watson a ‘covenant not to sue’ on ‘129 patent, however, Watson declined to accept the covenant and asked the court to declare that the '129 Patent is invalid and not infringed. A decision on Watson's Declaratory Judgment claim on the '129 Patent is subject to further proceedings by the parties. However, Watson believes that the '129 Patent is invalid for the same reasons that the court held the '373 Patent is invalid.
Earlier In 2005, innovators AlzaCorp and McNeil, sued Impax and Andrx Corporation for patent infringement related to the generic version of Concerta. Watson acquired Andrx Corporation in 2006.
Methylphenidate is a mild central nervous system stimulant thought to exert its effect by enhancing dopaminergic transmission in the brain. Methylphenidate is used to treat attention-deficit hyperactivity disorder (ADHD).

Source: Watson press release Here