Cevimeline Hydrochloride (Evoxac) 30 mg Capsules: Innovator Daiichi sued Apotex

Innovator Daiichi has sued generic player Apotex for filing ANDA with Paragraph IV certification to market Cevimeline Hydrochloride (Evoxac) 30 mg Capsules. Innovator has sued Apotex in US district court for the district of Delaware. Following patents are listed in the Orange Book for this product:

US4855290 (Expiry: Aug 30, 2009): which covers various quinuclidine derivatives as product


US5340821 (Expiry: Jul 7, 2013): The patent covers a method for treating the symptoms of Sjoegren syndrome

As per complaint, innovator has alleged infringement of ‘821 patent by Apotex.

Innovator got approval to market Cevimeline (2-methyspiro (1,3- oxathiolane- 5,3) quinuclidine) Hydrochloride hydrate (Evoxac) 30 mg Capsules on Jan 11, 2000.

Cevimeline is a parasympathomimetic and muscarinic agonist and clinically used for the treatment of dry mouth associated with sjoegren syndrome

Adalimumab (Humira): Jury found infringement of patent by Abbot

In one of the important jury verdict, an Eastern District of Texas jury has opined that Abbott should pay around $1.6 billion in damages for infringing Centocor and New York university’s following patent on TNF alpha:

US7070775 (Assignee: New York University & Centocor; Date of Grant: July 4, 2006): which covers an isolated recombinant anti-TNF-.alpha. antibody or antigen-binding fragment thereof, said antibody comprising a human constant region, wherein said antibody or antigen binding fragment (i) competitively inhibits binding of A2 (ATCC Accession No. PTA-7045) to human TNF-.alpha., and (ii) binds to a neutralizing epitope of human TNF-.alpha. in vivo with an affinity of at least 1.times.10.sup.8 liter/mole, measured as an association constant (Ka), as determined by Scatchard analysis.

The Jury has found that Abbot’s blockbuster drug Humira infringes claims 2, 3, 14 and 15 of '775 patent. Further, Jury has found the said claims are not invalid in the light of prior art. Also, Jury opined that patent fulfill criteria of patentability as per written description and enablement standard under 35 USC 112.

Also, Jury has found willful infringement against Abbot by clear and convincing evidence. Now, Eastern District of Texas Judge Ward will decide on jury findings.

Related news:

Link to Bloomberg news Here
Link to patentlyO Here

Prasco and GPhA response on FTC Report on Authorized Generics, during the 180-day Exclusivity Period

Various organisation have reacted diffrently to Federal Trade Commission report on Authorized Generics, during the 180-day Exclusivity Period. The generic player Prasco (an authorized generic leader) and Generic pharmaceutical Association (GPhA) has released press release on this issue.

Prasco applauds FTC report

Prasco Laboratories, a Mason-based independent authorized generic company, applauds the Federal Trade Commission (FTC) for issuing their interim report on the short and long-term effects of authorized generics on competition in the prescription drug marketplace.

Prasco commends the FTC in its approach. “This Interim Report is the result of a long and arduous process in response to a 2005 request by Senators Leahy, Grassley, and Rockefeller to review the impact of the practice of authorized generics on competition during the 180-day exclusivity period,” stated E. Thomas Arington, Chairman and CEO of Prasco. “The Commission’s analysis supports the pro-consumer impact of the increased competition that authorized generics bring to the generic drug industry, and the resulting savings to the American consumer,” stated Arington.

Prasco press release Here

The Generic Pharmaceutical Association (GPhA) opposed authorized Generics, during the 180-day Exclusivity Period

The Generic Pharmaceutical Association (GPhA) released the following statement today from GPhA President and CEO Kathleen Jaeger in response to the release of the FTC Interim Report on Authorized Generic Drugs.

“While we have not had an opportunity to read the entire FTC report, the fact is that authorized generics harm, not help consumers. Authorized generics are yet another tactic that brand pharmaceutical companies have in their arsenal to keep affordable generic medicines from consumers.

“Authorized generics undermine Congressional intent by undercutting the 180-day exclusivity period for generic manufacturers. Congress provided the 180-day incentive as a means to foster investment by generic companies to challenge questionable and weak brand patents with the ultimate goal of providing more timely access to and greater choices of affordable medicines. Simply put, but for the generic challenger, there would be no price competition. Permitting brand companies to undercut the incentive is just not sound public policy.

GPhA press release Here

Authorized Generics: FTC Issues Interim Report

'Authorized generic' is a contentious issue between generic players and pioneer companies. Various generic players have constantly opposed the launch of authorized generics by innovator, which affect sale of First Para IV filer generic player during 180 days generic exclusivity period. The “authorized generic’ launch is the last resort for innovator companies when the generic launch is imminent.

It’s almost 25 years of passage of Hatch-Waxman act which has revolutionised health care reforms in US by facilitating low cost generic version. Hatch-Waxman act stimulated the growth of robust generic drug industry and has balanced interests of pioneer companies and generic players. However, pioneer companies have intelligently devised strategies to thwart generic challenge by exploring loopholes like 'authorized generics' issues.

In the past, the 'authorized generic' launch by innovator has significantly affected the sale forecast of generic players. The 'authorized generic' launch of blockbuster molecules like Gabapentine (Neurontin), Paroxetine (Paxil), Ciprofloxacin (Cipro), Fexofenadine (Allegra), Pantoprazole (Protonix), Nitrofurantoin (Macrobid), and Alendronate Sodium (Fosamax) has significantly affected the sale of First Para IV filer generic player.

Also, generic players have unsuccessfully opposed 'authorized generics' at various forums like in courts and regulatory authority. 'Authorized generic' is like a sword for innovator companies and till date, there is no protective shield for generic players against this sword.

FTC report
In an attempt to review and address this issue, the US Federal Trade Commission (FTC) has issued “Authorized Generics: An Interim Report,” which presents the first set of results from a study conducted to examine the short-term and long-term effects of “authorized generics” on competition in the prescription drug marketplace.

An authorized generic exists when a pharmaceutical manufacturer sells a drug under both a brand-name and generic label. The FTC conducted the study in response to requests from Congress. Issues related to generic drug competition are relevant to current legislative debates and health care reform.

The FTC Interim Report examines the short-term effects of authorized generics during an initial period of generic competition.

Press release of FTC Here
Complete report of FTC Here
Earlier news of IP Pharma Doc on this issue Here


Dear Readers,

I would like to receive your expert comments on this issue

Regards
D.K. Sarwal

Levocetirizie Dihydrochloride (Xyzal) Oral Solution 2.5 mg/5ml: Innovator sued Synthon in a bid to block generic version

Generic player Synthon have filed ANDA with Paragraph IV certification against innovator Sepracor/UCB’s Orange Book listed patents on Levocetirizie Dihydrochloride (Xyzal) Oral Solution 2.5 mg/5ml. Following patent is listed in Orange Book for this product:

US5698558 (Expiry: September 24, 2012): This patent covers a method of treating the symptoms of seasonal and perennial allergic rhinitis in a human which comprises administering to a human in need of such symptomatic relief therapy an amount of (-) cetirizine, or a pharmaceutically acceptable salt thereof, substantially free of its (+) stereoisomer, said amount being sufficient to alleviate or palliate said allergic rhinitis.

After receipt of Para IV notice from Synthon on May 5, 2009, Belgian healthcare group UCB S.A. and Sepracor has filed a legal action on 17 June, 2009 against generic player Synthon for allegedly infringing ‘558 patent on its antihistamine drug levocetirizine (Xyzal) in the District court for the Eastern District of North Carolina .

Possibly, Synthon is first Para IV filer for this product. Also, Perrigo pharma will be the marketing partner of Synthon for this product.

Levocetirizie dihydrochloride (Xyzal) Oral Solution 2.5 mg/5ml was approved by USFDA on Jan 28, 2008. Also, this product has got new product exclusivity which will expire on May 25, 2010.

Further, innovator has already sued various generic players like Synthon, Sun Pharmaceuticals, Sandoz and Barr, who have filed ANDA for Levocetirizie dihydrochloride (Xyzal) 5mg tablets.

Perrigo Press release Here

Sildenafil Citrate 25 mg, 50 mg and 100 mg tablets: Actavis launch generic version in Bulgaria

Generic player Actavis has launched Sildenafil citrate tablets in Bulgaria. This is Actavis Group’s first launch of the product, which also was the first generic sildenafil to enter the Bulgarian market.

Sildenafil Actavis is the generic equivalent of Pfizer's Viagra® and is prescribed to treat erectile dysfunction. Sildenafil Citrate from Actavis is available in Bulgaria in 25mg, 50mg and 100mg tablets, in packs of one or four.

Annual brand product sales amounted to EUR1.5 billion worldwide in 2008; EUR1.4 million in Bulgaria (IMS Health data).

Sildenafil Actavis is manufactured by Actavis in Malta.

Source: Actavis press release Here

Oxaliplatin (Eloxatin) injection:District court opined in favor of generic player Sandoz, Teva and Mayne

In a significant decision, The U.S. District Court for the District of New Jersey has granted summary judgment of non-infringement in favor of generic players Sandoz, Teva and Mayne Pharma (Hospira) on Oxaliplatin (Eloxatin) 50 mg/, 100 mg/vial, 200 mg/vial and 5 mg/ml injection.

Eloxatin is covered by following Orange Book listed patents:

US5338874 (Expiry Apr 07,2013): Which covers Optically pure cis-oxalato (trans- 1-1,2-cyclohexanediamine) Pt(II) wherein the melting point thereof is between 198.degree. C. and 292.degree. C

US5420319 (Expiry Aug 08,2016): Which covers a Cis-oxalato(trans-1-1,2-cyclohexanediamine) Pt(II) complex having high optical purity represented by Formula 1 which possesses optical purity of 99.94% or more and a melting point between 198.3.degree. C. and 199.7.degree. C

US5716988 (Expiry Aug 07,2015) : Which covers a pharmaceutically stable preparation of oxaliplatinum for the administration by the parenteral route, consisting of a solution of oxaliplatinum in water at a concentration of 1 to 5 mg/ml and having a pH of 4.5 to 6, the oxaliplatinum content in the preparation being at least 95% of the initial content and the solution remaining clear, colorless and free of precipitate after storage for a pharmaceutically acceptable duration of time.

US5290961 (Expiry Jan 12, 2013): Which covers a process of preparing a cis-platinum (II) complex of a 1,2-cyclohexanediamine isomer

Sanofi-Aventis filed suit against Mayne Pharma (Hospira), Teva and Sandoz in June-July 2007 and their API supplier W.C. Heraeus GmbH in May 2008, for infringement of US5338874 which covers oxaliplatin as product.

The U.S. District Court for the District of New Jersey in it’s decision opined that although ‘874 patent covers optically pure oxaliplatin as product, however, the claim construction clearly suggest that claim in actual should be product by process claim. Also, court concluded that process limitation of ‘874 patent is separation of isomer using HPLC technique. Importantly, generic players are not using HPLC technique for resolution of isomer. Further, court upheld the validity of the patent but concluded no infringement of claim 1 by generic players Mayne Pharma (Hospira), Teva and Sandoz.

Oxaliplatin is a platinum-based chemotherapy drug in the same family as cisplatin and carboplatin. It is typically administered in combination with fluorouracil and leucovorin in a combination known as FOLFOX for the treatment of colorectal cancer. Compared to cisplatin the two ammine groups are replaced by cyclohexyldiamine for improved antitumour activity. The chlorine ligands are replaced by the oxalato bidentate derived from oxalic acid in order to improve water solubility.

Oxaliplatin was discovered in 1976 at Nagoya City University in Japan by Professor Yoshinori Kidani, who was granted US4169846 over the drug in 1979. Oxaliplatin was subsequently in-licensed by Debiopharm, a Swiss drug company headquartered in Lausanne and developed as an advanced colorectal cancer treatment. Debio licensed the drug to Sanofi-Aventis in 1994. Eloxatin gained European approval in 1999 and USFDA approval in 2004.

Press releaes

Hospira press release Here

Teva in a press release Here

Innovator Sanofi-Aventis press release Here

Galantamine (Raminyl) Tablets: EU court sided with regulatory authority on refusal to marketing authorization to Generics UK

In an interesting and well written decision, Court of Justice of the European Communities (including Court of First Instance Decisions) on reference for a preliminary ruling from the High Court of Justice of England and Wales (United Kingdom) in a dispute between Genericks UK V.s Licensing Authority of UK (MHRA) on Marketing authorization refusal to generic player for Galantamine (Reminy).

Background
Galantamine was first marketed in Austria In 1963, under the brand name 'Nivalin'for the treatment of Polio. Later in 1995, the authorisation of Nivalin was amended to include 'symptomatic treatment' of Alzheimer's disease, the original Nivalin dossier per se was never brought up-to-date in accordance with the requirements of Directive 65/65 and Directive 75/319, which had been applicable in Austria since 1 January 1994 by virtue of the EEA Agreement.Later on, innovator Waldheim withdrew Nivalin from the market in 2001.

Meanwhile, as a result of cooperation agreements with Waldheim, in 1999 Janssen-Cilag AB submitted a full application to the competent Swedish authority (the Swedish Medicinal Products Agency, 'the Swedish MPA'), pursuant to Article 4 of Directive 65/65 (now Article 8 of Directive 2001/83), for marketing authorisation for Galantamine under the brand name 'Reminyl', for the treatment of Alzheimer's disease (in particular, an Alzheimer-type dementia).

The application was submitted on the basis of the generic product exception in Article 10(1) of Directive 2001/83. Nivalin, which was the subject of an authorisation from Austria, was specified as the reference medicinal product authorised for a period of not less than 10 years in the EEA. The application also mentioned the British authorisation of Reminyl as the reference medicinal product in the United Kingdom, and as the product used for the bioavailability study necessary to show that the Generics's product was, in fact, a generic of Nivalin/Reminyl.

The Licensing Authority rejected Generics's application. It considered that Nivalin, covered by the Austrian authorisation, could not be used as the reference medicinal product for an application for marketing authorisation for a generic medicinal product within the meaning of Article 10(1) of Directive 2001/83, since its dossier had not been updated since 1 January 1994 to comply with the requirements of Community legislation, applicable in Austria following the entry into force of the EEA Agreement. As regards Reminyl, the 10-year period of protection referred to in Article 10 of Directive 2001/83 in its original version had not yet expired and, therefore, the authorisation could not be granted on that basis.

First, as regards the argument according to which Generics is relying on Nivalin's two variations of 1995, introduced after Austria acceded to the EU, Shire and Janssen-Cilag, the United Kingdom Government and the Commission correctly point out that such variations in and of themselves do not demonstrate that the entire package of data in the dossier for Nivalin conformed with the Community provisions in force. This is because the dossier relating to Nivalin for its original use (treatment of polio) was never updated and brought into compliance with the Community legislation.

in order to be able to grant a marketing authorisation for a generic medicinal product on the basis of the abridged procedure ... what matters is that all the particulars and documents relating to the reference medicinal product remain available to the competent authority for the Member State where the application for the marketing authorisation is made and not that the reference medicinal product has in fact been placed on the market

Decision of Court
Where a medicinal product falling outside of the scope of the Annex to Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products has been placed on the market in a Member State (Austria) under its national authorisation procedure prior to the accession of that Member State to the European Economic Area (EEA) or the Community and the dossier of the product in question was not updated in accordance with Directive 65/65/EEC (now Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use) after that Member State's accession to the EEA and the Community, that product is not to be considered to be 'a reference medicinal product which is or has been authorised under Article 6 ... in a Member State' within the meaning of Article 10(1) of Directive 2001/83.

However, where a product containing the same active ingredient has subsequently been authorised under Article 6 of Directive 2001/83 and placed on the market in the Community, that product may constitute a reference medicinal product for the purposes of Article 10 of Directive 2001/83, provided that the period of protection has expired and the bioequivalence of the generic product with this product has been demonstrated.

For complete opinion and facts on this case please use following link:

http://www.bailii.org/cgi-bin/markup.cgi?doc=/eu/cases/EUECJ/2009/C52707_O.html&query=galantamine&method=boolean

Update on July 10, 2009

IN THE HIGH COURT OF JUSTICE CHANCERY DIVISION MR ROGER WYAND QC (sitting as a Deputy High Court Judge)
Innovator Synaptech Inc. obtained European patent EP (UK) 0 236 684 which protected Galantamine or analogues thereof for treating Alzheimer's disease. That patent expired on 16th January 2007. However, Synaptech obtained a Supplementary Protection Certificate No. SPC/GB00/033. The SPC is due to expire on 15th January 2012. Generics (UK) Limited contends that this is wrong. They say that the SPC ought to have expired, at the latest, on 31st December 2008. Generics brought this action asking the court to determine the correct term for the SPC and to make an order for rectification of the register of patents under section 34 of the Patents Act 1977
Highlights of Court’s decision: It was argued on behalf of Generics that the Austrian marketing authorisation in this case should also be deemed to be Directive 65/65 compliant. However, it would appear from Article 19(1) of the SPC Regulation, as amended, that this would apply only to marketing authorisations issued after 1st January 1985. In the present case the Austrian marketing authorisation was granted long before that date and so is not deemed to be Directive 65/65 compliant. Accordingly, the Defendant's construction of the wording of the SPC Regulation is correct and I dismiss the Claimant's action.Deatiled decision of court: http://www.bailii.org/ew/cases/EWHC/Ch/2009/659.html

Pregabalin (Lyrica) 25, 50, 75, 100, 150, 200, 225, 300 mg/capsule: Pfizer asserted another patent against Sun Pharma

Innovator Pfizer has sued Sun pharma for the infrigement of US5563175 patent, which covers method of use of Pregabalin. Earlier, innovator has sued Sun for the infringement of US6197819 patent.

Background of litigation
Innovator Pfizer in a bid to protect it’s blockbuster neuropathic pain treatment Pregabalin (Lyrica) against generic challenge has filed patent infringement suit against various generic players in April 29, 2009 in Delaware District Court.

The said lawsuit was filed in response to ANDA filed by various generic players on this product for Pregabalin (Lyrica) 25, 50, 75, 100, 150, 200, 225, 300 mg/capsule.
The generic players have filed Para IV against following Orange Book listed patent:

US5563175 (Expiry: Oct 8, 2013): Which covers A method of treating a patient having seizure disorders which comprises administering to said patient an effective amount of a substantially pure compound of the formula S-(+)-4-amino-3-(2-methylpropyl)butanoic acid.

US6001876 (Expiry: Dec 30, 2018): Which covers method of treatment of pain using (S)-3-(aminomethyl)-5-methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid.

US6197819 (Expiry: Dec 30, 2018): Which covers S-(+)-4-amino-3-(2-methylpropyl) butanoic acid as a single optical isomer as product.

Subsequently, innovator sued following 7 generic players for patent infringement:

1. Sun Pharma
2. Lupin
3. Wockhardt
4. Cobalt
5. Actavis
6. Sandoz
7. Alpharma (Mylan)

The above generic players have filed their ANDA on Dec 30, 2008, i.e earliest ANDA filing date, accordingly, these generic players will be eligible for lucrative 180 days generic exclusivity as per Hatch-Waxman provisions.

Possibly, generic players have filed ANDA with invalidation grounds against Orange Book listed patent.

Importantly, innovator has sued all generic players for the infringement of ‘819 patent (product patent). Additionally, innovator has sued Lupin for ‘175 and ‘876 patent. Earlier, innovator got USFDA approval to market this product in 25, 50, 75, 100, 150, 200, 225, 300 mg/capsule on Dec 30, 2004.

Pregabalin is indicated for management of neuropathy pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, adjunctive therapy for adult patients with partial onset seizures and management of fibromyalgiaThis product has achieved approximately 2.0 billion USD global sales in the year 2007 and future sale forecast for this product is quite bright.

Atorvastatin (Lipitor): Pfizer Sues Matrix (Mylan) for filing ANDA with Paragraph IV certification

Pharma giant Pfizer has sued generic player Matrix (Mylan) for filing ANDA No. 91-226 with Paragraph IV certification against Orange Book listed patents for Atorvastatin (lipitor) instant release tablet formulation.

In the complaint filed in United States District Court For the District Of Delaware on June 15, 2008, innovator has requested court to block generic version till the expiry of crystalline polymorphic form patent.

In the complaint, Pfizer has alleged infringement of following patents under 35 USC 271:

US5969156 (Expiry: Jan 8, 2017): Which covers crystalline Polymorphic Form I, II and IV

US6087511 (Expiry: July 16, 2016): Which covers a process for the preparation of amorphous Atorvastatin where crystalline Form I of Atorvastatin is dissolved in a non-hydroxylic solvent and after removal of the solvent affords amorphous Atorvastatin

US6274740 (Expiry: July 16, 2016): Which covers a process for the preparation of amorphous Atorvastatin or hydrates thereof which comprises: (a) dissolving crystalline Form I Atorvastatin in a non-hydroxylic solvent at a concentration of about 25% to about 40%; and (b) removing the solvent by drying to afford said amorphous atorvastatin or hydrates thereof

As per complaint, Matrix (Mylan) has filed ANDA with amorphous form of Atorvastatin and notified innovator about ANDA filing by Paragraph IV notice letter dated May 1, 2009.

Innovator in it's complaint has alleged that an intermediate used by generic player for the synthesis of Atorvastatin is crystalline in nature, which will infriges pfizer's crystalline polymorph patent '156 and amorphous process patent '740 and '511.

The disputed patent ‘156 is Orange Book listed patent, however, ‘740 and ‘511 are process patents and are not listed in Orange Book.

Para IV filers on this product: Ranbaxy (First para IV filer), Teva, Cobalt, Apotex and Matrix (Mylan)

Generic player in litigation: Teva , Apotex and Matrix (Mylan)

Settlement: Ranbaxy has settled its pending patent litigation on Lipitor and Caudet on June 18, 2008 and will launch its generic product in November, 2011

Minocycline HCl (Solodyn) 45, 90 and 135 mg ER tablets: Innovator Medicis sued another generic player

Innovator Medicis has sued Indian pharma giant Ranbaxy in Delaware District court for filing ANDA with Paragraph IV certification against following Orange Book listed patent for Minocycline HCl (Solodyn) 45, 90 and 135 mg ER tablets:

US5908838 (Expiry: Feb 19, 2018): The patent covers method for reducing the incidence or severity of vestibular side effects resulting from the treatment of acne by the use of oral tetracycline antibiotics, comprising administering the oral tetracycline antibiotic (including Minocycline hydrochloride) in a slowly dissolving dosage form (patent covers primary indication).

The above patent was listed in Orange Book on Dec 5, 2008 as per § 4(b)(1) of the QI Program Supplemental Funding Act of 2008 for old antibiotic products. Earlier, old antibiotics approved before November 21, 1997 were not listed in Orange Book

Various generic players like Impax, Matrix and Sandoz have also filed Para IV against said patent, subsequently, innovator sued these generic players in Delaware district court and litigation is ongoing with these generic players.

Earlier, Generic player Teva (Barr) has settled pending litigation with innovator on this product in March, 2009 (as reported by IP Pharma doc Here ) and agreed to launch this product from November, 2011 onwards.

Annual sales of this product were approximately $365 million in the United States for the twelve months that ended January 31, 2009, based on IMS sales data

Pharma Press Releases

Andogel® (Testosterone gel) 1%: Unimed Pharmaceuticals, a wholly-owned subsidiary of Solvay Pharmaceuticals, Inc, has been informed by generic player Perrigo Israel Pharmaceuticals, Ltd. (Perrigo) that it has fiiled an Abbreviated New Drug Application (ANDA) with a Paragraph IV certification to the U.S. Food and Drug Administration, seeking the approval of a generic version of Andogel® (testosterone gel) 1% CIII in the United States.

Press release from Solvay Here

OxyContin® (oxycodone HCl controlled-release): Generic player KV Pharma announced that it has entered into a settlement agreement with innovator Purdue Pharma w.r.t the patent infringement lawsuit between the two companies.

Press release from KV pharma Here

Omeprazole Mg 20.6 mg capsule (OTC): Dr. Reddy’s Laboratories announced that the U.S. Food and Drug Administration has granted approval of the Company’s Abbreviated New Drug Application (ANDA) for Omeprazole Mg 20.6 mg capsule (OTC).

Press release fom Dr. Reddy Here

Calcitonin-salmon (Miacalcin ) nasal spray: Par Pharmaceutical has began shipping calcitonin-salmon nasal spray to the trade. Calcitonin-salmon nasal spray is a generic version of Novartis' Miacalcin(R).

Press release from Par Pharma Here

Risperidone ODT 0.25 mg, 3 mg and 4 mg Tablets ( RISPERDAL® M-TAB): Par Pharmaceutical has began shipping 0.25 mg, 3 mg and 4 mg strengths of Risperidone ODT to the trade. Probably, Par is first Para IV filer for this product.

Press release from Par Pharma Here

Guaifenesin+ Pseudoephedrine HCI 600mg/60mg and 1200mg/120mg ER tablets:Watson Files ANDA with Para IV certification

Generic player Watson Pharmaceuticals has filed an Abbreviated New Drug Application (ANDA) with the USFDA seeking approval to market its Guaifenesin + Pseudoephedrine HCI Extended Release 600mg/60mg and 1200mg/120mg tablets prior to the expiration of patents owned by innovator Reckitt Benckiser (as confirmed in press release Here ).

Watson's Guaifenesin+ Pseudoephedrine HCI ER products are the generic versions of innovator Reckitt Benckiser Inc.'s Mucinex(R) D product, which are indicated to help loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus and make coughs more productive.

Watson has challenged innovator Reckitt Benckiser following Orange Book listed patents on Guaifenesin+ pseudoephedrine HCI 600mg/60mg and 1200mg/120mg ER tablets:

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.

Reckitt Benckiser filed suit against Watson on June 5, 2009 in the U.S. District Court for the Southern District of Florida seeking to prevent Watson from commercializing its products prior to expiration of Orange Book listed patents:

Probably, Watson is first Para IV filer on this product and entitled for prized 180 days exclusivity under Hatch-Waxma provision.

For the twelve-months ended March 31, 2009, Mucinex(R) D products had total U.S. sales of approximately $62 million, according to IMS Health data.

Earlier, Watson filed ANDAs seeking approval to market generic versions of Reckitt Benckiser's Mucinex(R) and Mucinex(R) DM products as reported by IP Pharma Doc Here.

Levofloxacin (Levaquin) 250, 500, and 750 mg tablets: CAFC awarded $1.3 M litigation cost in favor of Innovator Daiichi

The Court of Appeal for Federal Circuit (CAFC) today affirmed an order by the District Court for the Northern District of West Virginia on litigation cost to innovator Daiichi under 28 USC 1920 and federal rule of civil procedure 54 (d).

The cost are related to following disputed patent listed in Orange Book for Levofloxacin (Levaquin) 250, 500, and 750mg tablets:

US5053407 (Assignee: Daiichi, Date of Grant: October 1, 1991, Expiry: June 20, 2011): which covers S(-)-9-Fluoro-3-methyl-10 -(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxa zine-6-carboxylic acid (Levofloxacin) as product

Mylan countered that the '407 patent was invalid and unenforceable. District Court for the Northern District of West Virginia opined that Mylan failed to establish ‘407 patent’s invalidity by clear and convincing evidence and upheld patent and awarded litigation cost against Mylan.

Daiichi calculated its costs as $2.2 million, but the district court in August 2008, reduced those costs by 40% to $1.33 million . The major portion of the calculated fees was w.r.t translation cost of about $1 million . On appeal, the CAFC affirmed these costs.

Mylan objected on a number of grounds, and argued for an apportionment of costs based on the fact that a portion of the discovery in the instant case had been conducted jointly with related action against another generic player Teva Pharma in the District Court for the District of New Jersey.

The ‘407 patent has been challenged by generic companies like Teva and Mylan on patent invalidation grounds. Further, generic player Lupin challenged the patent term extension of 810 days granted by USPTO under section 35 USC 156. In May 2009, Court denied summary judgment to Lupin and upheld the patent term extension.

It is pertinent to mention here that this is a second patent litigation, wherein, generic giant Mylan has to pay litigation cost. Earlier in Pioglitazone litigation, court has awarded attorney cost of $11.4 million from Mylan in favor of innovator Takeda for filing paragraph IV certification against product patent (generic player Alphapharm fined $5.4 million as attorney cost in the said case).

Levofloxacin which is an enantiomer of Ofloxacin has better physicochemical features and better efficacy in comparison to Oflaxacin. Due to it's better pharamceutical attributes and sale figures, the generic players has tried for early generic erosion, however, due to strong patent portfolio of innovator early generic erosion has not succeeded.

Opinion of court Here

Link to related news:

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Esomeprazole (Nexium): AstraZeneca faces early generic in Denmark

Innovator AstraZeneca's blockbuster stomach ulcer and acid reflux molecule Esomeprazole magnesium (Nexium) faces early generic competition in Denmark, where Sandoz launched a generic version this week.

An AstraZeneca spokesman said on Thursday the group was aware of the launch, adding that authorisations for generic forms of the medicine had also been granted in Ireland, Portugal, Austria, Hungary, Estonia, Latvia, Lithuania, Finland and Slovenia.

In major European countries, however, the product is still protected by market exclusivity that only expires in March 2010. (Source: Reuters article Here )

Further, generic players have opposed key patents of innovator in EU market like EP00652872 (revoked by EPO) and EP00773940.

In US market, innovator has fared well and was successful in blocking generic challenge. Generic players like Sandoz, Dr. Reddy and Ivax challenged innovator but have not succeded till date. Also, the first para IV filer Ranbaxy settled patent litigation with innovator and would be able to launch generic version under licencing agreement from May, 2014 onwards. Innovator Astra has strong patent portfolio for this product.

Earlier news of Ippharmadoc on this product Here

Review of Patent Settlements between Brand and generic: Mylan and FTC representative testified in front of Judiciary Subcommittee

The U.S. House of Representatives Judiciary Subcommittee on Courts and Competition Policy concerning patent is hearing various generic and innovator companies as well as regulatory authorities views on "Pay to Delay: Are Patent Settlements That Delay Generic Drug Market Entry Anticompetitive?," . The initiative is aimed to collect information about the effects of settlements and to address various contentious issue.

Mylan Opposed Authorized Generics During 180-Day Exclusivity Period

Various generic players are constantly opposing launch of authorized generics by innovator to affect sale of First Para IV filer generic player during 180 days exclusivity period. In the past, the authorized generic launch by innovator has hugely dented the sale forecast of generic player. The authorized generic launch of blockbuster molecules like Paroxetine (Paxil), Fexofenadine (Allegra), Pantoprazole (Protonix) and Alendronate Sodium (Fosamax) has affected the sale of First Para IV filer generic player.

Also, generic player Mylan's Chief Operating Officer (COO) Mrs Heather Bresch testified before the U.S. House of Representatives Judiciary Subcommittee on Courts and Competition Policy concerning patent litigation settlements between branded pharmaceutical companies and generic pharmaceutical companies (As reported by Mylan in a press release Here )

Further, Mrs Bresch conveyed Mylan's position that the launch of an authorized generic by brand companies during a generic company's 180-day exclusivity period undermines competition and delays timely access to high quality, affordable generic medications for patients, taxpayers, the government and businesses.

Bresch commented: "When it comes to settlements, Congress need look no further than the use and abuse of authorized generics by brand manufacturers. The increase in the number of patent litigation settlements in recent years is directly related to the increased use of authorized generics during the 180-day market exclusivity period. This tactic upsets the natural balance of incentives that Congress intended with its 1984 Hatch-Waxman legislation."

Bresch continued: "Congress has an opportunity to act now to ensure that timely access to affordable generics is offered to patients by restoring the true 180-day exclusivity period. This is even more profound and critical today as Congress deliberates on a regulatory pathway for life-saving generic biologics, treatments that can cost hundreds of thousands of dollars per patient per year."

A complete version of Bresch's written testimony for the subcommittee hearing can be found at Here (as announced by Mylan in a press release)

Federal Trade Commision representative Opposed pay for delay tactics

Testifying today on behalf of the Federal Trade Commission before the U.S. House Judiciary Committee’s Subcommittee on Courts and Competition Policy, Bureau of Competition Director Richard A. Feinstein said that anticompetitive patent settlements in the U.S. pharmaceutical industry delay consumer access to lower-cost generic drugs, and impose “enormous costs” on consumers; employers; federal, state and local governments; and our nation’s health care system. The testimony stated that congressional action to prohibit these “pay-for-delay” settlements between brand-name drug manufacturers and their generic competitors is “both appropriate and timely,” and would help contain spiraling health care costs.

(Source:FTC press release Here )

Etanercept (Enbrel ): CAFC opined non-infringement

The US Court of appeal for Federal Circuit (CAFC) has upheld Disctric Court for Delaware’s summary judgment opinion, wherein, district court held that innovator Amgen and Wyeth’s blockbuster molecule Etanercept [Enbrel, a tumor necrosis factor alpha (TNF-alpha) inhibitor used to treat arthritis pain] do not infringe Ariad pharma’s following patent:

US6410516 (Assignee: Massachusetts Institute of Technology, President & Fellows of Harvard College & Whitehead Instittue for Biomedical Research, Date of Grant: June 25, 2002) Entitled “Nuclear factors associated with transcriptional regulation” which has total 203 claims.

The said patent covers a method for inhibiting expression, in a eukaryotic cell, of a gene whose transcription is regulated by NF-kB, the method comprising reducing NF-kB activity in the cell such that expression of said gene is inhibited.

NF-κB plays a major role in regulating the immune response in wide range of infections and disease like cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development.

As TNF-alpha binds with cell and the NF-kB activity is increased in eukaryotic cell which is mainly responsible for harmful effect and pain. The reduction of NF-kB activity is important as increased activity of NF-kB can led to expression of harmful genes.

Earlier, Amgen and Wyeth filed declaratory judgement of invalidity and non-infringement of ‘516 patent in Disctric Court for Delaware, subsequently, patentee of ‘516 counterclaimed infringement of claims number 6, 18, 70-72, 183 and 184. The district court granted Amgen's DJ of non-infringement, subsequently, patentee Ariad appealed against said decision.

The court construed the meaning of claim langauage in the light of specification, prosecution history and expert testimony. The disputed term “reducing NF-kB activity in cell” were first construed and than Enbrel mechanism was compared in the light of construed claims. Court observed that ‘516 patent covers compound which can act inside (intracellular) the inflammed cell. Further, court held that Enbrel acts outside (extracellular) the inflammed cell (like some prior art molecules like some antibiotics), accordingly, will not be covered under the scope of 516 patent.

Opinion of court Here

Eralier in 2006, Ariad successfully asserted ‘516 patent against innovator Eli Lilly’s blockbuster medicines like Drotrecogin alfa (Xigris) and Raloxifene HCl (Evista). Further, U.S. District Court of Massachusetts awarded the patentee approximately $65 million in royalties and a 2.3 percent royalty on future U.S. sales of Evista and Xigris until the patent’s expiration in 2019.

Montelukast (Singulair) 10 mg tablets: Mylan announced tentative approval

Generic player Mylan has got tentative approval (as per Mylan press release Here ) to market Montelukast 10 mg tablets. Mylan got tentative approval on May 27, 2009. Mylan's generic version is bioequivalent to innovator Merck's Montelukast (Singulair) 10 mg tablets. As per IMS, Montelukast (Singulair) 10 mg tablets had total U.S. sales of approximately $2.6 billion for the 12 months ending March 31.

Mylan woyuld be able to market this product after the expiry of product patent US5565473 (in 2012).

Earlier, first para IV filer Teva got Tentative approval from USFDA on this product.

Earlier news of IP Pharma doc on this product Here