Memantine hydrochloride (Namenda) 5 mg and 10 mg Tablets: Lupin entered into licensing agreement with innovator

Indian Pharma Giant M/S Lupin Pharma has announced that it has settled the litigation with innovator Forest Lab and Merz Pharma, which was pending in Delaware District Court, Maryland District Court and District of Columbia w.r.t generic version of Memantine hydrochloride (Namenda) 5 mg and 10 mg tablets.

Innovator has listed following patent in Orange Book for Memantine hydrochloride 5 mg and 10 mg tablets and sued Lupin and other generic players for the infringement of the same:

US5061703 (Expiry: April 11, 2015): The patent covers a method for the prevention or treatment of cerebral ischemia comprising the step of administering, to a patient in need thereof, an effective amount of Memantine (The said patent has got five years of patent term extension as reported by us Here )


Under the terms of agreement, Lupin will have a license under the required patents to launch its generic Memantine hydrochloride (Namenda) 5 mg and 10 mg tablets in January 2015 or earlier in certain unspecified circumstances. Importantly, Lupin would be able to market generic version almost 3 months earlier from the patent expiry date.

Earlier, the various generic players like Barr Lab, Cobalt Lab, Lupin, Orchid, Teva Pharma, Upsher-Smith Lab, Genpharm, Sun, Ranbaxy and Wockhardt filed ANDA with Paragraph patent IV certification against ‘703 patent. Subsequently, innovator sued various generic players for the infringement of ‘703 patent in U.S. District Court for the District of Delaware. Also, innovator sued Lupin in Delaware District Court, Maryland District Court and U.S District Court for the District of Columbia.

Earlier in September, 2009, the chief judge honorable G.M. Sleet of U.S. District Court for the District of Delaware has signed off on a request to dismiss M/S Upsher-Smith Lab (and 3 other generic players like Wockhardt, Amneal Pharmaceuticals, Apotex) from a patent infringement lawsuit that innovator Forest Labs and Merz Pharma brought to thwart the generic challenge to the Alzheimer's drug Memantine (Namenda) hydrochloride 5 mg and 10 mg tablets. Also in Oct, 2009, generic player Sun Pharma has agreed to launch generic version after the expiry of ‘703 patent.

Further, generic players like Orchid, Mylan and Cobalt are still in litigation with innovator for this product.

The generic players were not able to invalidate the method of use patent of this billion dollar molecule, till date. Further, 3 months earlier market entry (from patent expiry) is a favorable situation for Lupin to consolidate it’s generic version before further generic erosion after the patent expiry.

Montelukast sodium (Singulair): USPTO upheld the validity of compound patent during re-examination

Refer to our earlier post on Montelukast reexamination Here, Now, an article published in reuters (here ) reported that USPTO has upheld the validity of the key patent during re-examination. Now, generic version would be blocked till compound patent expiry in Aug 3, 2012.

Background

Earlier, the United States Patent & Trademark Office (USPTO) had accepted the request of a Independent firm Article One Partners LLC on Ex partes re-examination of blockbuster anti-allergic medication Montelukast’s (Singulair) key patent.

Innovator Merck has listed following disputed patent in Orange Book for Montelukast’s (Singulair) 10 mg tablets and 4 mg granules:

US5565473 (Expiry: Aug 3, 2012): which covers unsaturated hydroxyalkylquinoline acids as leukotriene antagonists, including Montelukast as product.The said patent is a blocking patent for other generic players and is a barrier to generic entry.

In March 2009, a firm that specializes in challenging the validity of patents has requested the USPTO to re-examine innovator Merck’s Orange Book listed patent US5565473 for Montelukast Tablets (Singulair). Independent firm Article One Partners LLC announced that its online community found two pieces of evidence that suggest the asthma and allergy drug's key ingredient isn't novel. Law firm has alleged that innovator during prosecution of ‘473 patent has not disclosed some articles authored by Merck's scientist Dr. Robert Young (who proposed a receptor model on anti-allergic effects). Further, law firm had alleged that the said article were very important for patentability determination of ‘473 patent.

Earlier, U.S. District Court for the District of New Jersey has upheld the validity of said patent and opined that generic version of M/S Teva pharma would infringe the compound patent (as reported by this blog Here )

Omeprazole Delayed Release 20 mg and 40 mg Capsules (Prilosec OTC): CAFC upheld Dr. Reddy’s non-infringement strategy

The Court of Appeal for Federal Circuit(CAFC) has affirmed (Here) a summary judgment decision by U.S District Court for the District of New York on Omeprazole Delayed Release 20 mg and 40 mg Capsules (Prilosec OTC), wherein, court has opined that generic player Dr. Reddy’s generic version of Prilosec OTC would not infringe innovator Astra Zeneca’s following Orange Book listed patents:

US5900424 (Assignee: Astra Aktiebolag; Date of grant: May 4, 1999; Expiry: May 4, 2016):

The said patent has following independent claims :

Claim 1. An omeprazole magnesium salt having a degree of crystallinity which is higher than 70% as determined by x-ray powder diffraction.

Claim 20. In a process for the manufacture of a crystalline magnesium salt comprising, (a) treating omeprazole or a salt thereof with magnesium alcoholate in a solution, (b) crystallizing magnesium omeprazole and (c) isolating the obtained crystalline magnesium omeprazole, wherein the improved process comprises separating inorganic salts from the reaction mixture prior to the crystallization step by the addition of water.

US5690960(Assignee: Astra Aktiebolag; Date of grant: November 25, 1997; Expiry: Nov 25, 2014): The said patent has following independent claims:

Claim 1. A stable oral formulation comprising: a core containing a magnesium salt of omeprazole said salt having more than 70% crystallinity as determined by x-ray powder diffraction; a subcoating layer; and an enteric coating layer, whereby the thickness of the enteric coating layer does not effect the release of omeprazole into solution at the pH predominantly present in the small intestine.

Claim 10. A process for the manufacture of a formulation of a pharmaceutical composition for the oral administration of magnesium omeprazole comprising the steps of: (a) forming a core material containing magnesium omeprazole salt said salt having at least 70% crystallinity as determined by x-ray powder diffraction; (b) applying in the presence of water at least one subcoating layer onto the core; (c) further applying in the pittance of water at least one enteric coating layer onto the subcoated core; and drying the prepared formulation.

Claim 22. An improved oral pharmaceutical composition containing a core of omeprazole salt with a subcoating and an enteric coating wherein the improvement comprises magnesium omeprazole salt having more than 70% crystallinity as determined by x-ray powder diffraction.

Discussion: After ANDA filing by Dr. Reddy with Paragraph IV certification with non-infringement grounds on above patents, innovator Astra sued generic player in U.S District Court for the District of New York for the infringement of above patents in July 27, 2007.

Further, innovator alleged that Dr. Reddy’s generic version will be covered under the scope of above patents. However, Dr. Reddy prepared the generic version which was amorphous with 1% crystalline content. Also, Dr. Reddy’s were not using water during crystallization process as covered in ‘424 patent.

However, innovator alleged that the generic version contains 5-8% of water, which would infringe the claim 20 of ‘424 patent. Further, during Markman hearing on disputed claim term by “the addition of water” the court opined that Dr. Reddy’s process has not used water during manufacturing the amorphous product and the said water can be attributed to atmospheric water adsorbed/absorbed on Dr. Reddy’s amorphous product or was prsent in the starting material used for the manufacturing of amorphous product.

In the light of above, U.S District Court for the District of New York issued Summary Judgment opinion in March, 2010 in favor of Dr. Reddy’s.

Paragraph IV Patent Certifications Reported by USFDA as of December 7, 2009

1. Adapalene 0.30% Topical Gel (Differin): Paragraph IV filed on Sep 15, 2009

2. Colesevelam Hydrochloride 625 mg (Welchol ) Tablets: Paragraph IV filed on July 1, 2009

3. Fulvestrant 50 mg/mL, 2.5 mL and 5 mL syringe (Faslodex): Paragraph IV filed on Oct 1, 2009

4. Levofloxacin 25 mg/mL Oral Solution (Levaquin): Paragraph IV filed on July 30, 2009

5. Linezolid 2 mg/mL, 300 mL bag Injection (Zyvox): Paragraph IV filed on Sep 1, 2009

6. Ropinirole Hydrochloride 6 mg Extended-release Tablets: Paragraph IV filed on July 22, 2009

Source: USFDA para IV certification list Here

Atorvastatin (Lipitor): Pfizer sued Dr Reddy’s for the infringement of Polymorph patent

Innovator Pfizer has sued generic player Dr. Reddy’s on Dec 8, 2009 for filing ANDA with Para IV certification against Orange Book listed patents for Atorvastatin (Lipitor) tablets in the U.S. District Court for the District of Delaware

Innovator has asserted following polymorph patent against generic player:

US5969156 (Expiry: June 8th, 2017): Which covers various hydrated Polymorphs of Atorvastatin (Form I, II and IV)

As per complaint filed in the U.S. District Court for the District of Delaware, innovator has requested court to block generic version till the expiry of crystalline polymorphic form patent.

Earlier, Dr. Reddy’s lab send Para IV certification letter to innovator Pfizer against Orange Book listed patents for Atorvastatin (Lipitor) tablets on Oct 26, 2009 .

Venlafaxine HCl (Effexor XR) Capsules: Mylan Announced Settlement With Innovator

Generic player Mylan announced (in a press release Here) that its subsidiary Mylan Pharmaceuticals Inc. has entered into settlement and license agreements with Wyeth, now part of Pfizer, relating to Venlafaxine HCl (Effexor XR) 37.5, 75 and 150 mg Capsules.

Following patents are listed in Orange Book w.r.t Venlafaxine HCl (Effexor XR) 37.5, 75 and 150 mg 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

Earlier, innovator Wyeth had sued Mylan for the infringement of ‘171, ‘120 and ‘958 patents in the West Virginia North District Court in 2007.

Pursuant to the license agreement, Mylan will be granted a non-exclusive license to the relevant patents that would permit Mylan to launch Venlafaxine HCl XR Capsules in the U.S. on or after June 1, 2011, or earlier in limited circumstances. Additional details of the agreement remain confidential.


Earlier, innovator had settled with generic players like Impax, Osmotica, Wockhardt, Sun pharma, Lupin, Anchen and Teva on this product.

Venlafaxine HCl ER Capsules had U.S. sales of approximately $2.9 billion for the same strengths for the 12 months ending Sept. 30, according to IMS Health.

Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release version (sometimes referred to as controlled release) controls the release of the drug into the gastrointestinal tract over a longer period than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended release formula has a lower incidence of patients suffering from nausea as a side effect resulting in a lower number of patients stopping their treatment due to nausea.

(Source: the report is based on Mylan press release and some earlier posts of IP Pharma Doc on this product)

Ramelteon (Rozerem) 8 mg Tablets: Watson filed ANDA with Para IV certification

Watson Pharmaceuticals confirmed (in a press release Here ) that its subsidiary, Watson Laboratories filed an Abbreviated New Drug Application (ANDA) with the U.S. Food and Drug Administration seeking approval to market Ramelteon (Rozerem) 8 mg Tablets.

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

US6034239 (Expiry: Mar 6, 2017): The patent covers Ramelteon as product

Subsequently, in an attempt to block generic version of Ramelteon (Rozerem) 8 mg Tablets, innovator Takeda has filed an infringement action (based on '239 Patent) against generic player Watson in U.S. District Court for the District of Delaware. Earlier, innovator has sued generic player Teva for filing ANDA with Para IV certification.

As per press release, Watson believes it may be a "first applicant" to file an ANDA for Ramelteon (Rozerem) 8 mg Tablets, accordingly, may be entitled to 180 days of shared generic market exclusivity.

Earlier, innovator got approval to market Ramelteon (Rozerem) 8 mg Tablets on Jul 22, 2005. For the twelve months ending September 30, 2009 Ramelteon (Rozerem) 8 mg Tablets had total U.S. sales of approximately $91 million according to IMS Health data.

Atorvastatin (Lipitor): Pfizer sued Kremer-Urbans LLC and KUDCO for the infringement of Polymorph patent

Innovator Pfizer has sued generic player Kremer-Urbans LLC and its partner KUDCO for filing ANDA with Para IV certification against Orange Book listed patent for Atorvastatin (Lipitor) tablets in the U.S. District Court for the District of Delaware

Innovator has asserted following polymorph patent against generic player:

US5969156 (Expiry: June 8th, 2017): Which covers various hydrated Polymorphs of Atorvastatin (Form I, II and IV)

As per complaint filed in the U.S. District Court for the District of Delaware, innovator has requested court to block generic version till the expiry of crystalline polymorphic form patent.

The other Para IV filers on this product are Teva, Cobalt, Apotex, Matrix (Mylan), Dr. Reddy and Kremer-Urbans LLC and KUDCO

Earlier, Ranbaxy (First para IV filer) had settled its pending patent litigation on Lipitor and Caudet on June 18, 2008 and will launch its generic product in November, 2011