USV got patent on Donepezil Oxalate

USV Ltd. got a major success in a legal appeal, winning exclusive US rights to a new drug salt of Donepezil oxalate which is effective in treating Alzheimer's disease. USV applied to patent this compound in 2004. USV's patent application described its invention as a "Composition of matter," the legal term used in the US patent statute. Surprisingly, the US Patent Office then refused to issue USV's patent application, arguing that the phrase "composition of matter," which appears in the patent statute itself, is too vague to support proper patent rights. An appeals board in Washington disagreed. Rather, The Board of Patent Appeals and Interferences noted that a 1980 Supreme Court ruling involving another Indian inventor, Sidney A. Diamond v. Ananda Mohan Chakrabarty, concluded that the phrase "composition of matter" is perfectly acceptable. The appeals board thus concluded, in Ex parte Venkatasubraminarian Radhakrishnan Tarur et al., Appeal No. 2007-4478, that USV is entitled to its patent. The development is significant, since an important intermediate, Donepezil base is covered by several patents by the innovator company. USV’s patent on a novel salt, Donepezil Oxalate helps the company make Donepezil Hydrochloride (the active ingredient in Alzheimer drug Aricpet) without violating the innovator company’s patents on the intermediate, a company official explained.
Donepezil Hydrochloride it the active ingredient in Aricept, an over $ 2 billion Alzheimer’s drug from Japanese drug-maker Eisai Co Ltd . The US patent on Aricept, which is co-marketed with Pfizer Inc., expires in November 2010.
The patent-related development comes even as the Mumbai-based USV sets about its strategy of getting a process patent on a drug that is set to expire in the short term. This helps USV get some elbow-room for itself in a competitive generic drugs market.
The US Patent office though refused USV’s patent application, arguing that the said phrase was too vague, the note said. The company appealed to the Board of Patent Appeals and Interferences, which disagreed with the patent office’s view, the note added.

Generic Donepezil decision

Eisai filed a lawsuit in August 2006 against Mutual Pharma and United Research Laboratories, Inc. (collectively "Mutual") claiming that its submission of an abbreviated new drug application (ANDA) to the USFDA for Aricept ODT(R) (donepezil hydrochloride orally disintegrating tablets) would infringe Eisai's composition of matter patent.

On December 20, 2007 (U.S. EST), the U.S. District Court for the District of New Jersey issued a ruling dismissing the lawsuit against Mutual on the procedural grounds that there is no case or controversy between the parties, because Mutual did not make a certification challenging the patent and does not yet have FDA approval to market its product. The Court recognized that Mutual is required, by a stipulation entered between the parties and signed by the Court, to give Eisai 45 days' notice of any launch of a generic version of Aricept ODT(R), and Eisai may during that 45-day period bring an action against Mutual for patent infringement and seek injunctive relief against Mutual's sales of any such product. Therefore, Mutual cannot market the generic version of Aricept ODT(R) immediately.

The Court did not address the substantive merits of Eisai's infringement action against Mutual. Eisai believes that its donepezil composition of matter patent is valid and enforceable until its expiration date of November 25, 2010, and that Mutual would clearly infringe its donepezil composition of matter patent if Mutual were to launch a generic version of Aricept ODT(R) in the United States prior to the expiration. Eisai intends to vigorously enforce and defend that patent. The Court's ruling has no impact on Eisai's ongoing infringement action against Teva Pharmaceuticals for its ANDA for generic Aricept(R) (donepezil hydrochloride).

With inputs from Esai press release Here

Eisai Got Favorable Preliminary Injunction Ruling in Donepezil product Patent Infringement Lawsuit Against Teva

Eisai announced that the United States District Court of NewJersey has ruled in Eisai's favor with respect to Eisai's motion for a preliminary injunction in its patent infringement lawsuit against TevaPharmaceuticals and its division Gate Pharmaceuticals concerning Aricept tablets (Donepezil ). Eisai filed the infringement actions in December 2005 contesting Teva's submission of an abbreviated new drug application (ANDA) to the USFDA for Aricept(R). Teva received tentative approval from the FDA in January, and could receive final approval April 26, following a delay required under federal drug law because of the patent litigation.
Following patents are listed In the Orange book for 5 and 10 mg tablets of Donepezil
US4895841 (Expiry: NOV 25,2010)- Product patent
US5985864 (Expiry: DEC 30,2016)- Polymorph (Form-II, III, IV and V)
US6140321 (Expiry: DEC 30,2016)-polymorph
US6245911 (Expiry: DEC 01,2018)-Polymorph A, B and C
US6372760 (Expiry: MAR 31,2019)- Formulation
Teva alleged earlier that 841’ patent is unenforceable due to inequitable conduct (based on materiality and intent) as Esai had not disclosed to the patent examiner its co pending application (now US4849431 patent) at the time of prosecution of 841’ patent. Teva also said that an article by Dr. Kenley published in Journal of Medicinal Chemistry (JMC) in 1984 further suggest that 841’ invention is obvious and if patent examiner would have known about this patent (431') and JMC article he would have not granted the 841’ patent. Esai produced the testimony by Dr. Kenley who sided with Esai.
The U.S. District Judge Harold Ackerman concluded in his opinion that There is no doubt that Teva has infringed Eisai's valid patent, and Eisai will likely prevail at trial in demonstrating the enforceability of that patent over Teva's inequitable conduct defense
The other para IV filer against this product are Ranbaxy, Par and Roxane
Donepezil (2-[(1-benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one), marketed under the trade name Aricept (Eisai), is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. The USFDA first approved Aricept tablets in 1996. The drug is Tokyo-based Eisai's biggest product, with $2.16 billion in worldwide sales in the year ended in March 2007. (orangebookblog) (Eisai press release)

Teva Press Release

Teva Pharma that the U.S. District Court for the District of New Jersey has granted Eisai's motion for a preliminary injunction related to Teva's tentatively approved Abbreviated New Drug Application (ANDA) to market its generic version of Eisai's Alzheimer's treatment Aricept(R) (Donepezil Hydrochloride) Tablets, 5 mg and 10 mg. The injunction is based on Eisai's enforcement of US4,895,841 that Teva has asserted is unenforceable. A trial date has not been set.

Donepezil (Aricept) 5 mg and 10 mg Tablets: The district court declined Teva’s request for DJ

The US district court for the district of New Jersey declined M/S Gate pharma’s declaratory judgment request of non-infringement against 4 patents listed by innovator for Donepezil (Aricept) 5 mg and 10 mg Tablets

Following patents are listed In the Orange book for 5 and 10 mg tablets of Donepezil hydropchloride:

US4895841 (Expiry: NOV 25, 2010)- Product patent

US5985864 (Expiry: DEC 30,2016)- Polymorph (Form-II, III, IV and V)

US6140321 (Expiry: DEC 30,2016)-polymorph

US6245911 (Expiry: DEC 01,2018)-Polymorph A, B and C

US6372760 (Expiry: MAR 31,2019)- Formulation

Ranbaxy filed (first para IV filer) ANDA with Para IV certification against ‘864, ‘321, ‘911, ‘760 and Para III against product patent ‘841.

Generic player Teva filed ANDA on Oct, 2004, with Para IV certification against ‘864, ‘321, ‘911, ‘760 and Para III against product patent ‘841. Later, in Oct, 2005, Teva amended it’s ANDA with Para IV against product patent ‘841. Due to Para IV filing against product patent, Teva also got First Filer status.

Also, in late 2005, a subsidiary of Teva, M/S Gate Pharma filed ANDA with different API of Donepezil, with Para III certification against all O.B Patents. However, after nearly two years, Gate amended it’s ANDA on Nov, 2007 with Para IV against all patents.

Subsequently, innovator sued Gate and Teva for the infringement of ‘841 and the district court found the patent valid, enforceable and issued preliminary injunction against generic launch, as reported by this blog Here.

After the said decision, with an aim to trigger Ranbaxy’s exclusivity (and Teva’s, too), the Gate filed DJ action of non-infringement, citing ANDA approval delay by USFDA. Further, innovator has already disclaimed ‘864 and ‘721 patents and for '911 and '760 patents innovator issued ‘convenant not to sue’ to Teva. In its opposing motion, innovator Esai contends that the court lacks subject matter jurisdiction because Teva’s claim for DJ present no justiciable controversy.
The US district court for the district of New Jersey declined Gate pharma’s declaratory judgment of non-infringement against ‘864, ‘321, ‘911 and ‘760.

The district court opined that M/S Teva did not risk a lawsuit from innovator Eisai or face the threat that the USFDA might block its ANDA approval process.

Earlier, Apotex has also filed DJ action of non-infringement against above 4 patents with an aim to trigger Ranbaxy’s 180 days exclusivity.

Donepezil (Aricept) 5 and 10 mg tablets: Apotex filed DJ request in a bid for generic approval

Reuters has reported Here that Generic player Apotex in a bid to trigger 180 days exclusivity of generic player Ranbaxy has filed Declaratory Judgment request of non-infringement against innovator Esai’s Orange Book listed patents on Donepezil Hydrochloride (Aricept) 5 and 10 mg tablets in the U.S. District Court for the Middle District of North Carolina

Following patents are listed In the Orange book for 5 and 10 mg tablets of Aricept:

US4895841 (Expiry: NOV 25,2010)- Product patent

US5985864 (Expiry: DEC 30,2016)- Polymorph (Form-II, III, IV and V)

US6140321 (Expiry: DEC 30,2016)-polymorph

US6245911 (Expiry: DEC 01,2018)-Polymorph A, B and C

US6372760 (Expiry: MAR 31,2019)- Formulation

Apotex has filed ANDA with para III certification against ‘841 product patent and Para IV against rest of the patents.

The first ANDA was filed for this product around early 2003 by generic player Ranbaxy, accordingly, it’s a pre-medicare, prescription drug improvement, and modernization act of (MMA) case, wherein, generic company were eligible as First Para IV filer by filing patent specific para IV filing. Probably, Ranbaxy filed para III against Product patent and para IV against rest of the patents and innovator choose not to initiate litigation against Ranbaxy.

Now, to trigger 180 days clock of First para IV filer, following is desirable:
1) A court decision of patent invalidity or non-infringement by subsequent generic players
2) By any one of the first to file generic enter into the market

In case of ANDA filed prior to MMA act, a bottleneck can occur when the first para IV filer does not enter the market and innovator refuses to sue subsequent generic player, thereby preventing the finding of invalidity or non-infringement.

Ranbaxy and Teva are first para IV filer for this product. Teva, who has litigated with the innovator on invalidation of product patent ‘841 has got adverse decision from court on preliminary injunction decision as reported by us Here .

As per complaint, Apotex argues that due to Ranbaxy’s cGMP problems, Ranbaxy would not be able to get final FDA approval and launch the product after patent expiry, accordingly, a DJ action is necessary to remove the hurdles for subsequent ANDA filers.

Also, as per complaint, Apotex has highlighted the fact that USFDA has erroneous identified generic giant Teva as the first para IV filer.

Furthermore, the generic player Apotex has filed Citizen petition with USFDA on July, 2009 against First Para IV filer status of Teva for this product.

Donepezil (2-[(1-benzyl-4-piperidyl)methyl]- 5,6-dimethoxy-2,3-dihydroinden-1-one), marketed under the trade name Aricept (Eisai), is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. The USFDA first approved Aricept tablets in 1996. The drug is Tokyo-based Eisai's biggest product, with $2.16 billion in worldwide sales in the year ended in March 2007.

Ranbaxy gets tentative FDA nod for Donepezil copy

Indian Drug maker Ranbaxy Laboratories Ltd has won tentative approval from the U.S. Food and Drug Administration (USFDA) to make a generic version of Eisai Co Ltd's Alzheimer's treatment Aricept, the regulator's Web site showed.
The U.S. patent on Aricept, which is co-marketed with Pfizer Inc., runs out in November 2010.
Aricept, known generically as donepezil hydrochloride, garnered some $2.3 billion in sales for Eisai in the year ended March 31.

Donepezil (Aricept): 16 generic players got final approval after FTF expiry

About 16 players got final approval on Donepezil Hydrochloride 5 and 10 mg tablets for US market. Earlier, the First para IV filer Ranbaxy got final approval on Nov 26, 2010 after the expiry of compound patent.

After the FTF expiry on May 30, 2011, the USFDA approved generic version of this medication on May 31, 2011
1) Teva
2) Cipla
3) Mutual
4) Roxane
5) Aurbindo
6) Hikma
7) Sandoz
8) Pliva
9) Sun
10) Matrix
11) Actavis
12) Torrent
13) Jubilant
14) Wockhardt
15) Huahai
16) Dr Reddy

The sale of this molecule is about 3 billion USD.

IP Pharma Doc congratulate all the above players.

Eisai Mistake Allows Dismissal in Donepezil ODT Case

On December 20, 2007, the District Court in New Jersey granted Mutual’s Motion to Dismiss. Apparently, when Mutual filed its ANDA, there were no patents listed in the Orange Book. When Eisai submitted patents for Orange Book listing for the ODT product, it mistakenly filled out the forms (3542a instead of 3542) with the NDA number and product name of the tablet formulation, so FDA did not list any patents for ODT. As such, Mutual had no patents to certify against, and Eisai sued Mutual anyway for infringement of the sole Orange Book patent US4895841 (which covers Donepezil as product and also covers method of use in senile dementia of the Alzheimer type). In its press release, Eisai implies that they have reached an agreement (perhaps in lieu of an appeal of this decision as reported earlier in this blog) that Mutual will give Eisai 45 days notice before it launches. While the patent expires in 2010, there is a likelihood that Mutual will be approved before then, and if it decides to launch, expect to see a preliminary injunction filed by Eisai.

Teva got tentative approval for Donepezil tablets

Teva Pharmaceutical Industries Ltd. (in a press release) announced today that the USFDA has granted tentative approval for the Company's Abbreviated New Drug Application (ANDA) to market its generic version of Eisai's Alzheimer's treatment Aricept(R) (Donepezil Hydrochloride) Tablets, 5 mg and 10 mg. The brand product had annual sales of approximately $1.6 billion in the United States for the twelve months ended September 30, 2007, based on IMS sales data.Teva is currently in patent litigation concerning this product in the U.S. District Court for the District of New Jersey involving Teva's paragraph IV certification to U.S. Patent No. 4,895,841. Although a trial date has not been set, the Court has set a briefing schedule for a preliminary injunction motion under which Eisai must file its request no later than February 15, 2008. Final approval of this ANDA is anticipated on or about April 26, 2008, upon expiry of the mandatory stay of approval associated with the patent litigation.

USFDA Drug approvals (december 2007)

NCE and generics approved/ tentatively approved or revisions by USFDA in the month of December (till 23rd Decemeber).
Amlodipine Besylate Tablets, Caraco Pharma, Approval
Atrovent (ipratropium bromide) Nasal Spray, Boehringer Ingelheim, Labeling Revision
Calcium Acetate Capsules, Roxane Labs, Tentative Approval
Diovan (valsartan) Tablets. Novartis Pharma, Patient Population Altered
Granisetron Hydrochloride Injection, Abraxis Pharma, Approval
Letairis (ambrisentan) Tablets, Gilead Sciences, Labeling Revision
Metoclopramide Tablets, Northstar Healthcare, Approval
Ondansetron Oral Solution, Taro Pharma, Approval
SARAFEM (fluoxetine hydrochloride) Tablets, Warner Chilcott, Labeling Revision
Tenofovir Disoproxil Fumarate Tablets, Matrix Labs, Tentative Approval
Triesence (triamcinolone acetonide) Injectable Suspension, Alcon Research, Approval
Colgate Total (sodium fluoride & triclosan) Toothpaste, Colgate-Palmolive, Formulation Revision
Donepezil Hydrochloride Tablets, Ranbaxy, Tentative Approval
INOmax (nitric oxide) Inhalation, INO Therapeutics Inc., Labeling Revision
Malarone (atovaquone and proguanil hydrochloride) Tablets, GlaxoSmithKline, Labeling Revision
Omeprazole Delayed-Release Tablets, Dexcel Pharma, Approval
Phenytoin Sodium Injection, PharmaForce Inc., Approval
Pregnyl (chorionic gonadotropin) Injection, Organon Inc., Labeling Revision
REBETOL (ribavirin) Capsules and Oral Solution, Schering Corp., Labeling Revision
Venofer (Iron Sucrose) Injection, Luitpold Pharma, Labeling Revision
Gonal-f RFF Pen (follitropin alfa) Injection, EMD Serono, Manufacturing Change or Addition
Lovaza (omega-3-acid ethyl esters) Capsules, Reliant Pharma, Manufacturing Change or Addition
Mevacor (lovastatin) Tablets, Merck & Co., Manufacturing Change or Addition
Aredia (pamidronate disodium) Injection, Novartis Pharma, Labeling Revision
Ciprofloxacin Extended-release Tablets, Sandoz Inc., Approval
Derma-Smoothe/FS (fluocinolone acetonide) Topical Oil, Hill Dermaceuticals, Patient Population Altered
Kuvan (sapropterin) Tablets, BioMarin, Approval
Lamotrigine Tablets, Mylan Pharma, Tentative Approval
Oxcarbazepine Tablets, Teva Pharma, Approval
Singulair (montelukast sodium) Chewable Tablets, Merck & Co., Labeling Revision
Sonata (zaleplon) Capsules, King Pharma, Labeling Revision
Valtrex (valacyclovir hydrochloride) Caplets, GlaxoSmithKline, Labeling Revision
Vytorin (ezetimibe/simvastatin) Tablets, Merck & Co., Labeling Revision
Vyvanse (lisdexamfetamine dimesylate) Capsules, New River Pharma, Manufacturing Change or Addition
Zetia (Ezetimibe) Tablets, Schering Corp., Labeling Revision
AndroGel (testosterone) Gel, Solvay Pharma, Labeling Revision
Bleomycin Injection, Pharmachemie B.V., Approval
Floxin (ofloxacin) Tablets, Ortho-McNeil Pharma, Labeling Revision
Levaquin (levofloxacin) Tablets, Ortho-McNeil Pharma, Labeling Revision
Levaquin (levofloxacin) Injection and Levaquin (levofloxacin in 5% dextrose) Injection, Ortho-McNeil Pharma, Labeling Revision
Levaquin (levofloxacin) Oral Solution, Ortho-McNeil Pharma, Labeling Revision
LEXIVA (fosamprenavir calcium, FPV) Oral Tablets, GlaxoSmithKline, Labeling Revision
Ranitidine Oral Solution Syrup, Ranbaxy, Approval
Stavudine Capsules, Emcure Pharma, Tentative Approval
Cefdinir Oral Suspension, Aurobindo Pharma, Approval
DepoDur (morphine sulfate extended-release liposome) Injection, Pacira Pharma, Labeling Revision
Effexor XR (venlafaxine HCl) Extended-Release Capsules, Wyeth Pharma, New Modified Indication
Heparin Sodium Injection, Abraxis Pharma, Labeling Revision
Heparin Sodium Injection Baxter Healthcare, Labeling Revision
LEXIVA (fosamprenavir calcium) Oral Tablets, GlaxoSmithKline, Labeling Revision
Methimazole Tablets, Actavis, Approval
Omniscan (gadodiamide) Injection, GE Healthcare, Labeling Revision
Paromomycin Sulfate Capsules, X-Gen Pharma, Approval
Thyrogen (thyrotropin alfa) Injection, Genzyme Corp., New or Modified Indication
Buspirone Hydrochloride, Tablet, Actavis Totowa, Approval
Bystolic (nebivolol), Tablet, Mylan Bertek, Approval
Efavirenz, Tablet, Emcure, Tentative Approval
Extended Phenytoin Sodium, Capsule, Wockhardt, Approval
Levalbuterol Hydrochloride, Inhalation Solution, Breath Ltd, Tentative Approval
Metronidazole, Topical Cream, G & W Laboratories, Approval
Pantoprazole Sodium, Extended Release Tablet, Dr. Reddy's Labs, Tentative Approval

Eribulin mesylate: Delay in approval a setback to Esai

Eisai Co. fell the most in more than four years in Tokyo trading after the Japanese drugmaker was forced to delay seeking U.S. approval for its first potential new medicine since the Aciphex (Rabeprazole sodium), stomach ulcer treatment was released in 1999.
A third phase of patient studies is required on Eisai's experimental breast cancer treatment before it can apply to the USFDA, the Tokyo-based company said after markets closed on Feb. 1. It had requested bypassing that step, enabling a review as early as last quarter. Eisai now expects to seek FDA approval in the year ending March 2010, it said.
The delay is frustrating Eisai President Haruo Naito's attempts to develop successors to Aciphex (Rabeprazole sodium), and Aricept (Donepezil Hydrochloride), the company's best-selling treatment for Alzheimer's disease. Aricept sales, which accounted for 40 percent of group revenue last quarter, will slump once the drug loses patent protection in the U.S. in November 2010.
``The development delay is a disappointment,'' said Hirohisa Shimura, an equities analyst at UBS Securities Japan Ltd., in a Feb. 1 report. ``Prospects for developing a new drug candidate for Alzheimer's are also getting worse. Eisai may be forced to focus on other backup compounds.''
Eisai, Japan's fourth-largest drugmaker, plunged 6.6 percent to 4,100 yen on the exchange, the biggest one-day slide since July 7, 2003. Today's decline erased almost all the stock's gain this year.
Mizuho Securities Co. health-care analyst Hiroshi Tanaka cut his rating on Eisai shares to ``reduce'' from ``hold,'' and at least three brokerages lowered their price target for the shares after the company's announcement.
The FDA refused to expedite a review of Eisai's drug, known as E7389 or Eribulin mesylate, after the agency granted Bristol- Myers Squibb Co. accelerated approval for a similar treatment last year, Eisai said.
New York-based Bristol-Myers won FDA approval in October for Ixempra, an injectable drug to treat the most advanced form of breast cancer and the first new type of chemotherapy for the disease in 14 years.
The FDA granted Ixempra, also known as ixabepilone, priority review last June, reducing the approval process to six months from at least 10, because of its potential to treat unmet medical needs.
Women living in North America have the highest rate of breast cancer. About 180,000 new cases were diagnosed in the U.S. last year, and more than 40,000 women died from the disease, according to the American Cancer Society. Worldwide, about 1.15 million new cases of breast cancer are diagnosed annually, and 475,000 women die.
Eribulin mesylate contains a synthetic form of a substance first isolated from a type of marine sponge in 1992, according to Eisai. The Japanese drugmaker is also investigating whether its medicine can help a broader range of patients, including those with prostate and lung cancer.

Atorvastatin: Authorized generic arrived, Ranbaxy generic approved with help from Teva

The historic day for American public to welcome generic version of Blockbuster drug Atorvastatin hemicalcium tablets (Lipitor). In India, every person working in the Pharma industry was eagerly awaiting news about generic approval and launch by Ranbaxy. However, it was not clear that Ranbaxy would be able to launch the generic version till Nov 30 evening. However, Dec 1 morning in India bring good news for Ranbaxy and it was confirmed that Ranbaxy has been able to resolve the cGMP issues raised by USFDA against Ranbaxy's API and formulation manufacturing units located in India. The various news items confirmed that Ranbaxy has been able to get the approval from it's US subsidiary M/S Ohm lab. Earlier, some FTF products of Ranbaxy like Donepezil and Valacyclovir were launched from this facility only.

Launch with help from Teva: As per Ranbaxy's official press release the part of sale shall be shared with Teva which probably has helped Ranbaxy on resolving various technical issues with USFDA.
http://www.ranbaxy.com/news/newsdisp.aspx?cp=987&flag=LN

Other generic players: Earlier, the generic players like Actavis, Teva, Dr Reddy, Aurbindo, Mylan and few others have settled the patent litigation with innovator on crystalline form I patent and these companies have been eagerly awaiting the generic launch of Ranbaxy to subsequently launch their generic version after the expiry of 180 days exclusivity of Ranbaxy. These companies are expected to launch the generic version in first week of June, 2012.

Overall, this is a very good news for all the scientists of Ranbaxy who were instrumental in developing the generic version. As the Para IV filing was made about 8-10 years ago and some of those scientists may have been working in other organisations now. However, they will be very happy on this news and must be silently admiring this news.

Overall, a good finish in the end like a bollywood thriller.