Clopidogrel Generic in Europe: German court's green signal to generic launch, Innovator to appeal against ruling

In a significant ruling favoring generic palyers,a German court has allowed generic launch of Clopidogrel besylate. This ruling will led Cimex AG, Schweizerhall and Novartis to launch this product in Germany and subsequently into the European market. Innovator Sanofi-Aventis and its U.S. partner Bristol-Myers Squibb announced that they would challenge a German court's decision to immediately authorize marketing of the generic versions of their blockbuster blood thinner Plavix (Clopidogrel). The generic players intend to launch this product by different salt. The approved salt is Clopidogrel bisulfate and generic will launch their product with Clopidogrel BesylateEarlier news of Ippharmadoc on this issue Here, Here, and Here

Cinacalcet (Sensipar): Barr confirms Para IV Challenge to innovator's patents

Barr Pharma has challenged four orange book listed patents held by Amgen Inc. for its Cinacalcet or Sensipar (30, 60 and 90 mg tablets), used by dialysis patients to treat side-effects of the treatment. Innovator Amgen got approval on this product on Mar 8, 2004. Following are the Orange Book listed patents on this product:
US6011068 (Expiry: Dec 14, 2016)- Link
US6031003 (Expiry: Dec 14, 2016) Link
US6211244 (Expiry: Oct 23, 2015) Link
US6313146 (Expiry: Dec 14, 2016) Link
Sensipar or Cinacalcet (N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine) acts as a calcimimetic by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. It is sold by Amgen under the trade name Sensipar in North America and Australia and as Mimpara in Europe. Cinacalcet is used to treat hyperparathyroidism (elevated parathyroid hormone levels), a consequence of parathyroid tumors and chronic renal failure.
Barr said it filed ANDA with Para IV certification against Orange Book listed patents on Cinacalcet on March 10, 2008.
Sensipar recorded $377 million in U.S. sales during the 12 months ending May, Barr said.

Charges against Ranbaxy by Department of Justice likely to be withdrawn

In (Newindiapress has reported) a major boost to image of Indian pharma major Ranbaxy Lab Ltd, the charges leveled by USFDA and department of Justice against Ranbaxy for submitting fabricated data and supplying substandard generics in US market is likely to be withdrawn by 3rd August, 2008.
Mr. Malvinder Singh, CEO of Ranbaxy, who announced that they have received a written communication and once Ranbnaxy complete filing all the information sought by the US FDA, the motion against Ranbnax will be withdrawn.
Earlier news by Ippharmadoc on this issue Here and Here

Mylan launch first Nislodipine generic in US market, Ranbaxy launched authorized generic of Omeprazole

Mylan launch first Nislodipine generic in US market
Mylan got final approval from the USFDA for its Abbreviated New Drug Application (ANDA) for Nisoldipine Extended-release (ER) Tablets, 20 mg, 30 mg and 40 mg. Nisoldipine ER Tablets, indicated for the treatment of hypertension, are the generic version of Sciele Pharma's Sular(R) ER Tablets.
Ranbaxy launched authorized generic of Omeprazole
Ranbaxy announced that under an agreement with AstraZeneca Pharma it has launched an authorized generic of Omeprazole 40 mg Capsules in the U.S. market. Omeprazole 40 mg is indicated for the treatment of acid-related disease, including gastric ulcer and Zollinger-Ellison syndrome. Prilosec(R) 40 mg had sales in the U.S. market of $205 million.

Oxymorphone Hydrochloride (Opana ER): Innovator again sues Impax for Para IV filing against new strengths

Innovator Endo and Penwest has sued generic player Impax for patent infringement related to the pain treatment Oxymorphone Hydrochloride (Opana ER), after Impax has applied to make a generic form of recently approved strengths. Innovator sued Impax based on an amendment to ANDA application. The amendment added new dosages of the drug 7.5 mg, 15 mg and 30 mg.
Impax had already submitted ANDA for dosages of 5, 10, 20 and 40 mg. Both the companies are alredy in litigation on this product as reported earlier by Ippharmadoc Here and here. Following patents are listed in orange book for this product

US5128143 (Expiry: Sep 19, 2008): Covers a slow release pharmaceutical excipient of an inert diluent and a hydrodrophilic material including xanthan gum and a galactomannan gum capable of cross-linking the xanthan gum in the presence of aqueous solutions.

US5662933 (Expiry: Sep 9, 2013) which covers a sustained release pharmaceutical formulation and methods of making and using the same. The sustained release pharmaceutical formulation includes a sustained release excipient including a gelling agent, an inert pharmaceutical diluent, an optional hydrophobic material and/or hydrophobic coating, and a medicament for sustained oral administration.

US5958456 (Expiry: Sep 9, 2013) which covers a controlled release solid dosage form for oral administration of a therapeutically active medicament to a patient in need thereof, comprising: a pharmaceutically effective amount of a medicament to be administered to a patient in need of said medicament; a sustained release excipient comprising a gelling agent; a pharmaceutically acceptable hydrophobic material; and an inert pharmaceutical diluent wherein the ratio of said inert diluent to said gelling agent is from about 1:8 to about 8:1, said dosage form providing a sustained release of said medicament when exposed to an environmental fluid.

US7276250 (Expiry: Jul 3, 2022) which covers an oral sustained release formulation comprising from about 5 mg to about 80 mg oxymorphone hydrochloride and from about 80 mg to about 360 mg of a granulated sustained release delivery system, wherein the granulated sustained release delivery system comprises from about 8.3% to about 41.7% by weight locust bean gum, from about 8.3% to about 41.7% by weight xanthan gum, from about 20% to about 55% by weight dextrose, from about 5% to about 20% by weight calcium sulfate dihydrate, and from about 2% to about 10% ethyl cellulose.

Earlier, on Feb 29, 2008 Innovator got approval to market new strengths 7.5 mg, 15 mg and 30 mg doses of Opana ER.

Dr. Reddy ready for grand entry into biosimilar drugs

The Hyderabad based Dr Reddy’s Lab, the country’s third-biggest drug maker, will form a joint venture with one of the world’s biggest biotech companies to make biosimilars or generic versions of patented biotech drugs to take on Ranbaxy Laboratories, Reliance Life Sciences, among other Indian companies. Several drugs are expected to come off patent in this segment in the next five years. Link (Source: buisness standard)

Bad time for generic player in Canada and US market

After allegations of data manipulation and substandard generics on Ranbaxy, other generic players like Teva, Par and Sandoz are also facing similar charges either from regulatory agencies or from patients.
Teva Pharma and Par Pharma are facing a lawsuit in which a patient alleged that companies’ generic Pergolide, a treatment for Parkinson’s disease and restless leg syndrome (RLS), caused the valvular heart disease.

Also, Health Canada is warning consumers not to use Sandoz Canada’s Timolol Ophthalmic solution in 0.25% and 0.5%s strengths because solution may contain more of the active ingredient than indicated on the label. The Health Canada announced that it will monitor the effectiveness of Sandoz’s recall, and the company will send a separate communication to doctors and pharmacists. The eyedrops are the generic equivalent of Merck’s Timoptic (Timolol Maleate) and are used to treat increased intraocular pressure and glaucoma.

Topiramate got Pediatric exclusivity, Generic launch delayed till Mar 26, 2009

Innovator Ortho-McNeil Neurologics announced today that the USFDA has granted pediatric exclusivity for TOPAMAX(R) (Topiramate). The new expiries for Orange Book listed patents is as follows:
US4513006 (Expiry: Mar 26, 2009)
US5998380 (Expiry: Apr 13, 2016)
US6503884 (Expiry: Apr 13, 2016)
US7018983 (Expiry: Apr 13, 2016)
Earlier, U.S court has upheld innovator’s product patent ‘006 on appeal by MylanTopiramate (2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate) is an anticonvulsant drug produced by Ortho-McNeil Neurologics, a division of Johnson & Johnson.

The Generic launch will be delayed till Mar 26, 2009

European regulatory authority raises safety concern w.r.t use of Fluoroquinolones derivatives like Norfloxacin and Moxifloxacin

The European regulatory agency has raised safety concern w.r.t use of Fluoroquinolones derivatives like Norfloxacin and Moxifloxacin. Finalising a review of the safety of Moxifloxacin-containing medicines for oral use, the European Medicines Agency (EMEA) has concluded that these medicines should only be prescribed in the treatment of acute bacterial sinusitis, acute exacerbation of chronic bronchitis and pneumonia when other antibiotics cannot be used or have failed. The European Medicines Agency has recommended restricting the use of oral Norfloxacin containing medicines in urinary infections. The Agency’s Committee for Medicinal Products for Human Use (CHMP) has concluded that the marketing authorisations for oral Norfloxacin-containing medicines, when used in the treatment of acute or chronic complicated pyelonephritis (kidney infection), should be withdrawn because the benefits of these medicines do not outweigh their risks in this indication.

Drug Launch: Watson launch Omeprazole Delayed-Release Capsules USP, Sagent launched amiodarone HCl injection

Watson launch Omeprazole Delayed-Release Capsules USP

Watson Pharma announced that it has commenced commercial shipment of its Omeprazole Delayed-Release Capsules USP product in the 40mg with First To File 180 day’s exclusivity in U.S market. Watson pharma is known for launching authorized generics of some formulations like Alendronate sodium.

Sagent launched amiodarone HCl injection

Sagent Pharma announced that it has launched amiodarone HCl injection, USP, a class III antiarrhythmic, which will be available immediately in 150 mg/3 ml single dose prefilled syringes.

Fentanyl citrate buccal tablets:Barr filed Para IV, innovator sued Barr in U.S. District Court of Delaware

Barr announced that it has challenged Cephalon Inc.'s patent by filing Para IV for the analgesic drug Fentora(R) Tablets (Fentanyl citrate buccal tablets), equivalent to fentanyl base 100 mcg, 400 mcg, 600 mcg and 800 mcg.and in turn is being sued to prevent it from marketing a generic version.
The innovator on July 22, . filed a lawsuit in U.S. District Court of Delaware to prevent Barr from selling the product.

Product launch: Sagent launched Ceftazidime in US, Ranbaxy launch Amlodipine in Japan

Sagent Pharma launched Ceftazidime for injection USP

Sagent Pharma today announced that it has launched Ceftazidime for injection USP, a semisynthetic broad-spectrum, beta-lactam antibiotic. Sagent will offer ceftazidime in 1 and 2g single dose vials and 6g pharmacy bulk package vials. According to IMS data, 2007 sales of injectable amiodarone in the United States were approximately $45.7 million.
Sagent’s ceftazidime is the generic equivalent of GlaxoSmithKline’s FORTAZ®.

Ranbaxy Lab announced launch of Amlodipine tablets

Ranbaxy Lab announced launch of Amlodipine tablets 2.5mg & 5mg in Japan . Amlodipine is currently the largest molecule which has gone off patent in Japan and represents the biggest generic opportunity so far in the Japanese generic market. The product has a market size of around USD 2 Billion.

Another Takeover by Teva

Teva pharma has buy Spainish generic player Bentley pharma (120 products in European market) for $360 million. Teva Genericos Spain launched its product in Spainish market since 2004 and with the acquisition Teva will further consolidte its generics business in Spain and Europe.

Lamotrigine Tablets: Teva (First generic player) launched tablets in US market

Teva Pharma has launched Lamotrigine Tablets in the US market. This product is AB rated and bioequivalent to Lamictal® Tablets. Lamotrigine Tablets are available in 25 mg and 100 mg strengths, in bottle sizes of 100, and in 150 mg and 200 mg strengths, in bottle sizes of 60.
This product has one orange book listed patent US4602017 which will expire on JAN 22,2009.On February 17, 2005, Teva issued a press release regarding settlement with innovator GSK. As per settlement Teva was granted the exclusive right to manufacture and sell its own generic version of Lamotrigine tablets (25mg, 100 mg, 150 mg, and 200 mg) in the United States during pediatric exclusivity of this product from July, 2008. Following firms have received tentative approval and will launch their product from January 23, 2009 onwards, when the pediatric exclusivity of this product will expire.
1) GENPHARM
2) DR REDDYS LABS LTD
3) ROXANE
4) MYLAN PHARMA
5) ZYDUS PHARMS USA INC
6) CARACO
7) WATSON LABS
8) SANDOZ
9) MATRIX LABS
10) TARO
According to industry sources, Lamictal(R) Tablets had annual U.S. sales of approximately $2.6 billion.

Ranbaxy got favorable decison:Crown Court has quashed charges of fraud and price fixing

Indian Pharma giant Ranbaxy has announced that English Crown Court has quashed the U.K. Serious Fraud Office's (SFO) bid to prosecute Ranbaxy UK limited on the charges of fraud and price fixing.
The Crown court declined to send the case to the Court of Appeal and said the Serious Fraud Office should approach the court directly for permission.
Earlier in April 2006, SFO initiated criminal proceedings against RanbaxyUK limited on charges of fixing prices of medicines between April 1, 1998, and September 30, 2000.

Rabeprazole Sodium: CAFC upheld product patent, Setback to generic players (Teva, Reddy and Mylan)

The Japanese Pharma giant Esai, won a Court of Appeals for Federal Circuit's (CAFC) ruling that blocks generic competition to its blockbuster drug Aciphex (Rabeprazole sodium) till may 2013. The CAFC (CAFC:OPINION) has affirmed the District Court of New York's summary judgment ruling on the validity of Eisai's product patent US5045552 (Expiry: May 8, 2013) and its ruling on the enforceability of the composition of matter patent.
Eisai filed the infringement actions in 2003 contesting Teva Pharmaceuticals and Dr. Reddy's Laboratories' submission of ANDA to the USFDA with Paragraph IV certification for Aciphex(R) Orange book listed patents. In October 2006, Judge Gerard E. Lynch of the United States District Court for the Southern District of New York granted partial summary judgment to Eisai, upholding the validity of the Aciphex(R) product patent '552. In a subsequent ruling in May 2007, Judge Lynch also concluded that Eisai's patent is enforceable and affirmed infringement by DRL and Teva.
CAFC decision highlights:
Teva cited EP174726, a patent by Takeda which covers Lansoprazole (Teva claims Lansoprazole is a lead compound to arrive at Rabeprazole), US4255431, which covers Omeprazole and an article on SAR of Benzimidazole by Brandstorm.

Teva claims that teachings in the said prior art make Rabeprazole invention as obvious. The CAFC observed that selection of Lansoprazole as lead at the time of Rabeprazole invention was not obvious to Skilled artisan. CAFC also rejected generic companies claim of inequitable conduct based on co-pending patent application of Esai, which covers a structural analogue of Rabeprazole
The rabeprazole generated $1.63 billion in global sales in the year ended March 31 for Eisai, according to the company's annual report. Eisai co-promotes the drug with Johnson & Johnson, the world's biggest health-products company. In June, the U.S. Food and Drug Administration approved Aciphex for short-term acid reflux in children over the age of 12.

Clopidogrel Besylate: Generic launch delayed in Europe

Novartis has announced that the timing of generic Plavix with difrent salt (Clopidogrel Besylate)launch delayed in Europe. Novartis also announced that it's difficult to predict when a generic version of Plavix can be launched in Germany, after the German regulator suspended an approval that it had given earlier because the Sanofi-Aventis has opposed the approval of generic form with diffrent salt.
The launches in other European markets depends on the outcome in Germany, and till Germany regulatory agency reviews its decision its difficult to predict the launch of this blockbuster generic.

Swiss generics maker Schweizerhall had earlier received German approval for clopidogrel Besylate ( Sanofi's aproved form is Clopidogrel bisulfate in May.
Sandoz (generic unit of Novartis ) was set to market generic Plavix in Germany as per their agreement with Schweizerhall.

IPPharmadoc's earlier news on Clopidogrel Besylate approval.

Merger details:Teva to Acquire Barr

Teva and Barr announced today that they have signed a definitive agreement under which Teva will acquire Barr, the fourth largest generic drug company worldwide. Under the terms of the agreement, each share of Barr common stock will be converted into $39.90 in cash and 0.6272 Teva ADRs. Based upon the unaffected NASDAQ closing price of Teva's ADRs on July 16, 2008, the indicated combined per share consideration for each outstanding share of Barr common stock amounts to $66.50, or a total consideration of $7.46 billion plus the assumption of net debt of approximately $1.5 billion.
Teva expects the transaction to close in late 2008 and to become accretive to GAAP earnings in the fourth quarter after closing. This purchase price represents a premium of 32% to Barr's average daily closing price on the New York Stock Exchange for the 52-week period ending on July 16, 2008, and 42% to the closing price on July 16, 2008.
This acquisition will further enhance Teva's leadership position in the U.S. and will significantly strengthen its position in key European and Central and Eastern European markets. On a pro forma basis, 2007 revenues of the combined company would have been approximately $11.9 billion. The combined company will have an unmatched global platform, operate directly in more than 60 countries and employ approximately 37,000 people worldwide.
The companies' highly complementary product offerings and development pipelines will extend Teva's generic and proprietary offerings for customers globally. By adding development resources and breadth to Teva's product portfolio and pipeline, particularly the Paragraph IV and first to file opportunities, Teva will bring more products to market while increasing access to affordable medicines. The transaction also bolsters Teva's specialty pharmaceutical platform through the addition of Barr's substantial women's health portfolio to Teva's respiratory franchise, further enhancing Teva's balanced business model.
Shlomo Yanai, President and Chief Executive Officer of Teva, said, "The acquisition of Barr will elevate Teva's market leadership to a new level. The combination of our two companies provides an outstanding opportunity strategically and economically: It will enhance our market share and leadership position in the U.S. and key global markets, further strengthen our portfolio and pipeline, and provide upside to our strategic plan, by allowing us to exceed our 20/20 goals for 2012."
Mr. Yanai continued, "We have long admired Barr as a highly-focused company with an excellent management team. This is a transaction in which two great, strong companies are joining forces to capture an even greater share of the growing opportunities in generics and deliver even more value to our stakeholders."
Bruce Downey, Chairman and Chief Executive Officer of Barr, said, "This transaction will enable Teva to capitalize on Barr's portfolio of unique generic and proprietary products, benefit from our capabilities in biologics, and expand its presence in important Central and Eastern European markets. This agreement has the full support of Barr's Board of Directors and senior management, and will benefit the shareholders, customers and employees of Barr."
Key benefits of the transaction include:
-- Exceptional Fit Supporting Teva's Long-Term Strategy: The transaction combines two industry-leading companies, further enhancing Teva's lead in the U.S. and delivering increased scale and expanded geographic footprint in key global growth markets.
-- Expanding the Breadth of the Product Portfolio and Pipeline: Teva and Barr's product offerings are highly complementary, extending Teva's product portfolio and pipeline into new and attractive product categories. The combined company will have over 500 currently marketed products; more than 200 ANDAs pending with the FDA with annual brand sales of greater than $120 billion, including approximately 70 first to file Paragraph IV challenges; and approximately 3,700 product registrations pending with various regulatory authorities worldwide, primarily in Europe.
-- Strengthening Teva's Balanced Business Model: The transaction also bolsters Teva's specialty pharmaceutical platform through the addition of Barr's substantial women's health portfolio to Teva's respiratory franchise, further enhancing and diversifying Teva's balanced business model. Additionally, this transaction augments Teva's biologics capabilities.
-- Compelling Value Consistent with Stated Acquisition Criteria: The combination is expected to deliver significant revenue and cost synergies based on numerous operational efficiencies, increased scale and geographic scope. Teva anticipates the transaction will generate at least $300 million in annual cost savings within 3 years and will continue to provide additional cost savings well beyond 2011. The transaction is expected to be accretive to GAAP earnings in the fourth quarter after closing. The acquisition offers considerable value with a financial structure that preserves Teva's strong balance sheet and flexibility.
-- Enhanced Growth and Profitability Provide Upside to 20/20 Strategic Target: The Barr acquisition will enable us to exceed our 20/20 five-year strategic plan, which was to double revenues by 2012 to $20 billion with net income margins of at least 20 percent.
Transaction Terms:
Under the terms of the agreement, Teva will acquire 100% of the shares of Barr for total cash and stock consideration of $7.46 billion. Each share of Barr's common stock will be converted into $39.90 in cash and 0.6272 Teva ADRs. In addition, Teva will assume Barr's outstanding net debt of approximately $1.5 billion. Teva intends to fund the cash portion of the consideration by using its cash on hand and marketable securities and by approaching the long-term debt market for the remaining balance.
Approvals and Timing:
The boards of directors of both companies have unanimously approved the transaction. The acquisition is subject to approval by the stockholders of Barr, antitrust notification and clearance statutes in North America and Europe, as well as other customary conditions. The transaction is expected to close in late 2008.
The Merger Agreement may be terminated under certain circumstances, including if Barr's Board of Directors determines to accept an unsolicited superior proposal prior to approval of the merger by Barr's stockholders. If the merger agreement is terminated under certain circumstances, Barr will be required to pay Teva a termination fee of $200 million.
Lehman Brothers acted as financial advisor to Teva in this transaction, and Willkie Farr & Gallagher LLP provided external legal counsel for Teva. Banc of America Securities LLC acted as financial advisor to Barr in this transaction, and Simpson Thacher & Bartlett LLP provided external legal counsel for Barr.

Barr is a global specialty pharmaceutical company that operates in more than 30 countries worldwide and is engaged in the development, manufacture and marketing of generic and proprietary pharmaceuticals, biopharmaceuticals and active pharmaceutical ingredients. A holding company, Barr operates through its principal subsidiaries: Barr Laboratories, Inc., Duramed Pharmaceuticals, Inc. and PLIVA d.d. and its subsidiaries. The Barr Group of companies markets more than 120 generic and 27 proprietary products in the U.S. and approximately 1,025 products globally outside of the U.S.

(Source: Press release from Barr Here)

Generic to generic takeover: Mister Generic Teva to buy Barr

In pharma industry takeover of a generic company by a generic company is on the rise. Recently, some generic companies are aquiring other generic companies like Sun pharma trying hard to buy Taro.

Now, the Mister generic of Pharma world Teva Pharma (as declared by Teva's Chief Executive Shlomo Yanai Here) in a bid to aquire generic firms have paid $400 million to buy CoGenesys and is expected to close soon on a deal to purchase Bentley Pharmaceuticals for about $350 million. Now an Israeli news paper has speculated here that Teva will buy Barr Pharma for about 7-7.5 billion dollars

Barr is one of the frontier generic company with more than 100 approvals in regulated market and also has First to file 180 days exclusivity on some molecules in US market, so deal will be quite useful for Teva. In the past, both generic companies have shared 180 days exclusivity on some molecules in US market like in case of Fexofenadine and Alendronate.

Alendronate (Fosamax): Apotex's appeal on early entry into market foiled by CAFC

Apotex failed to enter early into the market during the 180 days exclusivity of Teva (Teva's exclusivity started on 6th February, 2007) w.r.t Alendronate (Fosamax) tablets. Apotex tried to trigger 180 days exclusivity of Teva in 2006, when innovator issued 'convenant not to sue' to Apotex. Apotex at that time was not satisfied and appealed to district court against convenant not to sue (Apotex wants decision from court that its ANDA do not infringe Orange book patents, which could have triggered Teva's 180 days exclusivity early). However, district court in its decision opined that when innovator has alreday issued convenant not to sue, there is no controversy and rejected Apotex appeal.
However, based on courts decision in Caraco v. Forest Apotex appealed in CAFC, which observed that the said case is diffrent from Caraco case as Teva has already started its 180 days exclusivity and as a result, Apotex no longer suffers a delay in entering the market under either the thirty-month stay provision or the 180-day exclusivity provision that is traceable to Merck and redressible by a court judgment.

Earlier in 1999, Teva filed an ANDA for a generic version of Fosamax, with paragraph IV certifications to all ten Orange Book-listed patents. Teva was the first ANDA filer, earning 180-day exclusivity. The Federal Circuit affirmed the validity of the product patent '077, but, in 2005 held two claims of the '329 patent (Method of use claims w.r.t 35 and 70 mg dose to be invalid for obviousness).

Apotex filed its ANDA for generic Alendronate Sodium sometime later, with a paragraph III certification to the product patent '077 and paragraph IV certifications to the rest of Orange Book listed patents. Merck sued Apotex for infringement and Apotex counterclaimed for invalidity and noninfringement. Following discovery, Merck granted Apotex a covenant not to sue and moved to dismiss the case.

Now, Apotex will enter into the market afetr the expiry of 180 days exclusivity on August 5, 2008.
CAFC vacated the district court's dismissal of Apotex's counterclaims as moot. (Opinion of court Here)

Venlafexine XR (Effexor XR): Innovator Wyeth settled with Impax

It’s settlement season between innovator and generic companies, after settlement with Sun pharma (convenant not sue for their ANDA on Venlafexine XR tablets), Teva (Venlafexine XR capsules) and Osmotica (Venlafexine XR tablets), innovator Wyeth settled with another generic player on Venlafexine XR capsules. In a press release, Wyeth and generic player Impax Lab have announced settlement of the patent infringement litigation pertaining to Impax's copycat version of Venlafexine XR Capsules, the settlement have been approved by the District Court of Delaware. The Court entered a consent judgment resulting in termination of the litigation effective July 16. 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

The Impax was in litigation with innovator for the infringement of ‘171, ‘120 and ‘958 patents. The litigated patents covers extended release dosage formulation and unit dosage form thereof of venlafaxine hydrochloride, an antidepressant, which provides better control of blood plasma levels than conventional tablet formulations which must be administered two or more times a day and further provides a lower incidence of nausea and vomiting than the conventional tablets.
Under the terms of the settlement, Wyeth has granted Impax a license that would permit Impax to launch its capsule formulation of Effexor XR on or after June 1, 2011, subject to earlier launch in limited circumstances, but in no event earlier than January 1, 2011. Further, Impax will pay Wyeth some royalty.USFDA approved NDA of wyeth for 37.5, 75, 100 and 150 mg capsules on October 20, 1997. Venlafaxine (Effexor, (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride) is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class first introduced by Wyeth in 1993. Venlafaxine was the sixth most widely-used antidepressant based on the number of retail prescriptions in the US (17.1 million) in 2006. Venlafaxine is used primarily for the treatment of depression, generalized anxiety disorder, social anxiety disorder, and panic disorder in adults
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.

Other generic players in litigation : Anchen Pharmaceuticals, Lupin, Sandoz, Mylan, Wockhardt, Biovail

Ranbaxy ready to share inernal audit report with USFDA

Indian Pharma giant has Responded to the complaint filed by US regulatory agency. Regulatory agency in its complaint has alleged that Ranbaxy declined to provide internal Audit report from consulting audit firm Parexel (citing attorney client privilege) w.r.t their assessment of deficiencies in Ranbaxy’s Paonta sahib Plant.
Ranbaxy filed its reply to the Maryland district court and has agreed to provide all documents to investigating agency. Ranbaxy also released a press release where it clarifies that USFDA over the last 3 yeras has checked around 200 samples of various generic products, and all samples conform to regulatory standards.
Ranbaxy announced that there will be no change in its deal with Daiichi.
Ranbaxy shares also fall in stock market and Ranbaxy has alleged that there are elements who are affecting its market stock here.
IP Pharma Doc believes that Ranbaxy can successfully defend the allegation
Also, mint has reported on possible harm in the reputation of indian generic players in US market due to Ranbaxy Controversy here.

Ranbaxy sued by US Goverment for falsifying records

The US Goverment (Justice department) has sued Indian pharma giant Ranbaxy for allegedly falsifying records that resulted in the production and sale of spurious, substandard dosage forms that did not meet federal standards. In its complaint filed at US District Court in Maryland , USFDA and Justice department alleged that Ranbaxy utilized substandard and unapproved outsourced API’s and fabricated stability and bioequivalent studies. Earlier, Ranbaxy have to recall around 70 million doses of generic Gabapentine, which is used to treat seizures. USFDA has also alleged that Ranbaxy produced fabricated data for antiretrovirals like anti AIDS medication which were approved as per President’s Emergency Plan for AIDS Relief program (PEPFAR) programme. USFDA has also accused Parexel (a consulting firm for plant audits), which hide its finding from USFDA w.r.t its assessment of Quality control, quality assurance and cGMP findings of Ranbaxy's Paonta Sahib plant (Himachal Pradesh). The trouble for Ranbaxy started in February 2006, when USFDA issued warning letter on finding less manpower and nonconforming cGMP compliance at Paonta Sahib plant
Similar type of charges was leveled against Able Laboratories and generic manufacturer has to recall products from US market in 2005.
It will be interesting to watch Ranbaxy’s defense against these allegations.
(The Federal agency’s complaint with all the details is here in Pharmalot)

Copaxone (R) (Glatiramer acetate):Innovator Teva ready to challenge generic players

Teva Pharma has initiated efforts to block generic challenge on Copaxone(R) (Glatiramer acetate) after information of Para IV filings by generic players like Momenta and Sandoz.Teva received Momenta/Sandoz's Paragraph IV certification notice referring to following orange book listed patents
US5981589 (Expiry: May 24, 2014)- Covers Copolymer-1 having a molecular weight of about 5 to 9 kilodaltons, made by a process comprising the steps of: reacting protected copolymer-1 with hydrobromic acid to form trifluoroacetyl copolymer-1, treating said trifluoroacetyl copolymer-1 with aqueous piperidine solution to form copolymer-1, and purifying said copolymer-1, to result in copolymer-1 having a molecular weight of about 5 to 9 kilodaltons.
US6054430 (Expiry: May 24, 2014)- covers an improved composition of copolymer-1 comprising copolymer-1 substantially free of species having a molecular weight of over 40 kilodaltons.
US6342476 (Expiry: May 24, 2014)- covers an improved composition of copolymer-1 comprising copolymer-1 substantially free of species having a molecular weight of over 40 kilodaltons.
US6362161 (Expiry: May 24, 2014)- covers an improved composition of copolymer-1 comprising copolymer-1 substantially free of species having a molecular weight of over 40 kilodaltons.

US6620847 (Expiry: May 24, 2014)- Covers Copolymer-1 having a molecular weight of about 4 to about 9 kilodaltons, made by a process comprising: treating trifluoroacetyl copolymer-1 with aqueous piperidine to form a solution of copolymer-1; and purifying copolymer-1, thereby producing copolymer-1 having a molecular weight of about 4 to about 9 kilodaltons.
US6939539 (Expiry: May 24, 2014)- Covers A copolymer-1 composition comprising a mixture of polypeptides composed of glutamic acid, lysine, alanine and tyrosine, wherein the mixture has an average molecular weight of about 4 to about 9 kilodaltons, wherein the mixture of polypeptides is non-uniform with respect to molecular weight and sequence, and wherein the composition is suitable for treating multiple sclerosis.
US7199098 (Expiry: May 24, 2014)- Covers a copolymer-1 composition comprising a mixture of copolymers of alanine, glutamic acid, lysine and tyrosine, the copolymer species in the mixture being non-uniform with respect to molecular weight and sequence, wherein over 75% of the copolymers in the mixture, on a molar fraction basis, have a molecular weight in the range of 2 kDa to 20 kDa and less than 5% of the copolymers have a molecular weight above 40 kDa, and wherein the composition is suitable for treating multiple sclerosis.
Teva believes designing around this formulation would be extremely difficult and presents a significant challenge. Also, once injected, it is rapidly hydrolyzed locally and no level of the intact drug can be measured in the blood, rendering a bioequivalence study comparing two formulations extremely difficult.Glatiramer Acetate is the generic name for Copaxone or Copolymer. It is an immunomodulator, licensed in much of the world for reduced frequency of relapses in relapsing-remitting multiple sclerosis. Copaxone is administered by subcutaneous injection at a dose of 20 mg per day. It is a non-interferon and non steroidal medication.Glatiramer acetate was originally discovered by Professor Sela, Professor Arnon and Dr. Teitelbaum at the Weizmann Institute of Science in Israel. Teva got license on this molecule and subsequently commercialised this product.

Teva is till date best IP designing around Pharmaceutical company and now it will be interesting to watch Teva's Defense as innovator.

Panacea Biotech Got Patent For Thank God (Euphorbia Prostrata) formulation

Panacea Biotec got a US patent (US7371412) for its hemorrhoids & piles medicine, Thank GodTM (Euphorbia Prostrata).
The patent covers novel compositions comprising of an extract of the plant Euphorbia prostrata, particularly with pharmaceutically acceptable carrier(s)/base(s), optionally with additional therapeutic agent(s) useful for the treatment of anorectal disease and colonic diseases such as hemorrhoids, fissures, cracks, fistulas, abscesses, inflammatory bowel disease, and the like. The novel compositions possess properties to control inflammation, prevent capillary bleeding and fragility in mammalians, particularly human beings. Process for the preparation of such novel compositions comprising an extract of the plant Euphorbia prostrata and pharmaceutically acceptable carrier(s)/base(s) useful for the treatment of anorectal disease including hemorrhoids, and colonic diseases are also provided. The composition comprise of flavonoidal and phenolic constituents extracted from the plant Euphorbia prostrata that possess anti-inflammatory, analgesic, haemostatic and wound-healing properties.
Thank GodTM (Euphorbia Prostrata) was developed in University Institute of Pharmaceutical Science (UIPS), Panjab University, Chandigarh. Prof. A.K. Singla and Prof. K.N. Gaind first identified potential of Euphorbia Prostrata for the treatment of hemorrhoids & piles. Panjab University, as per their Industry Institute Partnership programme licensed this molecule to Panacea Biotech. Panacea Biotech further developed this formulation into a successful commercial product.
The combined potential of anti-hemorrhoids & piles market in regulated market (U.S & Europe) is around USD 600-700 million.

ACULAR LS (Ketorolac Tromethamine opthalmic solution): Apotex lost due to Expert, RDOE and Res Judicata

In a significant decision CAFC granted summary judgment in favor of Roche's for their patent on US5110493: which covers an ophthalmologically acceptable non-steroidal anti-inflammatory drug formulation, comprising: an ophthalmologically acceptable non-steroidal anti-inflammatory carboxyl group-containing drug in an effective amount for ophthalmic treatment between 0.001% and 10.0% wt/vol; a quaternary ammonium preservative in an antimicrobially effective amount between 0.001% and 1.0% wt/vol; an ethoxylated alkyl phenol.
Apotex developed ACULAR (ketorolac tromethamine opthalmic solution) and ACULAR LS by designing around said patent. The two formulations differ in their proportion of preservative (benzalkonium chloride) and a surfactant (octoxynol 40).
When Apotex filed ANDA on said product Roche sued Apotex for the infringement of ‘493 patent. Earlier, in 2007 the CAFC affirmed for ACULAR that ‘493 patent is neither invalid and nor unenforceable and court further affirmed infringement.
For Acular LS Apotex argued that the district court erred in failing to find noninfringement under the Reverse Doctrine Of Equivalents (RDOE). The RDOE can be used to limit the scope of claim coverage where the device/element is so far changed in principle from a patented article that it performs the same or a similar function in a substantially different way, but nevertheless falls within the literal words of the claim. Apotex argued that their formulation will not infringe as per RDOE. However CAFC found no support for this principle in the patent specification, prosecution history or information in public domain. Further, CAFC concluded that Apotex relied exclusively on the declaration of its expert, who wrongly opined that Apotex will not infringe as per RDOE. As this RDOE has not get victory for any generic firm till date, Apotex should have checked prosecution history and prior art to substantiate its claim of non-infringement. Based on these facts, the court agreed that Apotex failed to make out a prima facie case of noninfringement under the RDOE, summary judgment of infringement of ‘493 was affirmed.
During trial, Apotex also tried to changed the line of defense with the benefit of the new KSR standards for obviousness. The court, however, refused this attempt by finding the claims precluded as per Res Judicata (when two similar parties are litigating on same patent which was earlier decided for similar product, the second suit with in same parties is not allowed and earlier decision remains affirmed). The Res Judicata doctorine was also used by Pfizer in Caudet (Atorvastatin and Amlodipine) litigation against Ranbaxy on '893 patent, where Pfizer said that Court has affirmed the validity of '893 patent earlier and now Ranbaxy Can't attack same patent for Caudet.

Indian IP sword and shield

India has got maximum outsorcing work on patents, with cities like Gurgaon, Noida, Banglore, Mumbai, Hyderabad and Chennai emerging as major IP hub. India in the recent times has proved its technical brilliance in all fields like Pharma and software industry. In pharma industry, Indian companies like Ranbaxy, Sun pharma, Cadilla, Cipla, Lupin, Dr. Reddy and Panacea has successfully exhibited their IP Capabilities against innovator companies either through patent challenge or by opposition to grant of patents.

Although, India lags in terms of patent filings (Link to IP pharma doc news on patent applications filed in 2007) but most of the IP work of innovator companies are outsourced in India. Further, India is a hub of patent design around strategies. There many examples in Pharma world, where Indian companies have successfully challenged Pharma giants. Indian generic firms have successfully design around patents on formulation, Particle size, bulk density, method of use etc. and thwarted innovator's attempt on patent evergreening after the expiry of product patent. Generic players like Lupin and Sun, who have successfully invalidated product patent on Ramipril and Pentoprazole proved IP capabilities of India.

Also, Indian company like Ranbaxy successfully challegend the innovator firms like Glaxo (Ceftin) and Pfizer (Lipitor) to win First to File 180 days exclusivity on blockbuster drugs, which is a huge financial benefit to generic company. Although, Ranbaxy has settled on Atorvastatin but still it will gain billions when its exclusivity will start in November, 2011. Its rare that innovator company like Pfizer settle with generic firm, but Ranbaxy has shown its IP worth to Pfizer by aggressively litigating on Lipitor. Also, Indian companies have First to File 180 days exclusivity on around 40-50 products in USA. So in nutshell, pharma world has recognised impotance of Indian brains in preserving intellectual property. For any company IPR group acts as Sword (for attacking patents) and shield (in protecting technology), and Indian IP sword is really sharp and shield is very firm.

A recent article published in Times of India here, also highlights importance of India as a hub for patent outsourcing work.

Race to takeover: Innovator to generic and generic to bigger generic; Teva to buy Barr pahrma?

In last few days a paradigm shift is being observed in Pharmaceutical industry. Innovator companies are turning to generic buissness. The recent exmple of Daiichi Sankyo aquiring Ranbaxy to enter into the generic market. Also, another innovator company Sanofi Aventis is making a bid to acquire Czech generics company Zentiva.
Generic to bigger generic
Also, some generic companies are aquiring other generic companies like Sun pharma trying to buy Taro. Teva in a bid to aquire generic firms have paid $400 million to buy CoGenesys and is expected to close soon on a deal to purchase Bentley Pharmaceuticals for about $350 million. Now a Israel news paper has speculated here that Teva will buy Barr Pharma for about 7-7.5 $ billion

Innovator to generic trend was started by Novartis by floating its generic unit Sandoz. Now many innovator companies are eyeing this strategy. The Reason for this U turn seems to be due to following factors:


1) Loss of innovation: Drug development is a very risky affair which can consume billion dollars. All the latest techniques of drug development have not led to a blockbuster drugs. In nutshell, the innovation pipeline has dried up. Although, research is going on but these companies know that its difficult to launch a drug in 2-5 yr time, to cover up that gap and fund research generic buissness is ideal choice


2) Off-patent Scenario: After the expiry of key patent of innovator, its difficult to sustain in competion with generic players. The market for innovator product after generic launch erode very quickly.


3) High cost of drug development: With drug intermediate and other raw material prices zooming, the new drug development has became more expensive. Further, clainical trials ae also becoming more expensive.

4) Thriving generic companies: Some of the generic companies have achieved sales equivalent to innovator. The innovator mostly get 5 yr exclusivity and sales normally rises yearwise. By the end of 4th year of exclusivity, generic companies are ready with their strategy and file dossier to challenge innovator. As in US First para IV filer got 180 days exclusivity, so if a generic player enter after the end of innovator's 5 yr exclusivity they got profit in the tune of millions (Some times sales achieved by innovator in first 3 years of exclusivity). Further, the risk and money involved for generic companies for development and launch is minimal.

5) Pro generic patent laws: The patent laws in US and EU are becoming more favorable to generic companies. The KSR V.s Teleflex decision which changed the obviousness concept is proving detrimental to product patents in US. Recent example for this are Pramipexole and Ramipril, whose product patent was invalidated by Us court. Recently, in Europe the product patent of Esomeprazole got invalidated.

6) Failure on Patent evergreening: Generic companies in the last 8 years have devloped their skills to stop patent evergreening attempts of innovator. Earlier, innovator in an attempt of evergreening of patent would get patents on polymorph, salt, formulation, purity, hausner ratio, bulk density, method of use, new combination etc. to thwart generic challenge. But all these patent are not sufficient to stop generic challenge once molecule or product patent expires.

Nebivolol: Janssen’s key patent invalidated in UK due to lack of novelty

Actavis (Generic) seeks revocation of EP0334429 whose assignee is Janssen (Innovator). The Patent covers method of use with stereochmical concept of an important antihypertensive beta blocker Nebivolol. Janssen has applied to amend certain claims of the Patent. Actavis maintains that the Patent, even if so amended would remain invalid for lack of novelty and lack of inventive step.
In Nebivolol, there are four pairs of enantiomers and two meso forms, a total of ten enantiomers. Nebivolol comprises a 1:1 mixture of two isomers: the SRRR and the RSSS. The former is referred to as d-nebivolol and the latter as l-nebivolol.
In the prior art discussion of ‘429 the patent describe US4,654,362 (cited as prior art in this case) which covers a class of 2,2'-iminobisethanol derivatives having ß-blocking activities.
The judge Floyd concluded that claims are not novel in the light of 362 disclosures and rejected the important claims. Judge observed that merely explaining the mechanism which underlies a use already described in the prior art cannot results into novelty and claimed invention in '429 lacks novelty and inventive step.

The above decision is an example to snub patent ever-greening attempts of innovator.

(Link to opinion)

Quetiapine (Seroquel) generic delayed: Court granted summary judgment in favor of innovator Astra

Astra has announced that the US District Court of New Jersey has granted the company's Motion for Summary Judgment with respect to no intent and materiality of Inequitable Conduct. AstraZeneca had sued Teva and Sandoz, for infringement of AstraZeneca's Product patent of Seroquel (R) (Quetiapine fumarate) US4879288 (Expiry: Sep 26, 2011) as a result of Teva's and Sandoz's filings of Abbreviated New Drug Applications (ANDAs) for 25, 50, 100, 150, 200 and 400mg tablets. Since the Court granted AstraZeneca's motion for Summary Judgment of No Inequitable Conduct in its entirety, trial is unnecessary. Teva and Sandoz had already conceded infringement and the validity of AstraZeneca's patent. Thus, only the inequitable conduct contentions remained to be resolved. The Court had previously set a date for trial beginning on August 11, 2008. This drug was approved by USFDA on September 26, 1997 and no generic player has got any final or tentative approval for this product.So now the generic can be launched after the expiry of ‘288 patent. Further, there will be no First to File exclusivity of 180 days for any generic player for this product

Risperidone (Riosperdal): Teva Launched Generic (with 180 days exclusivity) and Patriot launched authorized generic

Teva Pharma announced the launch of generic version of Janssen's antipsychotic agent Risperdal(R) (Risperidone) Tablets, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg. Teva is first Para IV filer and after the expiry of the product patent on 29th June 2008, Teva became eligible to launch generic version of Risperidone. Teva got this exclusivity by successfully relisting a patent (US5158952) on Paliperidone in Orange book by decision from a district court in April, 2011, where court sided with Teva and directed FDA to relist the said patent. The USFDA has appealed against this decision and a hearing has been scheduled in September, 2008.
Innovator Janssen in a bid to affect sale of Teva’s generic formulation announced that it has launched an authorized generic version of Risperidone through Patriot Pharma. The brand products had annual sales of approximately $2.5 billion in the United States.