COPAXONE COPAXONE STORYSTORY

USA & India

AMIT SATPUTEIPR Department

Why this is landmark Why this is landmark Case?Case?

• Teva’s Copaxone (Glatiramer Acetate) was challenged by ANDA’s before expiry of its patents.

• Litigation followed interesting twists.• Decision was even more surprising.

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• INNOVATOR: Teva Pharmaceutical Industries Ltd. (Israel Company)

• INNOVATOR PRODUCT: COPAXONE 20 mg/mL daily SC injection (Multiple Sclerosis)

• ACTIVE INGREDIENT: Copolymer-1/ Glatiramer Acetate, A polypeptide (Alanine, Glutamic Acid, Lysine Tyrosine)

• In US it costs US$40,000 per year• ANDA filed by: Mylan Inc. (June 29, 2009) (In USA) Sandoz (December 27, 2007) (GLATOPA) Natco (After agreement with Mylan on June 07, 2008, named

GLATIMER)• Overall Patent Expiry on OB for Copaxone: September 01,

2015 (Patents issued between 1998 to 2013)• In US, it was protected by at least 10 Patents.• Teva had licensed these Patents to Yeda Research and

Development company (Israel).

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Key pointsKey points Teva markets Copaxone 20 mg/mL SC injection

in US.

Natco, an Indian Company, had agreement with Mylan Inc. on June 07, 2008 for generic Copolymer-1 prefilled syringes giving exclusive distribution rights to Mylan in US and all major markets in EU, Australia, New Zealand, Japan and Canada and option to expand.

Sandoz, a Novartis company (HQ Switzerland), is a commercial partner to Momenta Pharmaceuticals, Inc. (HQ USA).

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Story in IndiaStory in India In 2003, Natco began research for Generic Copaxone in India. Natco developed novel process for preparation of

Copolymer-1. Yeda have got Patent IN190759 (Granted on March 15, 2004)

claiming process for manufacturing a copolymer-1 fraction. On February 05, 2003 Yeda filed Divisional Application no.

IN93/DEL/2003, for product Glatiramer acetate. Natco filed Pre-grant Opposition. Natco raised issues: Obviousness and lack of Inventive step U/S 3(d) of Indian Patents

Act, 1970. Not an invention U/S 2[1(j)] Application by Yeda got Refused. As a result of agreement with Mylan, Natco Developed two

different generics by two different manufacturing processes.• Copolymer-1 (To be sold in India only)• Copolymer-1 (Export to Mylan)

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Litigation in IndiaLitigation in India In 2007, Teva and Yeda filed lawsuit against Natco in Delhi HC

asking for permanent injunction restraining infringement of IN’759 Patent. (Included all the aspects)

Asked for damages of approx. US$41,000 from Natco. Natco argued, its Product “GLATIMER” and process for its prep. is

different than IN’759, so, non-infringing. Also argued that IN’759 is invalid.

In 2007, Natco also filed a counter claim for revocation of this patent.

The grounds stated in the counter claimed included lack of novelty in view of Teiltelbaum et al., 1971 and US 3,849,550, the process of preparation of Copolymer-1 was published, the process conditions for its extraction, isolation and purification were known to a person skilled in the art, the process lacked inventive step etc.

In 2011 Natco stated that there was no possibility of settlement. In May 2012, there were issues framed, including: jurisdiction,

whether the plaintiff was the proprietor of patent no. IN190759, whether the defendant infringed this patent, whether the patent is liable to be revoked, damages, rendition of accounts etc.

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On November 03, 2012 Teva, Yeda and Teva India filed second lawsuit in Delhi HC similar to first lawsuit.

Teva argued that HC enjoyed the Jurisdiction to entertain the lawsuit because Natco has establishment in Delhi.

Natco argued, IN’759 claims are not being practiced in Delhi, instead Natco has facilities in Hyderabad.

Decision by Delhi HC (February 28, 2014): High Court found that it lacked jurisdiction and dismissed the lawsuit. Source for Decision:

https://bricwallblog.wordpress.com/2014/03/05/the-copaxone-story-in-the-u-s-and-india/

HC reviewed two processes (Natco), and noted that present suit involved process for prep. of GLATIMER supposed to be exported to Mylan.

HC noted that plaintiff should file petition precisely. All these arguments by both parties were not supported by sufficient

evidences. Final Decision by Delhi HC (August 2014): The Delhi HC disposed off the case due to absence of evidence from both

sides. Source for Decision:

http://spicyip.com/2015/04/teva-v-natco-copaxone-litigation-update.html

Further update to this is, on June 19, 2015 Natco, on their website, announced that U.S Court of Appeals for Federal Circuit has again found Teva’s US Patent No.5.800.808 for Copaxone to be invalid as indefinite. The Company awaits USFDA approval to launch the Product. 7

Story in USStory in US On December 27, 2007 Sandoz filed first ANDA. On June 29, 2009 Mylan filed its own ANDA. Teva and Yeda separately sued Sandoz (August

2008) and Mylan and Natco (October 2009) in US District Court for infringement of 09 US patents (including 07 OB Patents).

First decision by District Court: District Court issued an injunction barring Sandoz

and Mylan from marketing their generic versions of Copaxone® until September 01, 2015.

Second decision by District Court (June 29, 2012):

Judge found all 09 Patents valid, enforceable and infringed (Mylan 07 Patents and Sandoz 04 Patents).

Source for Decisions: https://bricwallblog.wordpress.com/2015/01/22/the copaxone-story-in-the-u-s-and-india-u-s-supreme-court-decision/

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Litigation in USALitigation in USA First Decision by Federal circuit (July 26, 2013): 04 Patents are valid and 05 are invalid due to

indefiniteness. Among invalid Patents, the OB Patent US5800808 was having

longest expiration date (September 01, 2015). First decision by Supreme Court (November 13, 2013): Denial of Teva’s request to STAY the Federal Circuits decision

during Appeal. Source for Decisions:

https://bricwallblog.wordpress.com/2015/01/22/the copaxone-story-in-the-u-s-and-india-u-s-supreme-court-decision/

Sandoz and Mylan were permitted to launch their generics starting May 24, 2014 (Earlier than Expiration date of US’808 Patent).

On March 31, 2014 US SC granted Teva’s writ of cert petition to review Federal Circuit’s decision.

With this, Teva petitioned to clarify the correct standard of review used by Federal Appellate courts. 9

On April 04, 2014 Teva filed application at US SC to recall Federal Circuit’s mandate which modified district court’s injunction.

Teva stated, “it will likely face irreparable harm if the mandate is not recalled”.

Second decision by Supreme Court (January 2015): The SC ruled in Teva’s favour sending the case back down for

reconsideration. Source for Decision:

https://bricwallblog.wordpress.com/2015/01/22/the copaxone-story-in-the-u-s-and-india-u-s-supreme-court-decision/

Final decision by US Court of Appeals (June 2015): US Court of Appeals struck down the Copaxone Patents for

second time. Source for Decision:

http://www.fiercepharma.com/story/us-court-nixes-tevas-copaxone-patent-again/2015-06-18

As a result ANDA makers were no longer at risk of having to pay Teva damages.

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OutcomeOutcome Teva published data in January 2014 comparing

Copaxone with Natco’s GLATIMER. This Research article supported by studies in mice was

stating the differences about biological and immunological differences between branded and generic one.

Teva has developed a new “three times a week 40 mg/mL” dosing regimen and filed supplemental NDA for the same.

Also Teva got Patent Protection on new regimen as US8232250, US8399413, US8969302 and US9155776

(Expiry: August 19, 2030) (Exclusivity: NP January 28, 2017) Also PCT application was also published (WO2011022063

including India as designated state).

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Message Take Home from Message Take Home from CaseCase

Teva’s Strategy to delay the entry of Generic Player Teva’s Strategy to delay the entry of Generic Player in Marketin Market

Most interesting thing is that Teva engaged generic player in litigation to delay their entry and at the same time was planning “product life cycle” extending strategy by developing and protecting new product (long acting version Copaxone (40 mg/ml) thrice in a day) with patents.

Teva launched new product on January 28, 2014 before Sandoz and Mylan permitted to launch their generics i.e. starting May 24, 2014 (Earlier than Expiration date of US’808 Patent September 01, 2015).

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Teva was trying every possible way to protect its blockbuster's market share by switching patients over to a new, long-acting version of the drug Copaxone.

As on April 2015, Teva had already converted 67% of patients over to New, Long acting version of the drug.

Source: http://www.fiercepharma.com/story/us-court-nixes-tevas-copaxone-patent-again/2015-06-18

Even after entry of generic players, they are unable to enjoy Copaxone market on old product, as new version of Copaxone entered in market and have acquired near about 70% of patients.

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Active Ingredient: GLATIRAMER ACETATEDosage Form; Route: INJECTABLE; SUBCUTANEOUS

Proprietary Name: COPAXONEApplicant: TEVA PHARMS USAStrength: 20 mg/mLApproval Date: February 12, 2002

Patents(09)

Invalidated patents (05)US5800808 (longest expiry date September 01, 2015)US5981589, US6048898, US6620847, US6939539 all remaining patents expire on same day May 24, 2014.Valid Patents (04)US6054430, US6342476, US6362161, US7199098

Dosage Administration COPAXONE 20 mg/mL per dayActive Ingredient: GLATIRAMER ACETATEDosage Form; Route: INJECTABLE; SUBCUTANEOUS

Proprietary Name: COPAXONEApplicant: TEVA PHARMS USAStrength: 40 mg/mLApproval Date: January 28, 2014New Product Exclusivity January 28, 2017

Patents (04) US8232250, US8399413, US8969302, US9155776All OB listed patent set expire on Aug 19, 2030

Dosage Administration COPAXONE 40 mg/mL three times per week

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First Generic Player in US marketActive Ingredient: GLATIRAMER ACETATE

Dosage Form; Route: INJECTABLE; SUBCUTANEOUS

Proprietary Name: GLATOPA

Applicant: SANDOZ Inc

Strength: 20 mg/mL

Approval Date: April 16, 2015

Thank You

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