Saturday, November 17, 2012

In-depth analysis of Tarceva patent litigation

On September 07, 2012, the Delhi High Court in F. Hoffmann-La Roche et al v. Cipla Ltd. (No. 89/2008) ruled Indian Pat. No. 196774 jointly owned by OSI Pharmaceuticals and Pfizer for anticancer drug compound Erlotinib hydrochloride valid but not infringed by Cipla’s generic product Erlocip. In his painstakingly 275-page decision, the single judge, Justice Manmohan Singh opined that the generic product Erlocip manufactured and sold by Cipla contains polymorphic B variant of Erlotinib hydrochloride as active ingredient and hence do not infringed the compound per se claims of the IN‘774 patent. This case has avidly been followed by the life sciences industry with utmost interest and concern for guidance on how pharma patents will be adjudicated at judiciary level. It is likely that the reasoning of this decision may add yet another disappointment and further dismay for the pharmaceutical companies in enforcing their patents in India. Below, we discuss the decision in detail and meticulously examine the impact this case may have on patent protection for drug products in India.

A. Background of Tarceva patent
In March 1996, Pfizer and OSI Pharmaceuticals jointly filed the Indian Pat. App. No. 537/DEL/1996 for drug molecule Erlotinib hydrochloride and claimed priority from their corresponding US App. Sr. No. 08/413,300 dated March 30, 1995. The Application was originally filed with 27 claims but reduced to two claims during the examination proceedings and subsequently was placed in order for issuance on February 23, 2007.

On April 10, 2007, Natco Pharma filed an opposition against the issuance of the IN‘774 patent under Sec. 25 (1) of the Act (pre-grant opposition) on the grounds of obviousness and insufficient disclosure.

  • Natco cited various European patent disclosures as prior art including Gefitinib patent disclosure but to substantiate the obviousness argument, Natco submitted a hypothetically created structure of 4-anilinoquinazoline nucleus with conditional substitution of four functional groups, namely, (1) 2-methoxy, (2) 2-methoxy ethoxy, (3) hydrogen and (4) 3-ethynyl on record to assert Erlotinib structure as obvious compound. However, Natco never provided any reasoning on what may have motivated the person skilled in the art to arrive with conditional substitution.
  • Pfizer refuted Natco’s obviousness arguments and argued that the hypothetical structure is not found in any of the cited prior art disclosure and further emphasized inventiveness of substituting an “ethynyl group” at methane position of phenyl group. After hearing both Natco and Pfizer, the Controller found Natco’s obviousness argument unpersuasive and opined that mere structural similarity not sufficient to establish obviousness.
  • Interestingly, Natco’s insufficient disclosure was neither based on lack of enablement requirement nor lack of best method requirement but rather odd ground that the application lack XRD data of the claimed compound. Pfizer refuted Natco’s argument and argued that they disclosed all the required information for a person skilled in the art to understand the invention and further emphasized the object of the invention was to provide potent EGFR inhibitor and not to provide polymorphic form of Erlotinib hydrochloride. After hearing Pfizer and Natco, the Controller found Pfizer’s argument persuasive and opined that the applicant has described the invention sufficiently to be reproduced by a person skilled in the art.
  • Natco further raised Sec. 3 (d) objection during the hearing but the Controller strongly opined that once the invention has been found inventive, the invention cannot be held un-patentable under Sec. 3 (d) of the Act. 
On July 04, 2007, the Controller decided the pre-grant opposition and issued the IN‘774 patent for Erlotinib hydrochloride.

In another related development, OSI Pharmaceuticals filed a separate Indian Pat. No. IN/PCT/2002/507/DEL for polymorphic B variant of Erlotinib hydrochloride on May 14, 2002. The IN‘507 application is equivalent of the US Pat. No. 6,900,221 currently listed with the Orange Book that, in short, indicates Roche marketed Tarceva tablets contains Erlotinib hydrochloride matching the spatial arrangement of polymorphic B variant.

In January 2008, Cipla filed a pre-grant opposition against the issuance of patent for polymorphic B variant of Erlotinib hydrochloride on the grounds of insufficient disclosure and un-patentable under Sec. 3 (d) of the Act and the IN‘507 application was subsequently rejected on December 15, 2008. In this post will not discuss the rejection order in detail but one point that is worth highlighting here (and will be used later in our analysis) that the rejection of the IN‘507 application was primarily reasoned on the Controller’s opinion that compound Erlotinib hydrochloride per se and polymorphic B variant as disclosed in the IN‘507 application are same and only differ in the spatial arrangement of the molecule.

B. Suit for injunctive relief
In January 2008, various print-media newspaper reported Cipla planning to launch generic product Erlocip and that prompted Roche to file a civil lawsuit in the Delhi High Court on January 19, 2008 seeking an ex-parte interim injunction against Cipla. In reply, Cipla filed counterclaim to challenge the validity of the IN‘774 patent.

  • To contest validity, Cipla argued claims of the IN‘774 patent lacks inventive step over prior published European patents that disclose similar quinazoline nucleus structure (including Gefitinib) and un-patentable under Sec. 3 (d) as Erlotinib is a mere derivative of Gefitinib. Cipla further argued that attempt to patent Erlotinib is ever-greening and contrary to public policy and against the statutory language employed in Sec. 3 (d). 
  • To strengthen the validity challenge, Cipla questioned the IPO decision to grant patent for Erlotinib hydrochloride and reasoned that the issuance of the IN‘774 patent contrasted earlier IPO decision to decline issuance of patent for Gefitinib compound which share same 4-anilinoquinazoline nucleus structure as that of Erlotinib hydrochloride.
  • While responding to injunction motion, Cipla argued that the injunction not be issued on the grounds of non-working of the IN‘774 patent and public interest with respect to pricing and affordability. 
On March 19, 2008, the court refused to grant interim injunction to restrain Cipla from selling the generic product Erlocip relying on the principles laid down in the American Cyanamid Co. v. Ethicon Ltd. The court found that Cipla’s arguments raise credible challenge to the IN‘774 patent and refrained from conducting a mini trial at the interlocutory stage. However, while taking note of Cipla’s argument that Erlotinib is nothing but a mere derivative of Gefitinib and lacks inventive step, the court went down critical on the IPO for taking formalistic approach in applying TSM test to examine the non-obviousness and further criticized the Controller for non-application of mind with respect of efficacy requirement under Sec. 3 (d). Further, the court weighed the “balance of convenience” in favor of the public interest to have access of a life saving drug rather granting injunction to affirm patent during pendency of infringement action but instructed Cipla to maintain account of sales and annual sales statement (duly authenticated by chartered accountant) and to furnish an undertaking to pay damages in case the IN‘774 patent found to be valid. 

It is interesting to note that Cipla’s counsel never pleaded non-infringement of claims of the IN‘774 patent but tactfully and categorically brought reference of the US’221 patent during the pleadings to construct a mirage-like effect over the issue of Erlotinib hydrochloride. While referring to excerpt from the US‘221 patent Cipla’s counsel argued that claims of the IN‘774 patent is a mixture of polymorph A and B forms of Erlotinib hydrochloride and further argued that Tarceva product sold by Roche is polymorph B form of Erlotinib hydrochloride. In short, Cipla’s counsel persuaded the judge that Tarceva sold in India is covered by the IN‘507 application which is corresponding of the US‘221 patent. Though this argument was nowhere a deciding factor is refusing interim injunction but was a master-stroke and game-changer strategy by Cipla that worked later in deciding infringement issue.

Though this suit was focused on the issue of interim injunction and the judge, Justice Ravindra Bhat, was considerably diligent in deciding “balance of convenience” but lacked same level of diligence while deciding on Cipla’s credible challenge on the validity of the IN‘774 patent. Cipla’s validity challenge was constructed around the rationale that Erlotinib is mere derivative of Gefitinib and should not be issued patent since the IPO declined to grant patent for Gefitinib. Roche refuted Cipla’s arguments using more or less same arguments that were made during the pre-grant opposition proceedings and were found persuasive by the IPO to grant patent. Even the court agreed that Cipla neither brought new prior art document nor new argument that was not taken into account during the pre-grant opposition proceedings. Further, the court emphasized that at the stage of interlocutory injunction defendant need not prove actual invalidity but must put forth a substantial question of invalidity to show that the claims at issue are vulnerable. In short, the court opined that substantial question of invalidity requires less proof than the clear and convincing standard to show actual invalidity.

On the point of “substantial question of invalidity” what is perplexing that the court agreed with Cipla on the “mere derivative” argument without even weighing the correctness of derivative correlation between Erlotinib and Gefitinib. Merely because Cipla’s counsel raised “mere derivative” argument, the court castigated the IPO for granting the IN‘774 patent but how without even explaining “what is derivative” and “whether Erlotinib qualify as Gefitinib derivative” the learned judge concluded that the IPO overlooked “mere derivative” insight during the pre-grant opposition proceedings and patent issued is vulnerable. It seems to be that whole premise of “substantial question of invalidity” was merely and plainly influenced by Cipla’s “mere derivative” theory as there was neither any documentary evidence to support it nor the court weighed the derivative correlation. This decision is, unfortunately, creating a dangerous precedent where an unsubstantiated argument may qualify as “substantial question of invalidity”.

As expected, Roche filed an appeal against the decision on April 11, 2008. In next post will discuss the divisional bench decision on Roche appeal and the Delhi High Court decision on infringement issue.