In-depth analysis of Tarceva patent litigation

Continuing from the last post that discussed background of Tarceva patent and the single judge order rejecting Roche's application for interim injunction to restrain Cipla from manufacturing and selling generic product Erlocip, here we discuss appeal filed by Roche before the divisional bench at the Delhi High Court against the rejection order. 

C. Appeal before the Divisional bench
After briefly taking note of the key arguments pleaded by Cipla and Roche before the single judge and further briefly reviewing the observations made by the single judge, the divisional bench picked up the issue of or rather convinced to zero in over Cipla’s “polymorphs A+B” argument. This is the same argument that Cipla’s counsel tactfully pleaded before the single judge but this time the impact made was considerably far-reaching to convince divisional bench to refer compound as claimed by the IN‘774 patent as “polymorphs A+B” rather Erlotinib hydrochloride per se.

The divisional bench while taking note of Cipla’s “polymorphs A+B” argument, first and foremost, weighed whether Roche even made a prima facie case for injunctive relief. The divisional bench unequivocally agreed with Cipla’s counsel that the IN‘774 patent is a mixture of polymorph A and B forms of Erlotinib hydrochloride and Tarceva product sold by Roche is polymorph B form of Erlotinib hydrochloride and further opined that Roche not even made a prima facie case for injunctive relief as Roche do not hold patent for polymorph B form of Erlotinib hydrochloride in India.

The divisional bench insistently opined that the grant of injunction ought to be refused solely on the ground that Roche suppressed the fact that Tarceva product is polymorph B form of Erlotinib hydrochloride and the IN‘774 patent is “polymorphs A+B” of Erlotinib hydrochloride both before the Controller of Patents and the court. Keeping “polymorphs A+B” reasoning in mind, the divisional bench further noted

• That Roche tried to mislead both the divisional bench as well as the Controller of Patents that polymorph B was subsumed in “polymorphs A+B”. The divisional bench even reasoned that if Tarceva product corresponded to “polymorphs A+B” then there was no need for Roche to file a separate application for polymorph B. In short, the divisional bench entirely disagreed with Roche that polymorph B is subsumed in “polymorphs A+B”.

• That Roche failed to brought to the notice of the Controller of Patents that the IN‘774 patent is for “polymorphs A+B” of Erlotinib hydrochloride while prosecuting the application, which the divisional bench reasoned was not consistent with the requirement of a full disclosure. The divisional bench even reasoned that if the Controller of Patents was cognizant of “polymorphs A+B” fact then the Controller would have taken it in account under Sec. 3 (d) for efficacy requirement. In short, the divisional bench noted that failure to brought “polymorphs A+B” fact to the notice of the Controller raised a more than credible challenge on the validity of the IN‘774 patent.

• That Cipla raised serious doubt whether Roche even hold a patent for Tarceva product and made a prima facie case for injunctive relief under proviso of Sec. 11A (7) of the Act which states “provided that the applicant shall not be entitled to institute any proceedings for infringement until the patent has been granted.” The divisional bench further noted that Roche is not commercially exploiting the IN‘774 patent since Tarceva product corresponds to polymorph B of Erlotinib hydrochloride and not “polymorphs A+B”. In short, the divisional bench noted that Cipla demonstrated prima facie that Roche is not entitled to enforce the IN‘774 patent and cited Franz Xaver Huemer v. New Yash Engineers (AIR 2000 Del 23) where the court held that the patent which is not commercially utilized cannot be enforced.

• That the Controller rejected the IN‘507 application for polymorph B of Erlotinib hydrochloride but never took into account facts pertaining to polymorph B while deciding the pre-grant opposition concerning the IN‘774 patent. In short, the divisional bench noted the Controller failed to take into account facts about polymorph B of Erlotinib hydrochloride while deciding the patentability of the compound “polymorphs A+B” which add credible challenge on the validity of the IN‘774 patent.

• That the single judge proceeded on the fact that Roche holds a valid patent for Tarceva product but in view of the fact that Tarceva corresponds to polymorph B form of Erlotinib hydrochloride, the divisional bench noted that Roche failed to make prima case and injunction ought to be refused.

The divisional bench even laid down “must disclose” conditions for plaintiffs in order to make prima facie case for interim injunction categorically for infringement of patent covering pharmaceutical drug. First, plaintiffs have to disclose the XRD data of the product and make full disclosure of the complete specification of infringed patent. Second, plaintiffs have to make unequivocal disclosure that the patent covers the pharmaceutical drug. Third, plaintiffs have to disclose any other pending applications and issued patents pertinent to derivatives or forms of the pharmaceutical drug. The divisional bench further opined that absence of any of “must disclose” details would be a case of suppression of material facts.

The divisional bench while weighing whether Cipla raised credible challenge to the validity of the IN‘774 patent noted:

• That Cipla has been able to show that the Controller’s order to grant the IN‘774 patent was arguably deficient of the fact that the closest prior art EP‘226 teaches Erlotinib hydrochloride and therefore must be taken to have raised a credible challenge to the validity of the IN‘774 patent.
 
• That Cipla argued that substitution of methyl with ethynyl would be obvious to a person skilled in the art in light of the closet prior art Gefitinib as claimed in the EP‘226. Cipla further argued that methyl and ethynyl are normally used interchangeably in chemical arts because they share common attributes and the Controller ought of have examined the EP‘226 while examining the IN‘774 patent. Roche, relying on TSM test, argued that a person of ordinary skill in the art would find no motivation at all to replace the methyl group at position 3 by an ethynyl group. The divisional bench reasoned that these arguments never considered in the Controller’s order in detailed manner which add to raise credible challenge on the validity of the IN‘774 patent.

• That Cipla argued that the Controller confused the concepts of inventive step, anticipation and obviousness and particularly confused the tests of inventiveness with obviousness which the divisional bench reasoned are not without merit. Cipla even raised creditability of articles referred to in the Controller’s order concerning enhanced efficacy as studies were conducted or sponsored by OSI Pharmaceuticals. The divisional bench agreed with Cipla that articles published in the journals were conducted by OSI and therefore lack creditability in proving enhanced efficacy of Erlotinib hydrochloride over the closet prior art. The divisional bench opined that the Controller misunderstanding over the tests of inventiveness and failure to notice that articles proving enhanced efficacy were sponsored by OSI raised credible challenge on the validity of the IN‘774 patent.

The divisional bench lastly weighed Roche argument whether the single judge erred in applying issue of “public interest” and “pricing” in rejecting the injunction. The divisional bench, citing Sec. 83 (e) and 83 (g), disagreed with Roche and opined that the element of “public interest” is not alien to the Indian patent law. The divisional bench even agreed with the single judge reasoning that the general public access to life saving drugs assumes greater significance than the grant of injunction.

The divisional bench reasoned that the public interest in greater public access to a life saving drug outweigh the pubic interest in granting an injunction to Roche as Cipla prima facie demonstrated that Roche do not hold patent for Tarceva tablet which is polymorph B of Erlotinib hydrochloride rather mixture of "polymorphs A+B" as claimed by the IN‘774 patent, and raised credible challenge on the validity of the IN‘774 patent.

While weighing the principles that should have taken into consideration in deciding grant of injunction in a suit for infringement of a patent, the divisional bench agreed with the single judge reasoning that the IN‘774 patent need scrutiny under Sec. 3 (d) and uphold the rejection order. The divisional bench further concluded finding no merit in any of the arguments made by Roche and even ordered Roche to pay Rs. 5 lakhs to Cipla.

The divisional bench decision was considerably difficult to pen-down not because of complexity but more because it reasoned contrary to basic principles and nuances of patent law and lacked even the simplest understanding of organic chemistry and polymorphism. In my seven years of patent practice, never came across such fictitious and disastrous observations as made by the divisional bench. On most counts, the divisional bench reasoning was not only ridiculous but found no substantive support in patent law.

On the point of “polymorphs A+B” what is unfortunate that the divisional bench agreed with Cipla’s fictitious argument by merely taking note of plain English excerpt from the US‘221 patent rather understanding it technically. Even the divisional bench’s understanding of patent law was grossly questionable. While deciding patent matters, be it simple or complex, what the divisional bench cannot ignore is the fact that patent is a techno-legal disclosure and cannot be given plain English reading and further patent speaks to ordinary persons familiar with/skilled in the art to which it relates to as contrasted with being written to be understood by an ordinary member of the public. 

Not only the divisional bench erred in properly understanding excerpt from the US‘221 patent but also ignored basic facts what an ordinary person familiar with the related art would have considered while reading such the excerpt.

• First and foremost, an ordinary person would have never confused over the term “mixture” used in the excerpt as a chemical compound can never a mixture in whatever context it was used.

• Second, chemical compounds are and have a fixed ratio of atoms (chemical elements) that are held together in a defined spatial arrangement by chemical bonds. These spatial arrangements define and distinguish the phenomena called polymorph.

• Third, a chemical compound exhibit different physical property due to change in the spatial arrangement of atoms but the compound will remain the same.

In view of above facts, an ordinary person would definitely have not understood what the divisional bench understood reading the term “mixture” and would have easily acknowledged the fact that the XRD data of Erlotinib hydrochloride taught in the US‘498 patent (US equivalent of the IN‘774 patent) showed traces (peaks) of both polymorph A and polymorph B. In other words, US ‘221 patent excerpt reveals to an ordinary person that Erlotinib hydrochloride prepared according to the US‘498 patent exhibit two different spatial arrangements. Nowhere an ordinary person may have concluded what the divisional bench agreed that the IN‘774 patent is for “polymorphs A+B”. In fact, the Controller of Patents while rejecting the IN‘507 application too opined that Erlotinib hydrochloride per se and polymorph B of Erlotinib hydrochloride are same and only differ in the spatial arrangement. In short, the divisional bench observation to restrict Erlotinib hydrochloride per se to “polymorphs A+B” and considering polymorph B of Erlotinib hydrochloride and Erlotinib hydrochloride per se altogether different compounds were technically flawed and without an element of merit.

What was even more alarming that while deciding appeal the divisional bench never bothered looking into claims of the IN‘774 patent not even once and repeatedly agreed or rather seem convinced with Cipla’s “polymorphs A+B” argument merely taking note of excerpt from the US‘221 patent and the fact that Tarceva product is polymorph B form of Erlotinib hydrochloride. Here the divisional bench either seem to have no idea about “claim construction” or deliberately ignored taking note of claims of the IN‘774 patent. 

It is a well-established principle that “claim construction” is a question of law to be decided by the court and the judge must construe the claims from the view of “one ordinary skill in the art at the time of invention.” But contrary to established principle, the divisional bench construed claims reading an excerpt from the US‘221 patent dated four years after the priority date of the IN‘774 patent and that also without looking into the claims. 

Further in patent infringement suits, the court decides whether the accused product infringes the claim but rather making decision on accused product Erlocip, the divisional bench focused on whether the Tarceva product is covered within the claims of the IN‘774 patent and yet again without looking into the claims. 

Another point where the divisional bench erred and opined contrary to nuances of patent law is when the divisional bench noted that the Controller of Patents failed to take into accounts facts pertaining to polymorph B while deciding the patentability of the IN‘774 patent which add credible challenge to the validity of the IN‘774 patent. In patent law, patentability of an invention is examined over the references published before the filing date not after the filing date. Sadly, the divisional bench seems to have even lacked basic understanding of patent law.

The divisional bench even erred on the point of “requirement of a full disclosure” when it noted that Roche failed to brought to the notice of the Controller of Patents that Erlotinib hydrochloride as claimed by the IN‘774 patent is mixture of polymorphs A and B. In patent law, “full disclosure” need to comply with the requirement of enablement and best mode. The IN‘774 patent is directed to Erlotinib hydrochloride per se and to comply the “requirement of full disclosure” the patentee must disclose the information sufficiently to enable a person to make the invention and the method by which patentee performed the invention. Sadly, here too the divisional bench seems to have messed with “full disclosure” requirement by adding polymorph issue. 

In short, the divisional bench not only erred in understanding the case from the view of “one ordinary skill in the art” but also made observations which stand contrary to nuances of patent law and established judicial principles. In next post will discuss the the single judge's decision on infringement issue.

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. 

Compulsory licensing: some thoughts!

For some time now, we have been reporting on compulsory licensing case filed by Natco Pharma with respect to IN215758 for anti-cancer drug Nexavar marketed by Bayer. Natco mainly relied upon on the issues of (1) excessive pricing, (2) non-working of patent, (3) limited circulation of patented product, and (4) public requirements not reasonably satisfied. However, Natco provided no factual evidence/data to support most of its argument but merely relied on secondary sources that suggested statistical data about cases and deaths reported in India for Hepatocellular carcinoma (primary liver cancer) and renal cell carcinoma (kidney cancer), particularly in the year 2008.

In this post, we are not to discuss the merit of compulsory licensing case made by Natco but will discuss whether mere presumptive data or mere statistical data taken from secondary sources are sufficient to make prima facie case for compulsory license. 

In its application for compulsory licensing, Natco categorically highlighted that – 

• 18043 reported cases of death in India due to Hepatocellular carcinoma (numbers taken from secondary sources).
• 5733 reported cases of death in India due to kidney cancer (numbers taken from secondary sources).
• Over 24000 patients die in India every year due to different types and forms of renal cell carcinoma and hepatic cell carcinoma (numbers seem to be presumptive based on Natco’s business presence in the treatment of cancer for over 20 years).

None of the above statistical data was supported by any factual data collected from the field study/research. In India, it is more than a customary practice that drugs are prescribed by practicing doctors and that also prescribed using brand names (unlike US or Europe where drugs are prescribed using generic names). Also, in many cases, doctors have privilege to choose from various choices of prescription drugs depending on patient’s affordability quotient. For example, a doctor while prescribing medication for a diabetic patient in India does consider financial affordability of a patient and accordingly prescribe a drug to the patient. Not all patients in India are prescribed comparative expensive Vildagliptin for treating diabetes, most doctors prefer and still continue to prescribe cheaper alternatives like metformin and glipizide. 

Now let us suppose that a generic company files an application for compulsory license for Vildagliptin by mere highlighting alarming number of diabetic patients in India or high pricing of Vildagliptin, does that mean that all diabetic patients are prescribed and/or in need of Vildagliptin? Whether high pricing of Vildagliptin prevent diabetic patients from treatment of diabetes or from taking any cheaper alternatives? 

In short, mere presumptive or statistical data lacking factual evidence cannot be relied to make a prima facie case for compulsory license. Now coming back to Nexavar, it is not that all patients suffering from hepatocellular carcinoma and renal cell carcinoma go for drug medication. In many cases, patients are treated with surgery and radiotherapy. A mere presumptive or statistical data cannot differentiate the numbers where patients have undergone or likely to undergo for surgery/radiotherapy and patients are in need of or being prescribed Nexavar. 

The Controller of Patents probably must take into account some of these facets before examining the case of compulsory license or else it would be no surprise that the compulsory license may often be misused by providing presumptive and possibly deceiving numbers.

Compulsory licensing: Is presumptive evidence sufficient?

Sometime back, we posted on compulsory license triggered by Natco Pharma with respect to IN215758 claiming anti-cancer drug Nexavar, generically sorafenib tosylate marketed by Bayer. The Application for compulsory license (FORM 17) was filed on July 28, 2011 along with the details of documentary evidence as mandated under S. 84 (3) of the Act. Natco argument for issuance of compulsory license mainly relied upon on the issues that:

• patented product (sorafenib tosylate) not been manufactured in India. In other words, patented invention not worked within the territory of India.
• circulation of patented product limited to certain hospitals and metro cities. In other words, patented invention not worked to the fullest extent.
• unaffordable to 99% of patients. In other words, patented product not available at affordable price.
• requirement of patented product is far higher than what is available in Indian market. In other words, reasonable requirements of the public with respect to the patented product not been satisfied.
• patented product is found expensive in UK and US. In other words, Natco possibly trying to say anything that is expensive in UK and US will automatically be expensive in India.

Natco further provided details including regulatory approval, proposed manufacturing capacity (6,00,00,000 tablets per day) and proposed market price to a patient (INR 8,800 per month). Natco also proposed to provide free to patients who cannot afford even the proposed price. Interestingly, Natco’s application completely lacked factual evidence/data to support most of its argument rather Natco relied primarily on secondary sources collected from Mayo Clinic and Harward Center for Cancer Prevention. 

As per Indian patent practice, the Controller may either publish the application in the Official Journal (see S. 87 (1) of the Act) when a prima facie case is made by the Applicant or reject the application. In this case, the Controller found prima facie case and published the application is Issue No. 32/2011 dated August 12, 2011. 

Later Bayer petitioned for an extension to file notice of opposition and subsequently in November filed a writ petition with the Mumbai High Court challenging the Controller decision to publish the application. However, the Court refused to look into the merits of the case and disposed of the petition citing that the proper jurisdiction to file the petition would be the Delhi High Court. The Court also extended time to file opposition till November 18, 2011. 

Glivec patent dispute: the case so far Part III

Round Three: Appointment of IPAB Technical Member
After losing its first two rounds before the Madras Patent Office and the Madras High Court, Novartis third round came against appointment of technical member of newly-constituted IPAB. In April 2007, soon after the Central Government appointed former Controller General of Patents S. Chandrasekhar as a technical member on the Appellate Board, a three member quasi-judicial panel, the Madras High Court transferred Novartis’s appeal challenging the rejection order to the Appellate Board to adjudicate patentability of beta-crystalline variant of imatinib mesylate. But even before the Appellate could start hearing, Novartis debated the appointment of Chandrasekhar as technical member to hear the appeal.

Novartis protest was based on facts, that, firstly, Chandrasekhar was the Controller General at the time the application got rejected, and secondly he deposed an affidavit before the Madras High Court defending the rejection order. In short, Novartis doubted that Chandrasekhar cannot act as an impartial member of the Appellate Board and in July 2007 filed a petition before the IPAB praying for the appointment of another technical member in place of Chandrasekhar. The petition was penned around the fundamental principle of natural justice that no one can be a judge in his own cause but the appeal was dismissed by the Appellate Board relying on ‘doctrine of necessity.’ In August 2007, Novartis again approached to the Madras High Court filing a writ petition against the IPAB order allowing Chandrasekhar to hear the appeal.

In October 2007, the whole drama over the appointment of technical member saw an interesting twist when the Central Government stepped in with the proposal that the Appellate Board instead of three-member panel will now be two-member panel comprising a chairman and a vice-chairman excluding technical member. Wonder what made the Central Government to come with such a proposal. Smell like lobbying? Anyhow let’s stick to facts rather making wild guesses. 

In November 2007, the Madras High Court agreeing with the Central Government proposal allowed the Appellate Board to function without a technical member, removing Chandrasekhar from hearing the appeal. But even before the two-member Appellate Board could start hearing, Natco brought another twist by filing a special leave petition before the Supreme Court of India against the Madras High Court decision to allow the Appellate Board to hear Novartis appeal without a technical member. In January 2008, the Supreme Court agreeing with Natco issued a stay order halting the hearing before the IPAB.

While hearing the case, Justice SH Kapadia and Justice B Sundershan Reddy suggested the Central Government to consider appointing a new technical member to hear Novartis’s appeal and in October 2008, PC Chakraborty was opted and appointed as new technical member to hear the appeal and directed reconstituted IPAB to start hearing the matter on day-to-day. And finally hearing began in November 2008. 

So, precious one and a half years lost in mere constituting a three-member Appellate Board, showcasing the efficiency and sensitivity of Indian judiciary and patent system. As a patent practitioner, I always wonder.

• What made whole process dragged so long?
• Why the Appellate Board voluntarily never looked for new technical member?
• Why the Appellate Board strongly backed Chandrasekhar despite him being from non-chemistry and non-pharmaceutical background?
• Why neither High Court nor Supreme Court agreed with the IPAB’s “doctrine of necessity” argument?
• Is Indian patent system running in crisis to find a capable technical member and that also in a country with strong hold in global pharmaceutical industry?
• Whether the government need to re-look provisions and prerequisites for appointment of technical member?

These questions possibly will remain unanswered but a precious time got wasted for nothing.

Glivec patent dispute: the case so far Part II

Round Two: Madras High Court

Continuing from our earlier post where we discussed rejection of beta-crystalline imatinib mesylate application by the Madras Patent Office under S. 3 (d), we will now focus on round two where Novartis approached the Madras High Court challenging constitutional validity of S. 3 (d). Before we discuss the judgment, a quick reading of S. 3 (d) –

“mere discovery of a new form of a known substance which does not result in increased efficacy of that substance or the mere discovery of any new property or new use for a known substance or the mere use of a known process, machine or apparatus unless such process results in a new product or employs at least one new reactant.

Explanation: For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.”

The Patent Office rejection particularly involved the underlined portion of S. 3 (d) which Novartis in its appeal argued is vague, arbitrary and unconstitutional. Novartis also argued that S. 3 (d) is non-complaint with the TRIPS Agreement. The appeal was filed with the Madras High Court and was dismissed in August 2007.

TRIPS Compatibility

On TRIPS issue, the Madras High Court refused to address the question and categorically cited lack of jurisdiction to decide the validity of S. 3 (d) being in violation of Article 27 of TRIPS Agreement and further noted that the proper forum to bring this issue would be the WTO’s Dispute Settlement Body (DSB).

Constitutional Validity

On Constitutional validity issue, Novartis argued violation of Article 14 of the Constitution of India on the ground of vagueness, arbitrariness and conferring un-canalised powers on the Patent Office. During hearing, Novartis counsel particularly stressed upon that:

(1)   in the absence of proper guidelines as how to establish the enhancement of known efficacy of a known substance, the Patent Office is vested with arbitrary discretionary power to decide the enhancement efficacy.

(2)   in the absence of proper explanation and guidelines to the expression   “enhancement of the known efficacy” and “differ significantly in properties with regard to efficacy”, these expressions stand ambiguous.

Opposing counsels, however, defended use of general expressions and argued that the Legislature left these expressions for the Patent Office to apply mind and decide whether the invented drug is within or outside S. 3 (d) and further added that any fixed formula would be unwise and humanely impossible. 

The Madras High Court found none of Novartis arguments persuasive and hold S. 3 (d) not in violation of Article 14 of the Constitution of India. The High Court categorically relied upon (1) Medicinal Dictionary, and (2) Parliamentary debate to come to a decision over Novartis arguments.

While addressing Novartis argument that S. 3 (d) stands vague and ambiguous, the Court look into Dorland’s Medical Dictionary for the meaning of the expression “efficacy” in the field of Pharmacology which defines it as “the ability of a drug to product the desired therapeutic effect” where efficacy is independent of the potency of the drug. The court further noted the dictionary meaning of “therapeutic” which defines it “healing of disease – having a good effect on the body.” Taking both “efficacy” and “therapeutic” definitions into account, the Court came with the observation that the patent applicant is expected to show “how effective the new discovery would be in healing a disease/having a good effect on the body?”

The Court further limited applicability of the Explanation provided under S. 3 (d) to discoveries made in the pharmacology field. The Court particularly found that the Explanation creates a deeming fiction of derivatives of a known substance are deemed to be the same substance unless they differ significantly in properties with regard to efficacy. 

The Court finally came with the observation that S. 3 (d) along with the Explanation prescribes a test “to decide whether the discovery is an invention or not is that the Patent applicant should show the discovery has resulted in the enhancement of the known efficacy of that substance and if the discovery is nothing other than the derivative of a known substance, then, it must be shown that the properties in the derivatives differ significantly with regard to efficacy.”

In the course of addressing issue of vagueness and ambiguity, the Court surprisingly pointed that Novartis, being a pharmaceutical giant, “cannot plead that they do not know what is meant by enhancement of a known efficacy and they cannot show that the derivatives differ significantly in properties with regard to efficacy.”

The Court while addressing Novartis second argument that the Patent Office is vested with arbitrary discretionary power to decide the enhancement efficacy looked into Parliamentary debate for the Legislative object and purpose of enacting S. 3 (d). The Court observed that S. 3 (d) was included “to achieve namely, to prevent evergreening; to provide easy access to the citizens of this country to life saving drugs and to discharge their Constitutional obligation of providing good health care to it's citizens.” 

The High Court also relied upon the Supreme Court precedents recognizing that Legislature is permissible to lay down broad policy and delegate powers of rule making to the statutory authority to implement the policy, particularly in areas of specialized knowledge, where the Legislature lacks and knowledge and expertise to frame detailed rules.

In short, the Madras High Court dismissed Novartis plea challenging constitutional validity and TRIPS compatibility of S. 3 (d). The decision, however, lacked meticulousness that could have resolved uncertainty and debate concerning S. 3 (d) as the Madras High Court missed important opportunity by taking an approach which was more to defend the provision rather acknowledging and resolving the issue. If mere theoretical use of medicinal dictionary could have resolved such complex issue then neither Novartis (pharmaceutical major) nor the Patent Office (specialized body) would have ever approached the High Court just to hear dictionary meaning of “efficacy”. The Patent Office could have easily discussed and conveyed mere dictionary meaning to Novartis in their Office library. The expression “efficacy” needed more scientific and technical explanation which is obviously beyond the expertise of the Patent Office, in fact, Office of Drug Controller General of India would be the appropriate body to decide the efficacy enhancement.

In its decision, the Madras High Court restricted efficacy in terms of therapeutic efficacy for new discoveries made in the pharmacology field but the decision lacked diligent insight to take into account inventions such as polymers, liposomes, peptides, lipids, releasing agents etc. which are therapeutically inactive but broadly falls in the area of pharmacology and are used to deliver and facilitate absorption of therapeutic active agents. Is the Court expecting such inventions per se to show enhancement in therapeutic efficacy or else they altogether do not qualify for patent protection in India? In fact, we have been prosecuting more than dozen patent applications that claim classes of polymers and compounds used to deliver and facilitate adsorption of therapeutic agents and surprisingly all these applications got rejection under S. 3 (d) as the Patent Office contended that claimed subject-matter lack increased efficacy.

Ironically contrary to the High Court theoretical observations that S. 3 (d) is not vague and arbitrary and having hindsight to help Patent Office adjudicate patents applications in the field of pharmacology, the Patent Office continue to use fairly irrational discretions in applying S. 3 (d) even where it is not required. The so-called specialized body not only lacked insight to basics of pharmaceutical science but even failed to differentiate therapeutic active inventions from therapeutic inactive inventions. As of now, the Patent Office has been treating both therapeutic active compounds and therapeutically inactive agents (such as biodegradable polymers used as carriers for therapeutic active agents) exactly the same and constantly been applying S. 3 (d) rejections.

Using “efficacy” yardstick for inventions that are not therapeutically active but still falls in the area of pharmacology is correct or erroneous, not only leave considerable ambiguity but also arbitrariness on the Patent Office in deciding the same. As a patent practitioner, it is often hard to process the fact that the Patent Office asked for “therapeutic efficacy” for therapeutically inactive inventions.

Let us now summarize what the High Court observed in its judgment.

(1)   S. 3 (d) not in violation of Article 14 of the Constitution of India.

(2)   Lack jurisdiction to decide issue of TRIPS compatibility.

(3)   Inclusion of S. 3 (d) to prevent ever-greening.

(4)   Expression “efficacy” not vague and ambiguous.

(5)   Explanation under S. 3 (d) limited to discoveries in the field of pharmacology.

(6)   Patent Applicant either needs to show how effective new discovery would be in healing a disease or how effective new discovery would be in having a good effect on the body.

 

In light of facts covered so far, the expression “efficacy” contemporarily needs to be in terms of “therapeutic efficacy” which as the High Court observed can be gauged by showing effectiveness in healing a disease or showing effectiveness in having a good effect on the body. Let us end this post by putting the Court observation into analytical perspective.

(1)   Whether a toxic drug provides healing or good effect on the body? Or in other words, does the threshold to make drug non-toxic qualify for therapeutic efficacy?

(2)   Whether an unstable drug provides good effect on the body? Or in other words, does the threshold to make drug formulation stable/increase self-life qualify for therapeutic efficacy?

(3)   Whether lack of bioavailability provides healing or good effect on the body? Or in other words, does the threshold to make drug bioavailable qualify for therapeutic efficacy?

However, one point that we found hard to digest was the High Court observation that inclusion of S. 3 (d) was to prevent ever-greening. Anyone with experience working in pharmaceutical industry can easily understand that “ever-greening” is more of a business strategy for product lifecycle management to extend protection beyond original compound/patent by protecting incremental and even possibly trivial innovations. It would be completely wrong to acknowledge that ever-greening is only and all about trivial innovations. Now if we consider the Legislature has intention to prevent ever-greening then that would mean to rule out any protection beyond original patent. In that case, S. 3 (d) not only disqualifies trivial innovations but also genuine incremental innovations. And if incremental innovations are not what the Legislature wanted to exclude from patent protection then the word “ever-greening” is inappropriately used.

Glivec patent dispute: the case so far Part I

The high-profile Glivec patent dispute in which Novartis challenged the Madras (Chennai) Patent Office decision of rejecting its patent application for beta-crystalline version of imatinib mesylate under vaguely interpreted S. 3 (d) is now been heard in the Supreme Court of India. The dispute has been in print media more for the wrong reasons and widely reported as controversial because of NGOs vociferous criticism of Novartis’s legal recourse but for patent practitioners the case has been of significant concern to see how judiciary meticulously approaches to interpret S. 3 (d), more particularly efficacy. Despite the case is been heard by the Supreme Court, there had been various news floating across the internet and print media arguing that win for Novartis could have a “devastating impact” on access of medicines in the developing world and would increase the drug pricing drastically. Also, the case has keenly been followed by pharmaceutical sector in India outcome of which could outline the future of Indian pharmaceutical industry. In short, the Glivec dispute brought multifaceted debates in India (even across the border) but in this post we will try focusing more on facts rather falling trap to ‘vested’ debates. 

First Round: Madras Patent Office

In 1993, Novartis filed a patent disclosure for revolutionary anti-cancer molecule imatinib which was first drug in the class of tyrosine kinase inhibitors to reach the market. In July 1997, Novartis filed another patent application disclosing methanesulfonic acid (mesylate) addition salt of imatinib in two distinct crystalline variants: alpha and beta. During studies, Novartis found beta-crystalline to be more stable, commercially viable variant to manufacture Glivec oral tablets. 

In 1995, India became a signatory member of the World Trade Organization (WTO) and agreed to grant patent protection for pharmaceutical products more as a compulsion under TRIPS agreement. India further being a developing country got 10-years transition period to implement patent protection for drug products but at the same time had obligation to accept patent application under “mail-box” provision. The “mail-box” provision paved way for global pharmaceutical companies to file patent application for their drug products in India. 

Imatinib been a pre-1995 disclosure was not eligible for patent protection in India. In July 1998, Novartis filed application 1602/MAS/98 for alpha and beta crystalline variants of imatinib mesylate which stayed in “mail-box” till 2005. In November 2003, the Controller granted first Exclusive Marketing Right (EMR) to Glivec for a period of 5 years. The EMR gave Novartis the right to exclusively sell and distribute the drug in India which Novartis attempted enforcing against the generic manufacturers by filing suits in the Madras and Delhi High Court. In January 2004, the Madras High Court granted Novartis an interim injunction restraining generic manufacturers from manufacturing, selling, distributing or exporting the generic drug. The injunction was later made absolute by Justice R. Balasubramanian. In August 2004, Novartis voluntarily filed divisional application 799/CHE/2004 for alpha crystalline variant. Later in December 2004, Justice Deshmukh of the Delhi High Court disagreed with the Madras High Court decision to allow injunction and refused to grant temporary injunction to Novartis.

In 2005, the patent act was amended and Novartis application for beta-crystalline variant came up for examination. The 2005 amendment also provides that EMRs would either be replaced by patents (if granted) or cancelled (if applications were rejected). Later in 2005, various representations for pre-grant oppositions were made by Cancer Patients Aid Association and generic manufacturers for beta-crystalline variant and the application was rejected by the Madras (Chennai) Patent Office on January 25, 2006 and subsequently cancelling the EMR. The rejection was primarily made on the grounds of:

• Lack of novelty/Anticipation
• Lack of inventive step
• Non-patentable subject matter u/s 3 (d)
• Wrong priority

In May 2006, Novartis filed writ petitions before the Madras High Court not only against the rejection order but also challenging the constitutional validity of S. 3 (d) which was later converted into appeals. In April 2007, the Central Government notified operationalisation of the Intellectual Property Appellate Board (IPAB) subsequent to which appeals got divided between the High Court and the IPAB, earlier judging the constitutional validity and later to decide the patentability of beta-crystalline imatinib mesylate. 

In March 2009, Novartis’s divisional application for alpha crystal variant of imatinib mesylate also got rejected by the Madras Patent Office following representations for pre-grant opposition made by generic manufacturers. The rejection was primarily made on the grounds of:

• Lack of inventive step
• Lack of utility
• Non-patentable subject matter u/s 3 (d)
• Insufficient disclosure

To this point, the whole Glivec patent dispute remained with and was decided by the Madras Patent Office which can briefly be summarize into following key points covered so far.

1. Imatinib per se not patented in India.
2. Imatinib mesylate per se not patented in India.
3. Application for beta-crystalline variant of imatinib mesylate stand rejected.
4. Rejection order for beta-crystalline appealed before the Madras High Court.
5. Appeal against rejection order for beta-crystalline transferred to newly formed IPAB.
6. Application for alpha-crystalline variant of imatinib mesylate rejected.
7. Madras high court only to decide constitutional validity of S. 3 (d).
8. IPAB only to decide patentability of beta-crystal variant of imatinib mesylate.

To put it more simple, generic manufacturers are safe, in fact, are free to manufacture and sell tablets which may contain either of the following: imatinib free base, imatinib mesylate, or any other form of imatinib mesylate. In addition, following the patent office decision to reject patent applications for both alpha and beta crystalline variants, generic manufacturers are also free to use alpha crystalline variant but the only area of concern remains if generic manufacturers are using or intending to use beta-crystalline variant since the rejection order got appealed by Novartis.

Technically, none of generic manufacturers is barred from manufacturing and selling generic imatinib mesylate tablets; it is just the specific crystalline form, i.e. beta-crystalline variant which need attention as long as Novartis exhaust all its legal options. And even if Novartis wins the case, it would be a mere child’s play for competitively talented generic manufacturers to avoid using or designing-around beta-crystalline variant. In fact, inclusion of S. 3 (d) was advocated on the fact that inventing new polymorphic form involves no inventiveness (human ingenuity) and is mere more of a routine practice within the industry. So what’s the big deal if Novartis receive patent protection for specific beta-crystalline form of imatinib mesylate? In patent domain, such patent are considered extremely narrow patent.  

In light of facts covered so far, the argument that the win for Novartis would adversely impact the drug supply and pricing stands dubious, misleading, and motivated to malign spirit/nuances of patent system in India. In fact any generic manufacturer using imatinib mesylate other than beta-crystalline variant does not need to have even a slight concern about Novartis patent dispute.