Part II: IPAB revokes Allergan's patent on eye drugs Ganfort and Combigan

Patent II [ORA/21/2011/PT/KOL]

The  application was filed against  patent No.219504 “Combination of Brimonidine and Timolol” for topical Opthalmic use. The combination is commercially marketed as "Combigan." The revocation was sought for on various grounds viz., that the Patent was obtained on a false suggestion or representation, that it was obvious, that it did not sufficiently disclose and violated Section 8 of the Patents Act, 1970. The patent was successfully revoked. 

Applicant

According to the applicant, the only advantage of the ophthalmic pharmaceutical composition of the impugned patent is that the patient is exposed to lesser amount of benzalkoniuim chloride (preservative) (BAK) during daily treatment regimen.  Prior art suggested that a combination of brimonidine and timolol may have potential in the treatment of glaucoma. The only difference between the impugned patent and prior art was the combination in a single composition and combination as individual composition.   Therefore the mere fact that Brimonidine and Timolol were administered in a single installation was not indicative any inventive step. Also, it was obvious that the amount of BAK required for a combination in a single composition would be less than that required in when the two drugs are administered separately. 

Furthermore, the complete specification of the impugned patent merely disclosed the constituents of the composition and not about the prior art that lead to the proposed composition.  The invention was a mere admixture the benefit provided by the invention is additive where each of the two drugs caused the respective therapeutic effect independent of each other. The advantages of combination of two drugs were known in the state of the art.

According to the applicant, the invention was not patentable under S. 3 (d) either. There was no data in the specification to show that the invention had an enhanced efficacy. The applicant submitted that S. 3(d) included “combination” and that the respondent had only shown the advantageous effect of combination of the two active ingredients over the individual active ingredients.The respondent ought to have shown the advantages of the single composition over the serial administration of the two drugs. 

Further, the respondent also failed to disclose to the controller the information required by Section 8 of the Act, in particular, the European counterpart of the subject Patent- which was not granted by the EPO.

The applicant also cited the US  Court of Appeals judgment in respect of the US counterpart of the impugned patent Allergan Inc vs. Sandoz where the patent was invalidated:

"There is extensive evidence in the prior art showing the concomitant administration of brimonidine and timolor multiple times per day, that the combination had benefits over the administration of either alone, and that there was a motivation to combine the two achieve better patient compliance."

Respondents 

The Respondents contended that the combination of two drugs in a fixed combination was neither taught nor

suggested by the prior art. This combination was purely the result of an inventive step. Serial administration and combination were two different modes of administration. The most common form of treatment was serial or concomitant administration of two or more different medications provided in two or more separate bottles. According to the respondent the teachings and prior art were against such combination. Thus, the respondent overcame these challenges which would have discouraged the person skilled in the art from trying the invention combination. Further, BAK was known to be toxic to cells. Therefore the ingredients in the uptake were not desirable.  The combination reduced side effects, was more effective than its components and was approved by the FDA. The counsel pleaded dismissal of the revocation application for applicant's lack of evidence and failure to discharge the burden of proof. Also, according to the respondents S.8 (2) spoke of processing of the application in a country outside India and it meant that the patentee’s compliance was complete if one foreign application was filed. The Patentee could not be asked to furnish details regarding the proceedings in all countries, contrary to the statute.

Decision 

The Board examined the Canadian, US and EPO judgments on challenges of the same patent.

It held that there was definitely a reasonable expectation of success, and thus the invention was obvious. The Board stressed on the importance of adducing evidence in pharmaceutical patent revocation cases, and that it is not always sufficient to rest on prior arts. In this case the history of the state of the art showed that the two drugs were popular, and that the two drugs were combined serially, and that the serial administration showed advantages over single therapy, and that Brimonidine BID was not unknown and in fact except for USA Brimonidine was given BID elsewhere, and that composition of two drugs in one bottle was known, and the claimed preservative (it was optionally claimed in fact in Claim 3) was used, and so the invention was obvious. This may not be so clear in other cases.  Also, the respondent failed to show enhanced efficacy of 'Intra ocular pressure' lowering effect of the invention compared to the serial application of Brimonidine and Timolol. It was held that in view of non-compliance of S.8 and obviousness of the patent, it was not necessary for the Board to even delve into the issue of S. 3(e). 

The Board came down heavily on the patentee for non-compliance of S. 8 and reiterated the necessary aspects for fulfilment of S.8: 

• It must be pleaded and proved that the lapse was with regarding applications in respect of the same or substantially the same invention
• The documents to prove this must be filed at the earliest if they are filed belatedly , costs may be imposed.
• The law does not say that the failure to furnish the S.8 details must be deliberate and willful or that the failure must be in regard to material particulars.
• It has been introduced to facilitate examinations and therefore the patentee must be candid and fair.
• The Controller cannot deal with this ground casually. They must adhere to the law nor can they dilute it. 
• The Patentee has a statutory duty under S.8, he cannot say that the particulars are available on the website. Nor can the Examiner condone the non-disclosure by saying the details are on the website.
• It is not a penal provision and the object of the law is clear disclosure and there can be no dilution.
• Rule 12(3) is part of the statute and indicates why this provision has been introduced and reflects the sentiments of the Ayyangar Committee report.
• The article “a” in the law cannot be understood to mean only one. Once the S.8(1) detailed particulars are given, the Controller may ask for the details relating to ‘a’ country. This means any. The Controller May ask for the Rule 12(3) details regarding any application.

More interestingly, the Board remarked: 

"It is no response to say that standard must be more lax today because information is available on the internet. It is no defence to say that if the patent is valid otherwise then discretion should be exercised in the respondent‘s favour. In any event it has been brought to our knowledge that EPO has rejected the patent and it has become final. On appeal USA has also rejected the patent. So it is not as if the respondent held an infallible patent. Above all, it is clear that the respondent withheld information that ought to have been furnished under Section 8. The patent deserves to be revoked on this ground alone."

The patent was revoked. No order was made regarding costs. 

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Part I: IPAB revokes Allergan's patent on eye drugs Ganfort and Combigan

Crying their eyes out?

This two part post is about the recently revoked patents owned by Allergan Inc (USA). The patents covered the drugs Ganfort and Combigan, and were used in the treatment for Glaucoma. The drugs essentially reduced pressure in the eyes. The revocation applications were filed by Ajanta Pharma Ltd, a leading Indian drugmaker. Both applications applied for a revocation on  the grounds of obviousness and non-compliance of S. 8, and were successful on the same.  The Board consistently held that non-compliance of S. 8 will attract invalidation of the patent. The decisions were pronounced by Justice Sridevan (alongwith DPS Parmar) on her last day as the Chairman of the IPAB. Ajanta Pharma previously lost a trademark infringement suit to US drugmaker Alcon in 2008, in relation to similar brand-names of drugs used in treatment of Glaucoma. 

Patent I [ORA/20/2011/PT/KOL]

Ajanta Pharma Ltd filed a revocation application against Allergan's patented eye drug to cure Ocular Hypertension(Glaucoma). Allergan had claimed to achieve enhanced treatment of ocular hypertension with reduced side effects. The IPAB revoked the patent without costs. The invention was titled “Hypotensive Lipid (prostaglandin derivatives) and Timolol composition and methods of using same" [Patent No.212695] and, covered the drugs Ganfort and Combigan. The revocation application was filed on the grounds of non-compliance of s. 8 and obviousness of the invention. 

Applicants 

The applicants stated that the respondents had a duty to disclose information as per the requirements of s. 8 and the respondents did not disclose application numbers of the patent grant applications pending in various countries to the Indian Patent Office, despite providing undertakings for the same. 

The impugned patent was a fixed combination of Bimatoprost and Timolol. The only issue which the applicants focused on was whether the combination was obvious in view of simultaneous (five minute gap) administration of these known drugs referred to as serial or adjunct monothrapy. A number of citations were relied on but the obviousness argument principally rested on the previous combined fixed dose containing Latanoprost and Timolol, each disclosed by prior publication.    The counsel  submitted that the combination of Bimatoprost [US 5688819] and Timolol[US W09730710]  was obvious because it was only a matter of conventional and routine experimentation, to arrive at the claimed combination. The applicants stated that in absence of data that compares the claimed combination to combinations known in prior art, specifically, closest prior art combinations employing Timolol and a prostaglandin analog i.e. Latanoprost, there was no inventive merit or enhanced treatment that was exhibited.  In the present matter, it was obvious that a combination of a prostaglandin analog and a beta blocker, specifically Timolol, would result in an additive enhanced effect. This motivation with a reasonable expectation of success was sufficient to render the impugned patent obvious and devoid of inventive merit.

Respondents

Respondents contended that the revocation application was time barred because the patent had been granted in 2007, and the revocation application was filed only in 2011.

The respondents attempted to prove that the therapy was an unexpected result. According to the learned counsel the structural similarities between bimatoprost and latanoprost were overemphasized by the applicants.There were many chemical compounds that are as close structurally to latanoprost as bimatoprost is, and there is no reason why one of skill in the art would have considered bimatoprost alone as the best compound for modification of a latanoprost composition.

Decision

The IPAB held that the application was not time barred. The right to revoke patent any time after the grant of patent under section 64 cannot be extinguished by applying limitation of three years under Article 137 of the Limitation Act. This will run contrary to the scheme of the patent law and the application for revocation can be filed before Appellate Board any time after the grant of a patent.

The IPAB found that Latanoprost and Bimatoprost were analogs of Dinoprost.  Latanoprost, sold as Xalatan and Bimatoprost as Lumigan, both widely recognized in the treatment for glaucoma. Prior art taught use of Timolo and Latanoprost combination. . The Board categorically held that "We do not agree with the respondent that ‘no comparison was required as Latanoprost is different from Bimatoprost and a comparison of combinations comprising the two would be akin to comparing apples to oranges, as we find both are ‘oranges’ Bimatoprost [akin to seedless orange] better than latanprost [akin to orange with seeds] to lower the IOP."   The respondents may have been easily led to believe by prior art teachings that Bimatoprost like Latanoprost is capable of producing the same result if not better.  Therfore, the choice of Bimatoprost to replace Latanoprost was obvious use of a material generally available in the market and suitable for purpose. 

With respect to S. 8, yet again, the IPAB pointed out the unpleasant term 'settled' used in communication between the Controller and the respondents in respect of settling for submission of prosecution details of any one of the major Patent Offices internationally. The Board sincerely hoped that the practice dies a natural death. The Board held that in this case there was non compliance of S. 8(2) as no information relating to
prosecution of same application in other countries was provided even when the respondent agreed to do so as whenever it became available. "In the present case the ground of the violation of section 8 has been clearly made out and we have no hesitation say applicant succeeds on this ground of revocation"

The patent was revoked. No order was made regarding costs. 

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Breaking News: GSK patents challenged: IPAB revokes one, upholds another

The IPAB recently decided upon revocation petitions of two GSK patents, applications for which were filed by Fresenius Kabi Oncology Limited, an Indian pharma company. The IPAB pronounced orders for both revocation petitions on the same day. 

The first revocation petition was filed for Patent No. IN221171 titled Quinazoline Ditosylate Salt Compounds[Patent 1], and the second one was for Patent No. IN221017 titled Bicyclic Heteroaromatic Compounds[Patent 2]. The IPAB revoked Patent 1, and dismissed the revocation petition for Patent 2. These decisions are a testament to a healthy Indian IP regime and snub US's repeated assertions that Indian IPR policies are detrimental to granting patents.

GSK disclosed Patent 2 as prior art in the complete specifications for Patent 1. Further, there were parallel revocation proceedings for Patent 2 also. The essential subject matter of the patents was Lapatinib and its compounds. These inventions were marketed as a product under the trademark TYKERB in the US and international markets, including India, and under the trademark TYVERB in Europe. 

Revocation petition of Patent 1

Contentions

The petitioner filed a revocation application on the grounds of of obviousness, S. 3(d) and, non-disclosure under S. 8 of the Patents Act, 1970. It argued that it did not require great skill to expect that the new crystalline form would have better stability. The invention was merely a result of routine testing. They submitted that the impugned invention was obvious to try with reasonable expectation of success in view of the combined teachings of the Exhibits read together. According to the petitioners Exhibit-B which was an admitted prior art, teaches the claimed compound (Lapotinib ditosylate salt) itself. Further, the use of tosylate salts has increased manifold( Sorafenib, the first CL drug in India is a tosylate salt). Thus, there existed a clear direction towards choice of tosylate.

Then, the petitioners raised an objection under S. 3(d) stating that the only improvement that invention had was that it provided superior moisture sorbing properties and enhanced stability. The two qualities were physicochemical and not related to therapeutic efficacy. Both these qualities can be expected by a person skilled in the art. Further, they argued that the respondents made no efforts to disclose the grants, rejection, abandonment of patent application in relation to the same subject matter in foreign jurisdictions, as required by law under S. 8. Thus, they were in clear violation of S. 8.

The respondents pointed out that the petitioners did not file any evidence to support their revocation petition, and on this ground alone the revocation application deserved to be dismissed. Further, the matter of selection of salts was very unpredictable and the choice cannot be made merely by trial and error. The invention was not the result of routine experimentation, there was an inventive step. In conclusion they submitted that the ditosylate salt of Lapatinib being thermodynamically more stable and less hygroscopic did not attract S. 3(d).

Also, the respondent’s defence was that it had complied with S.8, and that it had made divisional applications in respect of these patents in foreign jurisdictions. The records placed showed that the respondent submitted Form 3(details of only 3 applications) which were for the same/substantially the same invention.

IPAB decision

The IPAB held that regarding the S.3(d) bar, the respondent’s own statements and the expert’s affidavit demonstrated that this invention cannot be held to have enhanced therapeutic efficacy. Thus, the patent was revoked at the outset. 

However, the Board made pertinent observations on the issues of obviousness and S.8. Regarding obviousness, the Board held that the prior arts filed were clues sufficient enough for any person skilled in the art to arrive at these results. 

With respect to S.8, the Board indicated the principles behind the S.8 objection- how it should be raised, defended and decided. The Board observed that the petitioners did a shoddy job of making out a case of S.8. The petitioner's objection was rejected due to their failure to plead the facts and, state how the particular undisclosed application was for the same or substantially the same invention. It was not enough to just file the documents along with an affidavit. In the present case the IPAB rejected the S.8 objection only because the petitioner failed to make out the grounds of attack by stating the facts.

It came down heavily on the respondents for non-compliance of S.8. It observed that the object behind introducing S.8 was that the applicant should disclose all foreign applications so that the Indian examiner may know if it contained obviousness objections or any amendments and so on. The application outside India must be for the same invention or for substantially the same invention. Thus, the subject matter of the invention must be the same or almost the same. The IPAB has in its decisions clearly held that it is the duty of the Patentee to furnish the particulars under S.8.. A S.8 violation has severe consequences and may be a potential ground for a challenge to a patent grant. It cannot be said that the omission to comply with the requirement of Section 8 was not serious enough to affect the decision of the Controller to grant patents. The Board expressed its indignation at the Controller taking liberties to ignore and 'settle' non-compliance of S. 8 in this particular case( GSK and Asst. Controller settled that GSK will be required to submit the ‘prosecution‘ details of any one of the major Patent offices in respect of which Form 3 were to be submitted). Reiterating the Ayyangar Committee Report, the IPAB was of the opinion that if in any of the foreign offices the patentee had made a division or was required to make a division, in respect of the same or substantially the same invention or had amended or was required to amend in respect of the same invention or substantially the same invention such information regarding division or amendment would also be information required to be furnished under Section 8. 

Ultimately, the IPAB allowed the petition with costs of Rs. 50,000.

Revocation petition of Patent 2

In the second revocation petition, the application was made on similar grounds - S. 3(d), non-obviousness and S. 8. The Board upheld the respondent's pleadings with respect to S. 3(d) because the petitioners failed to show a known compound with equivalent therapeutic efficacy. With respect to obviousness, the Board after elaborate scientific examination of the prior arts concluded that the invention was non-obvious. Thus, the claimed New Chemical Entity was upheld as an invention. The IPAB expressed a similar opinion ( as in the petition discussed above) regarding S. 8 and held that violation of S. 8 was not proved by the petitioners, hence rejected this ground.

In this case, the IPAB noted that there were substantial discrepancies between the PCT application relating to this invention, and the complete specifications placed before the Board due to deletions made by the Controller, without specifying the reasons thereof. It observed that such sweeping and large scale deletions and changes when allowed must be cautiously done and not casually. 

The petition was dismissed with costs of Rs. 50,000.

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DIPP refuses CL plea for Herceptin: Health ministry requests Govt to revoke patent in public interest.

In a surprising move,DIPP has taken a decision to refuse grant of CL for anticancer biologic Trastuzumab/Herceptin as reported by Sidhartha of Times of India.

Background:

Earlier in Nov 2012 and again in March 2013 campaign for affordable trastuzumab (an association of patients and NGO’s) had urged the Govt to take appropriate measures to ensure affordability of Herceptin. Subsequently Trastuzumab was recommended for CL by the health ministry. Read our previous posts (here and here).

However after several months of deliberation and debates, the DIPP has refused a plea for CL for Trastuzumab. India, in the recent past has attracted strong criticism from several quarters for taking a pro-patient stand in its patent disputes involving Pharma MNC’s. International scrutiny on India’s IP policies, heightened when India granted its first ever CL against Bayer’s anti-cancer drug Nexavar (read Shamnad’s post here). Ergo, I believe the DIPP must have decided to take it easy with grant of compulsory license.

Prashant makes a very interesting point here; does the DIPP have the right to turn down the recommendations of the health ministry? If the DIPP and health ministry disagree on the grant of CL for Herceptin, the matter should ideally have been directed to the Prime Minister’s office or Cabinet.

Image from here

Herceptin patent status:

Apart from platform technology patents, Herceptin is protected by three patents in the US viz. US6339142, US6407213 and US7074404, all of which expire in 2019. In India however, I am aware of only one granted patent relevant to Herceptin IN205534. This patent broadly covers a method of purification where a product molecule must be separated from a very closely related contaminant molecule (acidic variant). I have covered this in detail in this post here.

What next?

Now after refusal of plea for CL, the health ministry has suggested that the government use powers vested with it under section 66 of the Indian Patents Act to revoke the patent in public interest.

Revocation of patent in public interest: Where the Central Government is of opinion that a patent or the mode in which it is exercised is mischievous to the State or generally prejudicial to the public, it may, after giving the patentee an opportunity to be heard, make a declaration to that effect in the Official Gazette and thereupon the patent shall be deemed to be revoked.

History of Section 66 shows that it has been used only a couple of times to revoke patents. The first instance was when a process patent was granted to Agracetus, a U.S. company, for genetically engineered cotton cell lines. Around the year 1997, this patent was revoked in public interest because it was viewed as being prejudicial to farmers’ rights. The Govt was of the view that Cotton is an important crop essential to national economy and should not be the subject matter of patents.

The other instance was when Indian patent 252093 was granted to Avesthagen for “synergistic ayurvedic/functional food bioactive composition”. The patent covered the composition consisting of jamun, lavangpatti and chandan to be used for treatment of diabetes, which is in effect traditional knowledge (section 3(p) of Indian patent act precludes patenting of traditional knowledge). Thus the patent was revoked as it was deemed to be generally prejudicial to public. Prashant has covered this development extensively in his blog posts here, here and here.

In both instances the patents were revoked either because their working was detrimental to public interest or because they contravened provisions of the Indian patent act. As I see it, Section 66 is a safeguard against patents (detrimental to public interest), which have been inadvertently granted by the patent office. However in this case, the fact that Trastuzumab/Herceptin is exorbitantly priced; can it be construed as being generally prejudicial to public?

CL u/s 92 versus Patent revocation in public interest

Provisions relating to grant of CL u/s 92 require that an interested person should make an application after weighing the benefits conferred by the CL against other costs like payment of reasonable royalties to the patentee, manufacturing costs etc. However these factors need not be considered by a potential biosimilar manufacturer if a patent is revoked u/s 66.

I believe that high price of Herceptin alone is not reason enough for the Govt. to invoke Section 66. It would be unfair to the patentee. Compulsory license would have been a better option in my opinion. Also if DIPP has refused a plea for CL; we wonder whether it will accept a plea for revocation of patent in public interest. It remains to be seen, what stance will be adopted by DIPP regarding this. Interesting times ahead!

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