Novartis Update, 29.03.07

[Guest guest]

The Novartis appeal resumed today. Shanti Bhushan continued his argumentthat

the ¦Â-crystalline form of imatinib mesylate resulted in an enhanced efficacy

over the free base. He pointed to the study conducted by Novartis on rats that

allegedly showed a 30% increase in bioavailability of ¦Â-crystal form of

imatinib mesylate over the free base. At this point, J. Balasubramaniam

observed that this study had been conducted on rats. He asked what conclusions

we could draw from a study conducted on rats.

Bhushan replied that rats, humans, and monkeys are warm-blooded animals, and

that one could assume that an increased bioavailability in rats could also have

a similar effect on humans.

Bhushan argued that the compound described in the current patent application

represented a two-step improvement over the prior art:

1. The selection of the mesylate salt amongst what he alleged were " thousands "

of possible salts disclosed in the 1993 patent (US 5,521,184) that had claimed

imatinib and " all pharmaceutically acceptable salts thereof " ; and 2. The

creation of the ¦Â-crystalline form of the mesylate salt. He pointed out that

the generic companies were free to manufacture any of the " thousands and

thousands " of

other possible salts; and that it was indicative of Novartis' inventiveness that

all other generic companies only wanted to copy this particular form of

imatinib.

In attempting to distinguish between incremental innovation and

evergreening, Bhushan claimed that if a salt form did not improve the drug, then

it would admittedly be evergreening, but where a salt did improve the drug, then

it could not be considered evergreening.

Bhushan then cited to a series of cases (the table of cases cited will be made

available on our website) relating to selection patents to argue that Novartis'

selection of the mesylate salt, with its specially beneficial properties, from

" tens of thousands " of possible salts. Bhushan argued that the essential

holding of these cases was that where a prior art reference discloses a large

number of possible permutations, an applicant who was able to identify a

sub-class of these that possess a characteristic that was " significantly more

advantageous " than the others was entitled to a selection patent.

At this point, J. Sridevan asked whether the requirement of showing

significant advantageousness was similar to showing a significant

enhancement of efficacy under section 3(d). J. Sridevan asked Bhushan

whether if selection patents are allowed, wouldn't 3(d) be equally valid? To

this, Bhushan replied in the affirmative.

Bhushan then introduced some documents: an article on solid state

pharmaceutical chemistry and two entries printed from the Wikipedia website, to

show the steps in drug development and to show the complexities involved in salt

selection and polymorph discovery. At this point, several counsel objected to

Bhushan's reliance on Wikipedia.

Bhushan then read the relevant portions from the Indian application to show the

potential use of imatinib to treat various disorders, including CML, restenosis,

and thrombosis. He also read the portion in the Indian application that states:

" It goes without saying that the indicated inhibitory and pharmacological

effects are also found in the free base¡Äor other salts thereof. " He further

read the portion which admitted that the activity of the mesylate salt was

described in a 1996 publication.

He then went through the USPTO prosecution history and pointed out that in the

USPTO as well, the patent examiner had initially rejected the subject

application on the grounds of anticipation and obviousness. He pointed out that

the USPTO Appeals Board reversed the patent examiner's rejection, holding that

the patent examiner had not relied on any data to show that the 1993 patent

" inherently disclosed " the ¦Â-crystalline mesylate salt.

In response to test data that Natco had submitted during the pre-grant

opposition phase which showed that the ¦Â-crystalline form was inherently formed

when the mesylate salt was prepared, Bhushan attempted to introduce an expert

affidavit dated April 2006, four months after the Patent Controller's Order. At

this point, Grover objected on the grounds that under the Indian Code of Civil

Procedure, Novartis could not introduce evidence that was not before the Patent

Controller unless it could show that despite due diligence, it could not have

made such evidence available to the

Patent Controller. Grover argued that Novartis had ample opportunity to, and in

fact did, reply to the tests that Natco had submitted, and that Novartis was now

barred from introducing new facts before the Court. The justices replied that

the objections had been noted and that the respondents could argue this at the

time of response.

Bhushan then took the Court through the data submitted by Natco, which were

submitted by two reputed institutes: the Indian Institute of Technology (Delhi)

and the Indian Institute of Chemical Technology (Hyderabad), which had confirmed

that in making the mesylate salt of imatinib in a variety of conditions, the

¦Â-crystal form was invariably produced. Bhusan claimed that this data was

entirely irrelevant, as Natco had allegedly supplied the institutes with the

¦Â-crystalline form. Moreover Bhushan claimed that the data was irrelevant

because these institutes were merely reproducing the

mesylate salt by combining methane sulfonic acid with imatinib, which would

obviously result in the mesylate salt. He asserted that this proved nothing,

and that the true test to show that Novartis' patent application was without

merit would be for Natco to have supplied the institutes with nothing more than

the '93 patent, and asked them to come up with a suitable salt with equivalent

or better bioavailability as the mesylate salt.

He then started to go through the affidavit that had been objected to, when J.

Sridevan interjected and stated that given the tenor of the affidavit, which

implied that IIT and IICT had inadequately performed these tests without taking

proper precautions, she felt that it was unfair for Novartis to rely on such an

affidavit. She stated that ruling on this would require the Court to question

the integrity of these institutes. Bhushan conceded this point.

He then relied on another affidavit that had been made available to the Patent

Controller which stated that it was unsurprising that IIT and IICT could come up

with nothing but the ¦Â-crystal form, as Natco had never had access to the

¦Á-crystal form, and that the samples that Natco had supplied to these

institutions would have inevitably been contaminated with ¦Â-crystal seeds, thus

invariably resulting in the creation of the ¦Â-crystalline form.

Bhushan then relied on some orders passed in infringement proceedings

against Natco in the UK, in which Natco had agreed not to market or sell the

¦Â-crystalline form because it would infringe Novartis' '93 patent.

At this point, the Court adjourned for the day. Bhushan will continue his

arguments tomorrow.

[correction: yesterday's update incorrectly mentioned Ranbaxy's holding

counsel's name as Ganeshan. The lawyer representing Ranbaxy was Mr. Anil

Mishra.]

In solidarity,

Lawyers Collective HIV/AIDS Unit

Anand

Chan

Divya

e-mail: <george.julie@...>