Thursday, February 19, 2009

Minor Modification & Structural Similarity Not Sufficient to Establish Obviousness - II

Continuing from our earlier preliminary post on Erlotinib pre-grant opposition, we now discuss the pre-grant opposition judgment in detail. Following Natco’s pre-grant opposition, the Assistant Controller prominently discussed the obviousness arguments in detail. Natco argued that the compound of the present invention is an obvious derivative derived from 4- Anilinoquinazoline nucleus and such compounds have been covered by earlier patents EP 0566226A1, EP0602851A1, EP0635507A1, EP0635498A1, EP0520722A1 published before the priority date of the present invention. Natco further argued that combination of simple functional groups like alkoxy, alkyl, alkynyl, halo to already known basic nucleus or compound is obvious to a person of ordinary skill in the art. Interestingly, while arguing obviousness Natco provided a chemical structure and argued that Erlotinib is easily derived from the structure when a person skilled in the art made obvious substitution of R1 with CH3CH2CH2O (2-methoxy), R2 with CH3OCH2CH2O (2-methoxyethoxy), R3 with H (hydrogen) and R4 with 3-ethynyl (not one, not two there are four conditional substitutions of functional group to render Erlotinib obvious). However, Natco nowhere argued that what may have motivated the person skilled in the art to arrive at obvious substitution of R1, R2, R3 and R4. Natco further broadly argued that prior art compounds are structurally similar to Erlotinib and hence rendering Erlotinib obvious. In counter statement, the Applicant (Pfizer) argued that Natco created their own chemical structure to establish that the claimed compound is an obvious derivation of said structure which is actually not found in any of the prior art citation. Applicant further emphasized inventiveness of substituting an “ethynl group” at methane position of phenyl group. After hearing both Natco and Pfizer (Applicant), the Controller decided that Natco probably failed to properly evaluate the strength of the invention. He further concluded that sometimes the modification in the prior art technologies which appear to be minor may bring great revolutions in the world which could never be predicted by the society of intellectuals. Also adding that a structural similarity as deduced by Natco for a compound (Erlotinib) having great medicine value may not be accepted to establish Erlotinib as obvious. During hearing Natco also brought section 3(d) argument but the Assistant Controller rightly argued that once the invention has been found inventive (non-obvious) it cannot be held non-patentable under section 3(d).

Natco also challenged the issuance of patent on the ground of insufficient disclosure arguing that the Application failed to disclose polymorphic form of Erlotinib. Natco further added that it is very pertinent and relevant to have the details of the current form for the product claimed in the current application. In reply, Applicant strongly objected Natco arguments stating that the object of the invention was to provide a potent EGFR inhibitor Erlotinib and not to provide polymorphic form of the compound of the present invention. The Assistant Controller without any further thought rejected Natco’s insufficient disclosure argument. We, in fact, wonder what can be more frivolous argument than Natco’s objection for insufficient disclosure asking XRD data in the patent application covering the active drug substance (not polymorphic form).

We finally end our post with some intriguing questions for our readers to think about. Why Cipla’s counsel argued the Court to disregard the IPO finding in favor of Roche? Why Cipla argued that the Controller merely addressed arguments on “novelty” and did not even considered obviousness arguments during the pre-grant opposition? Are such arguments misleading to the Court? Was it intentionally done to deceive the Court proceedings? Or was it done to tarnish pre-grant opposition judgment of the Controller?

19 comments:

  1. Anonymous11:10 AM

    Intriguingly informative post!

    Thanks

    ReplyDelete
  2. Dear Varun,

    I do not agree with you that Natco did not argue motivation for person skilled in the art to arrive at substitution of R1, R2, R3, and R4. Natco had submitted document entitled BURGER'S MEDICINALCHEMISTRY AND DRUG DISCOVERY, Fifth Edition. This document clearly states that cyanide and ethynyl groups are bioisosteric equivalents and therefore interchangeable. Bioisosterism is the phenomenon exhibited by substituents or groups with similar physical or chemical properties that impart similar biological properties to a chemical compound. Patent no. EP 0566226 covers N-(3-cynophenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine (compound 1)and also covers Gefitinib.The difference between the Erlotinib and the above mentioned compound 1 is of substitution at meta position of Phenyl ring.
    In the light of above definition, groups -CN and -C≡CH (ethynyl) have same biological activity upon the substitution to phenyl ring. So a person skilled in the art can easily arrive at this substitution using the concept of Bioisoterism and this concept is well known in the field of medicinal chemistry. Therefore what I feel, a scientist in medicinal chemistry (person skilled in the art) can easily arrive at this obvious substitution. I hope you will reply to my argument. Hoping for a healthy debate.

    ReplyDelete
  3. Anonymous11:50 AM

    This is a great post!!!

    I was just wondering that whether the conclusion, as worded by you and reproduced below, of the Assistant Controller is hinting towards 'SELECTION PATENTS'. What do you think?

    "He further concluded that sometimes the modification in the prior art technologies which appear to be minor may bring great revolutions in the world which could never be predicted by the society of intellectuals"

    Regards.....

    ReplyDelete
  4. Great! Thanks Varun for this post!

    Your blog is adding great source for us to understand India’s patent office approach to evaluate pharma inventions. This judgment is a developing sign of India’s patent law to merit bird-eye innovation.

    ReplyDelete
  5. Great! Thanks Varun for this post!

    Your blog is adding great source for us to understand India’s patent office approach to evaluate pharma inventions. This judgment is a developing sign of India’s patent law to merit bird-eye innovation.

    ReplyDelete
  6. Anonymous2:48 PM

    Really its a great post.In my view if we concider the person skilled in art i.e a medicinal chemis,it is a regular practice to substitute the other group which can be help in establishing a new compound as said by Mr.Ajay Chauhan. So the controller conclusion i.e.sometimes the modification in the prior art technologies which appear to be minor may bring great revolutions in the world which could never be predicted by the society of intellectuals".so its really creat a ambiguity question in mind of everyone.

    ReplyDelete
  7. Dear Anonymous

    i agree with you that the compound (Erlotinib) was novel but can we consider the substitution of ethynyl group at meta position of phenyl ring an inventive step? A medicinal chemist can easily arrive at this obvious substitution as i said in my earlier comment.

    ReplyDelete
  8. Varun Chhonkar1:25 PM

    Hi Ajay,

    Thanks for your comment. Apart from being an avid blogger I am also a working professional often busy with commitments so couldn’t find sufficient time to reply back to your comment. Often I do not prefer replying any comment that lacks fundamental understanding of any aspect of patent law but still considering your interest in the issue I will be happy to reply your comment.

    To start with, let us discuss motivation. To provide with the case of “motivation” one has to provide evidence of a teaching or suggestion to make a particular modification to the prior art. Motivation can be implicit or explicit but do require an evidence to make a genuine case. Now coming back to Erlotinib, let us first discuss what is covered and exemplified by Gefitinib patent (i.e., EP0566226). Gefitinib patent claims markush 4-anilinoquinazoline derivative structure (a backbone structure shared by both Gefitinib and Erlotinib) and teaches/exemplifies over 80 compound structures in examples.

    Notably, in most of the exemplified examples the preferred group substituted at anilino ring is 3’-methyl which is enough reason to assume that a person skilled in the art would easily be motivated to work around Gefitinib patent teachings with 3’-methyl group attached to the anilino ring (not with cyano group). However, apart from 3’-methyl group, other exemplified groups substituted at anilino ring include 3’-bromo, 3’-chloro, 3’-trifluoromethyl, 4’-fluoro-3’-trifluoromethyl, 4’-fluoro, 3’-chloro-4’-fluoro, 3’-chloro-4’-cyano, 3’, 4’-dichloro, 3’-nitro, hydrogen, 4’-chloro-3’-nitro, 4’-fluoro-3’-nitro, 3’-acetyl, 2’, 6’-difluoro, and last but most important for our discussion 3’-cyano.

    Example 73 of Gefinitib patent do suggest 3’-cyano group attached to anilino ring but nowhere suggest substitution of 2-methoxy-ethoxy group at 6- and 7-positions of quinazoline ring. I do accept that 6, 7-di-(2-methoxyethoxy)-4-(3’-cyanoanilino) quinazoline is broadly covered within the scope of Gefitinib patent (when anilino ring is substituted by 3’-cyano group and 6- and 7-positions of quinazoline ring is substituted by 2-methoxyethoxy group) but the what is more important to acknowledge is that this combination is nowhere exemplified and taught (or even suggested) in the examples.

    Since Gefitinib patent covers a markush structure that may have easily have more than ten thousands (or even more than that) of compounds when substituted with combination of R1 and R2 values but only exemplifies over 80 compounds in examples with no example providing teaching for 6, 7-di-(2-methoxyethoxy)-4-(3’-cyanoanilino) quinazoline, one cannot argue that Gefitinib patent provide motivation for conditional substitution of 2-methoxy-ethoxy group at 6- and 7-positions of quinazoline ring and 3’-cyano at anilino ring and later using bioisosterism to replace cyano with ethynyl group. Surely one has to do sufficient and laborious research to figure out therapeutic combination of R1 with 2-methoxy-ethoxy group at 6- and 7-positions of quinazoline ring and R2 with 3’-cyano group at anilino ring and obviously for me it is not a mere substitution (and neither for Indian Patent Office).

    According to Natco’s argument (as well as yours), substitution of 2-methoxyethoxy group at 6- and 7-positions of quinazoline ring and 3’-ethynyl group at anilino group is obvious in light of Gefitinib patent which factually do not even exemplified or provided motivation for conditional substitution of 2-methoxyethoxy group at 6- and 7-positions of quinazoline ring and 3’-cyano group at anilino group. It may be easy/acceptable for Natco (that also without doing research) to come out with conclusion based on Gefitinib patent teachings that to substitute 6-and 7-positions of quinazoline ring with 2-methoxyethoxy (selected from many other substituent groups) and substitute anilino ring with 3’-cyano (selected from many other substituent groups) and then applying bioisosterism to replace cyano with ethynyl group is obvious to a person skilled in the art.

    Even for you and me to do such analysis is easy because we have the privilege of knowing structure of Erlotinib to do reverse-engineering in Gefitinib patent to find out the closest structure which, in fact, not even exemplified!

    Regards,
    ---
    VC | Patent Circle

    ReplyDelete
  9. Varun Chhonkar1:34 PM

    Hi Anonymous,

    I would not say that Erlotinib is an explicit case of selection patent because substitution of ethynyl group at anilino ring is not covered by Gefitinib patent disclosure but what is commendable that the Indian Patent Office judged it perfectly. Let’s see what the Delhi High Court has to say about it?

    Kind Regards,
    ---
    VC | Patent Circle

    ReplyDelete
  10. Varun Chhonkar1:40 PM

    Hi Brian,

    Yes we are trying to merit innovation but the only concern is whenever our patent practice tries to take a step forward there are many who keep pulling two steps backward.

    Regards,
    ---
    VC | Patent Circle

    ReplyDelete
  11. Varun,

    A great applaud for the befitting reply to all the comments.
    I totally agree with your replies and hope that those on the other side of the deck understand your thoughts.....

    ReplyDelete
  12. Anonymous1:53 PM

    Varun,

    As you are [no doubt] aware, at least 2 US companies have filed P.IV in the US on this same compound.

    I believe that at least one of them has filed a p.IV against the compound patent [in debate here] and not just the HCl salt patent.

    Any thoughts/ views on the same?

    Regards,
    Frequently Anon.

    ReplyDelete
  13. Varun Chhonkar7:41 PM

    Mere filing paragraph IV certification for erlotinib compound patent has nothing to do with validity and patentability until and unless compound patent is knocked down in litigation. Only filing of paragraph IV for erlotinib compound patent doesn’t mean that patent is weak, it is still very immature to make such statement. In past, there had been innumerous patent litigations where drug compound patents are challenged (para IV) but not many can be invalidated. In many cases, generic challengers just for sake of FTF status move quickly with paragraph IV certification rather than on the ground of concrete evidences.

    Kind regards,
    ---
    VC | Patent Circle

    ReplyDelete
  14. Anonymous2:00 PM

    Varun,

    While I appreciate your feedback, I don't recall calling the Erlotinib compound patent as weak.
    Hence, calling a statement as immature, when the statement itself was not made, needs re-thinking.

    Regards,
    Frequently Anon.

    ReplyDelete
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