Timely post on litigation and polymorphism: Case study with Celgene’s Revlimid

Hi there, folks.  It has been a while since I blogged.  I decided that I would continue once again and share some of the references that I came across while perusing the journals, while using the free blog-hosting services that are available.  This particular post was something I came across while looking at some stocks online.  I was searching taking a look at Celgene (CELG) stock and came across this discussion regarding the tricky world of patent litigation and more specifically, its application to matters concerning crystal form and polymorphism.  Having worked both sides of generic and brand-name pharma, I am interested in how this case will work out.

I know that this article’s subject matter is on the periphery of what is involved in developing a process.  I have worked on crystallizations and been concerned with polymorph control, so this is a textbook case, that is current, about patent coverage, polymorphs and generic competition.

Revlimid  is a thalidomide analog that is used for the treatment of multiple myeloma.  Apparently, as commonly occurs in the pharmaceutical industry, one tries to write the patents to cover as many crystal forms as you can and hope this delays the generic pharmaceutical companies from swooping in with a patent submission for a form you forgot to cover.  Apparently, with Atoravastatin (Lipitor), the patent coverage for the amorphous form was not covered and this was exploited to bring a generic version to market quicker, circumventing the existing patent.

Structure of Celgene's Revlimid

Structure of Celgene’s Revlimid

The issue is that patent US Patent 7,465,800 describes 8 polymorphs, A-H which include which include three unsolvated forms, the hemihydrate, a dihydrate, an acetone hemisolvate, an acetonitrile solvate, and a dehydrated form of the dihydrate.  The hemihydrate is the only one covered by the patent.  The patent covering composition of matter describes an anhydrous preparation of the drug substance.

Natco and Activis are taking a shot at challenging Celgene’s patents on Revlimid.  It is important to note that Revlimid is providing Celgene with 67 % of its 2013 revenue, so this is a fight worth fighting for.  Celgene has 11 patents covering Revlimid, so it will not be an easy task for a generic company to navigate around them.

It is a really well-written article and I thought I would share.  Stay tuned for more.

Celgene: Do The Revlimid Polymorph And Use Patents Matter?

Follow me on Twitter: @DevelopProcess.

Feel free to comment on this interesting story.

Update:  Celgene won its case in court.  Found this morning on Barron’s.

 http://blogs.barrons.com/stockstowatchtoday/2014/05/20/celgene-won-won-revlimid-patent-hearing/?mod=BOLBlog

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7 thoughts on “Timely post on litigation and polymorphism: Case study with Celgene’s Revlimid

  1. In addition to the Revlimid patent case, there was an interesting development yesterday regarding Gleevec. Novartis composition of matter patent expires July 2015 but they have a polymorph patent on the mesylate salt that does not expire until 2019. (This is the famous patent at the center of the controversy in India a couple of years ago). Anyway, Novartis settled out of court yesterday with Sun Pharma that will allow Sun to sell their generic version of Gleevec in the US starting on Feb 1, 2016. So Novartis was willing to settle for only another 6 months of market exclusivity by this agreement with Sun. Just another example where polymorph patents don’t hold up generic competition for long – although the 6 month extension is worth $1 B in sales to Novartis, so the polymorph patent was in fact very valuable.

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  2. What I would like to know is why drug companies aren’t patenting all possible forms. In the Revlimid case, there are different polymorphs mentioned. Is it too much to ensure that those forms are protected ? I will have to look into that. Unless one of my readers knows the answer.

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    • Pfizer patented many polymorphs and salt forms of atorvastatin – 15 or 20 if I remember correctly. Their form patent is valid until 2017 but clearly did not stop the generics from getting ANDA approval with their formulations of amorphous drug. Drug companies are actively patenting polymorphs and salt forms but it has become more difficult since the applicant now has to show utility as well as novelty – that is, what value does it have over the patented form, such as better stability, bioavailability, or processability. So a company has to be a little more selective over what it tries to claim in a form patent. In the Revlimid ‘800 patent, Celgene describes 8 forms but only claims the hemi-hydrate. I don’t know if they tried to get claims on the other forms, but in the end they have a claim on the form they use in marketed Revlimid.

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  3. I guess that always leaves a loophole if you don’t cover all the forms, but it makes perfect sense on why you wouldn’t cover them all as it requires. Like you have mentioned, extra effort would be required to determine if one form has better stability, bioavailability or processability. I might not go to that extra effort of gathering that much information. I could also understand if you didn’t want to characterize the new polymorphs. Why give someone some help in developing a crystal form to develop a generic to steal away your profits ? Great discussion. Thanks for your input.

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