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Amgen Will See You In Court – Again

If they ever get around to making movies about drug discovery and development, perhaps someone will take on PCSK9. It has a neat origin in mutated humans, a race to the clinic, big money and big hopes, dramatic uncertainty (will it actually give better cardiovascular outcomes? Stay tuned!), and now it has courtroom scenes, too.

That’s because a couple of years ago, Amgen tried enforcing a patent claim to a whole class of PCSK9 antibodies (one particular epitope), which still lands right on top of Regeneron and Sanofi. Last spring, a jury found that the companies had indeed infringed Amgen’s patent, and the judge involved told everyone to come up with some sort of royalty agreement. Sanofi and Regeneron tried to get that verdict overturned, but on Tuesday, the judge denied the motion. Yesterday, the court granted an injunction request by Amgen: Sanofi and Regeneron are now enjoined to stop selling their competing drug (Praluent). That’s a pretty rare event – Matthew Herper at Forbes was asking for examples, and they can be counted on one hand. Needless to say, an appeal is being filed with what I can imagine is great speed and vigor – the injunction itself does not take effect for 30 days, to allow for this filing to take place. Whether or not it stays in force during the appeals process, I don’t know enough law to say.

There are several issues to argue here. The big one is, of course, whether Amgen’s patent claim really does hold up. I’m not going to speculate on that, or not yet – case law, as I rather dimly understand it, points both ways on something like this, and I have not studied the jury’s decision in any detail. That was by choice: any big patent case that’s decided by a jury is going to end up in the Court of Appeals for the Federal Circuit anyway – that’s what it’s there for. The question right now is whether or not Praluent is still going to be on the market while that all works itself out.

Here’s a law professor (Jacob Sherkow) who’s puzzled by the injunction (that’s the first of a series of tweets on the subject). The current standard for this sort of thing was set by Ebay v. MercExchange in 2006, a Supreme Court ruling that specifically addresses injunctions in patent disputes. The Ebay case didn’t actually set new standards – it reaffirmed the traditional “four-factor” test that had been applied in such cases, reversing a new CAFC ruling that said that injunctions should actually be granted more broadly in patent infringement cases. Those factors are: (1) that the patent holder has “suffered an irreparable injury”; (2) that the legal remedies available are inadequate to compensate for said injury; (3) that a “remedy in equity” is warranted, when you consider the hardships that both parties could suffer; and (4) that the public interest “would not be disserved” by issuing a permanent injunction. Sherkow believes that these factors are not actually in Amgen’s favor, and that the judge seems to have disregarded the four-factor test to such a degree that this injunction won’t hold up.

We’ll see. One thing’s for sure, though, the one that’s always for sure in these situations: the billable hours will pile up, and the lawyers will do just fine. Amgen’s legal team in particular is probably quite well-compensated; they’ve been very active in court over the years, prompting Matt Herper to term them “a law firm with a biotech company attached”. When it comes to PCSK9, the flasks and pipets have been put aside – it’s a briefcase war now.

26 comments on “Amgen Will See You In Court – Again”

  1. A Nonny Mouse says:

    Does the COX-2 case not set some sort of precedent?

  2. Anonymous says:

    It’s not straight forward. If you are referring to the Rochester case, there the invalid claims were to any compound, later discovered, that inhibited COX-2. There was little to no guidance in the Rochester patent. From Derek’s discussion, these claims appear drawn to any antibody, later prepared, against a specific epitope of PCSK9. Not all antibodies. I’ve never made an antibody and I don’t even know if PCSK9 is the protein which reacts with antibody or the antibodies themselves, but I would guess the skilled immunologist would know how to make such antibodies.

  3. steve says:

    I’m not sure I understand your question about if PCSK9 is the protein which reacts with the antibody – it definitely is. The patent claims are drawn to an antibody that reacts with a specific epitope of PCSK9. An epitope is defines as that part of an antigen (in this case PCSK9) to which an antibody attaches. I’d be interested in hearing a patent lawyer’s opinion. Given the recent Supreme Court cases (e.g., Myriad) it would seem that you can’t patent an epitope itself since it is naturally occurring. What then is the basis of their claim? Is it a method claim inhibiting the activity with an antibody that contacts the epitope? Or is it a composition claim for any antibody with a certain affinity for that epitope? Whichever it is, a lot of people will be copying it should it survive challenge.

    1. will says:

      The 741 patent claims an isolated monoclonal antibody, having the properties of (a) binding a particular epitope and (b) blocks binding of PCSK9 to LDLR

      Assuming that the monoclonal antibodies are not naturally occurring, this claim does not run afoul of the Myriad BRCA1 case. It is what we call a “reach through” claim, in that it covers all antibodies which perform the claimed function, not just the ones conceived by the inventors.

      There is no hard and fast rule saying reach through claims are invalid, although they are vulnerable to description challenges. It’s a judgement call as to whether it is valid or not. In the Cox2/Rochester case, the reach through patent did not identify a single compound capable of performing the claimed function; presumably that is not the case here.

      For biotech, the technology is so complex that it often comes down to which sides lawyers and expert witnesses are more persuasive.

      1. Anonymous says:

        It will depend upon how much guidance is in the patent for making the antibodies and how routine is making antibodies against a particular epitope of a known protein. My cynical view is experts can be found saying it is routine and others to say it is not routine. My two cents worth is that it is routine but I am far from an expert on this. A knowledgeable immunologist could probably change my mind. Before anyone decides to bet on the outcome by buying stock in the winning company my even more cynical view is the answer will depend on exactly which panel of judges is drawn to rule on this case at the Court of Appeals for the Federal Circuit.
        Nearly every chemical claim is a “reach through” claim to some extent or other. The only exception to this would be a claim for a specific compound that you have made and tested. Every other chemical claim ranges from the modestly speculative to the wildly speculative unless you think medicinal chemistry is 100% predictable. Personally I have not found the concept of the “reach through”claim to be as helpful as that of a broad claim versus an narrow claim.

  4. Jim Teason Cromey says:

    Lenny Schleifer would be upset by this and his recent verbal beating by sir Ian Read at last month’s Forbes Healthcare Summit, if it wasn’t for his obscenely unfair high salary.

    1. Jim Teason Cromey says:

      Olivier is not having a great year or tenure either

  5. RBW says:

    Being a small molecule man, can someone explain the reach through in biologics? I recall Sugen claiming all kinase inhibitors and Pfizer all PDE5 inhibitors and these claims are invalidated. How is this different from claiming any antibody that recognises a particular epitope?

    1. Anonymous says:

      I think an important difference between organic chemistry claims and antibody claims is the nature of the science behind the claims. An organic (small) molecule can be characterized by an exact written formula, A chemist will know exactly what you are talking about, but she may not know how to make it. A similar formula cannot be written for an antibody. Immunologists can broadly characterize its molecular weight, they know it is made from a limited variety of naturally occurring amino acids, and only a limited number of possible post translations modifications can be made. The immunologist knows against what the antibody reacts and how it was made. That is how an antibody can be claimed in a patent.
      In this case,the claim is fairly narrow. Only antibodies reacting with a specific portion of a protein, not all antibodies reacting with the protein. Making such antibodies is described in the patent and other methods would be routine, I think, to the skilled immunologist. Basically I think the organic chemist has a far larger range of colors on his pallet than does the immunologist. The Rochester, Sugen, and Pfizer claims were to anything, a small molecule, an antibody, inert gas, fairy dust, etc. as long as it inhibited a specific enzyme. I am not sure the structures of all such possible inhibitors could be written down during our lifetime. I could figure out how to make some of these inhibitors. A clever person could figure out how to make some more of these and for many of these inhibitors, no one could figure out how to make them. The claims of the Rochester, Sugen, and Pfizer patents were so broad so as to be literally unbelievable.

      1. Some idiot says:

        A good description from Anonymous. Let me try and describe it from another angle as well.

        “Reach through” claims are in no way restricted to biotech. More generally (and put crudely), when someone writes a patent, they tend to claim the sun and the moon, as well as a small rock on planet earth. They actually have examples in the patent to describe the small rock. How broad the final granted patent will cover depends on a lot of things, but is broadly a case of how much the patent examiner can be persuaded is reasonable. Broadly speaking, the more novel an area is, the more latitude the examiner will give to claims which are not directly supported by examples in the patent (i.e. something which can in many cases be seen of as “reach through”).

        I will try to illustrate this through a pretty crude example. Imagine someone in 1930 discovered and patented a process for coupling amines, alcohols etc with aromatic halides, using palladium. Lets say that the author gave examples of two metals, 3 ligands, and two different nucleophiles, one oxygen, one nitrogen. Since the area would have been _completely_ new at the time, then the patent examiner would probably accept broad claims such as “a coupling between an aryl halide and a nucleophile catalysed by a complex of a transition metal with a ligand.”

        Anyone trying to do that these days would be laughed out the door, since the area has now been worked over so much. A patent for a new ligand or ligand class may well be allowed, but the examiner would now limit the breadth of the patent significantly, for example to the precise ligands exemplified (or maybe the class if it was sufficiently novel), and presumably only with the metals that had been exemplified. In other words, “reach through” (or perhaps in other cases breadth of claims) is more or less given as a reward for really novel work, whereas “me too” patents tend to looked at far more sternly. A good example of this is polymorph patents. To begin with (when they were novel) they used to be granted fairly easily, but these days, if you want a patent on a polymorph, you generally need to show that it is useful for something (i.e. gives a technical advantage over other solid forms in one area or another).

        Having said all that, just because a broad patent is granted, does not necessarily mean that it will survive a challenge in court. That will be up to the judge(s), plus how convincing the two different teams of lawyers and hired experts are. This one will be fun watching… From a distance…

        1. steve says:

          @Some idiot, I’m afraid that what you said doesn’t really comport with patent law. If the claim is appropriately worded, for example, a method of lowering cholesterol levels in a subject by contacting an epitope on PCSK9 (which would need to be appropriately described of course) with an antibody that binds said epitope with an affinity no greater than 5nM, then it could be very broad and cover any antibody to that epitope. I made this up on the spur of the moment but you get the point. That would be a method claim; what I’d like to hear from a competent patent lawyer is whether a composition claim on the epitope would be granted nowadays in light of recent Supreme Court decisions like Myriad.

          1. Some idiot says:

            @Steve, you have a good example there of a (potentially very broad) method claim from the biological area. The point I was trying to make was that the subject matter does not have to be biological to have “reach through” (or equivalent). From my (fictitious) example above, a claim for “a coupling between an aryl halide and a nucleophile catalysed by a complex of a transition metal with a ligand” would cover _any_ coupling (using and aryl halide and a nucleophile) using _any_ transition metal and _any_ ligand. I accept that this is not completely the same as epitope binding, but I believe that my point is still valid, i.e. sufficiently broad method claims can come from both small molecule stuff (my area) and biological areas (sounds like your area). How often such broad claims are going to be accepted in the future is another question, but….! (-: And yes, I have had a lot of practical experience with these sorts of claims and processes in the small-molecule area.

  6. mike b. says:

    Theranos firing 41% of their employees.

  7. Anonymous says:

    Other examples? I’m not sure what specific point is to be further exemplified. In the early 1990s, there were competing claims over urokinase (recombinant vs naturally derived?) and who owned the sequence. And a few years later, urokinase was off patent but there were more lawsuits over who was entitled to sell it. I haven’t checked lately, but it wouldn’t surprise me if the lawsuits were still ongoing.

    “The one great principle of [patent litigation] law is, to make business for itself.” – Bleak House, Charles Dickens.

    Miss Flite’s Birds: Hope, Joy. Youth, Peace, Rest, Life, Dust, Waste, … PCSK9, Praluent, Urokinase, Daraprim, Epipen, Isuprel, …

  8. Thomas Lumley says:

    What I think’s surprising isn’t the patent-validity part of the injunction being granted, but the irreparable harm.

    Backing up, since I don’t know from patents, the usual idea of an injunction is that you claim (A) you have a reasonable chance of winning the case because you’ll claim evidence I,II,III,IV,V(a), V(b),V(b)(i-xl) and (B) but it will be too late and totally not fair because the bad guys will kill the dragon and marry the princess by then and bigamy is a crime.

    Here, especially given the argument above, it seems (A) includes “That’s what the patent says” and “these antibodies are so specific and well-characterised that they’re just the cDNAs in the Myriad case” and “the lower court said so”. They don’t have to win at this point, just to show they have a reasonable prospect of winning (at whatever the standard is for patents), so that doesn’t seem ridiculous.

    On the other hand, irreparable harm usually has to be harm for which money damages isn’t adequate. It’s clear how Amgen is harmed by these other products, but I can’t see why big truckloads of cash wouldn’t compensate. Following the links, that also seems to be one of Jacob Sherkow’s points “The court is WRONG about lack of remedies @ law. $AMGN not averse to $. Damages quantifiable. And no one doubts $SNY ability to pay. 9/15”

  9. steve says:

    Since we’ve all been blowing smoke I thought it would be good to look at the actual patent claims (U.S. Patent Numbers 8,829,165 and 8,859,741). These are actual composition claims, not just methods claims.

    Claim #1 of 8,829,165 reads “An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR”

    Claim #1 of 8,859,741 reads: “An isolated antibody that binds to PCSK9, wherein the isolated monoclonal antibody binds an epitope on PCS

    K9 comprising at least one of residues 237 or 238 of SEQ ID NO: 3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR”.

    I’m rather surprised that the courts would allow for a broad claim of any antibody that binds a particular epitope.

    Here is the analysis from Law360 from the earlier case that Regeneron/Sanofi appealed https://www.law360.com/articles/799626/sanofi-wants-jury-verdict-axed-in-amgen-drug-patent-row

    “A patent that claims antibodies by way of function rather than by structure may be valid if the patent’s specification discloses either a representative number of antibody “species” falling within the scope of the “genus,” or it discloses structural features common to the members of the genus so that a person of skill in the art can recognize the members of the genus, Sanofi said.

    But Amgen’s patents fail on both prongs, according to Sanofi.

    ‘The antibodies disclosed in Amgen’s specification cannot plausibly be considered representative of the variability of the broader genus, and there is no basis for concluding that members of the genus share common structural features so that one of skill in the art can ‘visualize or recognize’ the members of the genus,’ Sanofi wrote in its motion.

    Sanofi further contended that Amgen’s patents are invalid as a matter of law for lack of enablement — a requirement that the claimed invention is disclosed in enough detail for a person skilled in the art to be able to practice it. It claimed that Amgen’s disclosure for its patents was no more than a starting point for further research into the full scope of the claimed invention.”

  10. Amgen will be waiting for the appeals to fails so we can buy them at a dumpster discount, raid them, then sell off the rights to Praluent to another big pharma with conditions so that the brand never threatens Repatha. Thank you Donald Trump!

    http://cafepharma.com/boards/threads/amgen-to-hold-praluent-ransom-to-keep-drug-on-market.603706/

  11. Kent G. Budge says:

    I think I agree with Sherkow. There’s no irreparable harm from allowing the drug to remain on the market during appeal; if the appeal goes against Sanofi and Regeron, I would think that awarding royalties for sales during that period to Amgen would “make whole.”

    But I’m not a lawyer, either.

  12. Chrispy says:

    Unless there is something magical about the epitope, reflected perhaps in the particular immunogens used to generate the antibody, why should anyone be able to patent an epitope? Just as I can’t patent any compound that binds COX-2, or I can’t broadly patent any antibody to PCSK-9, why should I be able to patent any antibody that binds to particular residues on PCSK-9? Is this not equivalent to trying to patent any molecule that binds in the active site of COX-2? The fact is that an antibody to PCSK-9 has to bind somewhere, and knowing the bound crystal structure of Amgen’s antibody does not sufficiently inform you about other antibodies that could bind to overlapping regions to make them. So there’s a failure of the written description to adequately enable the generation of the antibodies covered by epitope claims. The old fashioned way to claim epitopes was to claim your antibody and any antibody that competes with your antibody — these were the kind of claims that Abbott (Humira) used against J&J/Centocor (Simponi), as I recall. This suit failed but I am not sure what the basis of the failure was, or if the “any antibody that competes with our antibody” claim received enough attention. Of course, these kinds of competition claims don’t tell you anything about how to make a competing antibody, either. One thing’s for sure: if this holds then epitope claims are going to be a very important part of antibody IP going forward, perhaps becoming more important than the composition claims on the antibody sequence.

    1. Anonymous says:

      The claims concern monoclonal antibodies to the epitope of PCSK9, not the epitope itself. One can clearly ascertain “the hand of man” in such claims. Whether such claims are enabled and why they differ from rejected claims in the COX-2 case have been discussed at length above. Opinions are divided whether the claims are enabled. IMHO they are and the most import reason why I think so, is the state of the monoclonal antibody arts. For you legal fans, that is one of the eight Wands factors used for making an enablement determination. The other important Wands factor pointing towards enablement is the number of working examples of monoclonal antibodies against the epitope of PCSK9 in the patent.

      1. Chrispy says:

        OK, the enabling part of the patent is the antibody sequences. In no way does knowing the epitope allow you to make an antibody to that epitope. It’s akin to making a small molecule inhibitor, solving the crystal structure, and then trying to claim all inhibitors with any structure. In fact, if you made a new antibody with an entirely different sequence that bound PCSK-9 you would not even know if you were infringing until you determined the co-complex crystal structure. (Isn’t the amount of required experimentation a Wands factor, too?) The thing is that this is all hindsight — the epitope information is not enabling because it doesn’t tell you how to make an antibody to that epitope. They made an antibody and it happened to bind this epitope — it is an intrinsic quality of the antibody.

        1. steve says:

          Not true. Having an epitope is exactly what you need to make an antibody.

        2. Anonymous says:

          It’s not the epitope which enables (or does not enable) the claims but rather the entire patent document, all the references in the document, and most importantly in my opinion the knowledge of a skilled immunologist. In about two years a three judge panel at the Federal Circuit will tell us the answer. You or I may not agree with the answer but one thing courts do is end a dispute.
          You are correct, experimentation is another of the eight Wands factors. If anyone is interested (http://patenttips.blogspot.com/2009/04/factors-in-determining-enablement-wands.html) provides a brief and clearer explanation of all eight factors. However, it is not undue experimentation but rather the amount of experimentation that is a factor. “Undue” is a possible conclusion reached after considering all eight factors. A claim can be enabled even if it requires enormous experimentation to practice if the other seven factors are satisfied. Rather than simply saying a claim is enabled, practitioners of the dark patent arts say, “practicing the claim would require only routine experimentation”. Conversely rather than saying the claim is not enabled one says, “ practicing the claim would require undue experimentation”. The language comes from the original Wands court decision. I have never liked the practice of reusing the turgid prose of an important court decision and not simply and clearly saying what you mean.
          This all could have been avoided if enablement had been addressed during the initial examination. It rarely is except in the most egregious cases. Because of the count system, which limits the time available and because there are eight damn Wands factors, all of which are supposed to be addressed, there is never enough time to address enablement thoroughly. Rather all the time is spent on prior art and the clarity of the claims. And to end this rant, guess what there are two separate parts of enablement, enablement for making and enablement for using. What we have been discussing for the last four days is enablement for making. One would presumably known how to use a PCSK9 monoclonal antibody but it is a completely separate issue with a completely independent Wands analysis.

  13. David says:

    We’ve had movies about codebreaking, I’d love to see some about drug discovery.

  14. Amgen announced that the US District Court of Delaware denied Sanofi’s and Regeneron’s motion to stay (suspend) the injunction pending the appeal of the ongoing PCSK9 litigation in the Court of Appeals for the Federal Circuit (CAFC). In this ruling, the District Court did extend the timing of the injunction from 30 to 45 days, allowing Sanofi and Regeneron to seek review of the Court’s injunction and stay denial at the CAFC.

    Additionally, Amgen announced during the 35th annual J.P. Morgan Healthcare Conference that the company will present Repatha cardiovascular outcomes (CVOT) data at the American College of Cardiology Conference (ACC) taking place in Washington D.C. on 17-19 March 2017.

    Denying the stay could accelerate both the appeal process and potential Praluent removal from the US. In light of yesterday’s block of the injunction stay and after our further consultation with expert legal counsel, we now believe that the appeals process is likely to be substantially accelerated, with a potential final decision from the CAFC as early as April 2017. Since we continue our belief that there is a greater than 75% likelihood that the CAFC will uphold the original decision on the injunction, we now believe it is possible that Praluent could be removed from the US market within a few months.

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