By Kevin E. Noonan —

The disconnect between patents and medicine (and more particularly, between physicians who prescribe patented drugs and the pharmaceutical companies who produce them) was illustrated nicely in a recent dustup between doctors working for the National Health Service in the UK and innovator drug company Pfizer over its patented Lyrica^® drug (pregabilin).

As reported on the Biospace GenePool website, the patent protecting the drug itself expired in July 2014, but Pfizer also has a patent on uses of the drug for neuropathic pain (the use most Americans would recognize based on countless viewings of televised commercial advertisements).  But it seems that Lyrica^® was first approved for generalized anxiety disorder (GAD) and epilepsy and that the pain indication was disclosed and claimed in a later patent that does not expire until July 2017.

Accordingly, generic versions of pregabilin have been approved only for the GAD and epilepsy indications, and treatment of neuropathic pain with generic pregabilin would be an "off-label" use that would be an act of patent infringement.  While drug companies rarely sue doctors, generic drug companies and others who promote such off-label uses can be sued for inducing or contributory infringement (or both) under U.S. law, and while this situation has arisen in Britain it appears that similar grounds of legal liability exist under UK law.

Pfizer addressed these issues in a letter to "physicians" (but, it seems, directed to pharmacists and hospital administrators either in addition to or instead of physicians themselves), setting out what Pfizer characterized as "relatively unusual circumstances":

Re. Lyrica^® (pregabalin) pain patent

I am writing to you to ensure you are informed about the relatively unusual issues surrounding the loss of exclusivity situation for the Pfizer product Lyrica (pregabalin) and so that you can take necessary action to prevent patent infringement by your organisation.

An appendix is attached describing the factual aspects of the situation in detail to ensure that you have the full information available.  You will see that, whilst the basic patent for pregabalin has expired and regulatory data protection for Lyrica expired in July 2014, Pfizer has a second medical use patent protecting pregabalin's use in pain which extends to July 2017.  Pfizer conducted further research and development on pregabalin leading to the invention of its use in pain and hence was granted a second medical use patent for this indication.  This patent does not extend to pregabalin's other indications for generalized anxiety disorder (GAD) or epilepsy.

As a result of the pain patent, we expect that generic manufacturers will only seek authorisation of their pregabalin products for use in epilepsy and generalised anxiety disorder and not for pain, whilst Pfizer's pain patent is in place.  Generic pregabalin products therefore are expected not to have the relevant information regarding the use of the product in pain in the PIL (Patient Information Leaflet) and SmPC (Summary of Product Characteristics).  In other words, the generic pregabalin products are expected to carry so-called a so-called "skinny label" and will not be licensed for use in pain.  In the circumstances described above, Pfizer believes the supply of generic pregabalin for use in the treatment of pain whilst the pain patent remains in force in the UK would infringe Pfizer's patent rights.  This would not be the case with supply or dispensing of generic pregabalin for the non-pain indications, but we believe it is incumbent on those involved to ensure that skinny labeled generic products are not dispensed and used for pain.

In this regard, we believe the patent may be infringed, even potentially unwittingly, by pharmacists and others in the supply chain, if they supply generic pregabalin for the pain indication.  Without information, guidance and practical solutions from the authorities, Pfizer believes that multiple stakeholders, possibly without realizing, may contribute to patent infringement which would be an unlawful act.  This runs contrary to the government's established policy of rewarding additional research by the granting of a second medical use patent.

We also note that, by issuing guidance, your CCG is able to influence patterns of prescribing and dispensing in your area.  We believe these powers must be exercised responsibly and with a view to avoiding the infringement of Pfizer's pain patent.

In view of the above, Pfizer requests that you issue appropriate guidance to prescribing clinicians within your CCG to help to ensure that our pain patent is respected and that all prescribing clinicians are aware of the pain patent situation.  There are a number of ways in which this might be achieved, but the simplest solution, we believe, is for clinicians to be advised to prescribe Lyrica^® by brand when prescribing pregabalin to treat neuropathic pain.  Pharmacists will then be able to dispense Lyrica^® against such prescriptions and this will ensure that they do not infringe the pain patent.  In addition this will mean that patients with pain will be provided with a PIL that describes the use of pregabalin in pain.

Your CCG may also consider reviewing patient records retrospectively (in advance of the availability of generic drugs) and use prescribing decision support mechanisms such as Scriptswitch to support appropriate ongoing prescribing.  We are willing to discuss, or assist CCGs with, the development of other solutions.

We should also note that, in our view, (i) CCG guidance instructing or encouraging the usage of generic pregabalin in pain would amount to procurement of patent infringement (an unlawful act); and (ii) your CCG is under an obligation to address the risk of wide scale infringement of Pfizer's patent rights.  Pfizer therefore formally reserves all of its legal rights in this regard.  If you have any questions in relation to the above please contact Pfizer Ltd on 01304 616161.

Yours sincerely

Ruth Coles

Legal Director

APPENDIX

Lyrica^® (pregabalin) Pain Patent: Statement of Facts

A. Background

1. Regulatory data protection (data exclusivity) for Lyrica^® expired in July 2014 across the European Union. Therefore, generic companies may now submit their applications for marketing authorisations for generic versions of pregabalin.

2. The composition of matter (basic) patent for pregabalin has also expired and the Supplementary Protection Certificate (SPC) relating to this patent has lapsed. There may be inaccuracies in some publicly available records — but as far as we are concerned the basic patent and the SPC are no longer relevant.

3. A patent protecting pregabalin's use in pain is in force for the product until July 2017. This patent (sometimes called a 'second medical use' patent) arises from further research and development on pregabalin leading to the invention of its use in pain, after the original invention of the compound for other uses.

4. As you may be aware, Lyrica^® is authorised for treating neuropathic pain, epilepsy, and generalised anxiety disorder. Pfizer's pain patent only provides patent protection in respect of the use of pregabalin to treat pain.

B. Pain patent facts

Broadly speaking, a 'second medical use' patent is one that relates to a new medical use for a known pharmaceutical or biological compound. The use in question may consist of a new condition that can be treated with the compound (i.e. a new indication). Provided the new use meets the usual tests for patentability (i.e. novelty, an inventive step, etc.) then a patent can be granted to protect it. In fact, the use in question does not have to be the second medical use, since it could be the third, fourth, etc, and the same rules would apply.

This has been the case in Europe for many years. Second medical use patents are recognised in Art 54(5) of the European Patent Convention 2000, provided that the specific use is novel (i.e. not comprised in the state of the art). Art 54(5) of the European Patent Convention 2000 is implemented by primary legislation in the UK through section 4A of the Patents Act 1977 (as amended by the Patents Act 2004).

Pfizer's Lyrica pain patent in Europe is number EP 0 934 061. Details can be found on the European Patent Office online register here:

https://register.epo.org/application?number=EP97932617&tab=main

Pfizer believes the patent is valid and that it prevents the sale of pregabalin for use in pain, which is the largest indication for which Lyrica is prescribed (pain comprises the majority of all prescriptions in the UK).

Accordingly, Pfizer believes that appropriate safeguards should be put in place to ensure that the generic product is not dispensed in situations where pregabalin has been prescribed for pain. Pfizer has no issue with generic supply / dispensing of generic pregabalin for the non-pain indications. Both Generics (UK) Limited (trading as Mylan) and Actavis Group PTC ehf have sought to challenge the validity of the pain patent in the English Patents Court. The two sets of proceedings will be heard together at a trial commencing in June 2015. Pfizer believes the pain patent is valid and will be contesting the case vigorously.

C. Generic pregabalin

Whilst Pfizer's pain patent remains in effect, we expect that generic manufacturers will generally only seek authorisation of their pregabalin products for use in epilepsy and generalised anxiety disorder, i.e. the two indications for which Pfizer has no patent protection. This would mean that generic pregabalin products will not have relevant information regarding neuropathic pain in the PIL (Patient Information Leaflets) and Summary of Product Characteristics. Pregabalin generics will contain the same active substance as the originator branded medicine, Lyrica^® and (as mentioned above) are generally expected to obtain a licence which will only cover the epilepsy and generalised anxiety disorder indications, based on their ability to demonstrate bioequivalence with Lyrica^®. There will be no clinical superiority of the originator branded medicine Lyrica^® over generic pregabalin.

Pfizer is not involved in the regulatory procedures of generic competitors. However, we have been notified by one generic company (Actavis Group PTC ehf) that it intends to launch generic pregabalin in the UK in December 2014 or January 2015, with an authorisation and label that will only cover the epilepsy and generalised anxiety disorder indications. Other generic companies may be operating to a similar — or even a faster – timeframe.

On 8 December 2014, Pfizer issued infringement proceedings against Actavis Group PTC ehf, Actavis UK Limited, and Caduceus Pharma Limited concerning the proposed launch of their generic pregabalin product. Pfizer also issued an application for interim relief on this date, seeking appropriate precautions to minimise the risk of the Actavis generic pregabalin product being prescribed or dispensed for pain. The interim relief sought by Pfizer does not interfere with Actavis' ability to sell its generic pregabalin product for the epilepsy and generalised anxiety disorder indications for which it is authorised. Pfizer has no issue with Actavis selling its generic pregabalin product for non-patented indications. Indeed, Pfizer proposed to Actavis to engage in a collaborative effort to ensure that its generic pregabalin is not supplied or dispensed for pain and could accordingly be launched without the need for a court dispute.

D. What it means

The Lyrica^® pain patent situation is a legal issue rather than a clinical one. Pfizer believes the supply of generic pregabalin for use in the treatment of pain, whilst the pain patent remains in force in the UK, would be infringing Pfizer's patent protection and would constitute an unlawful act. The patent may also be infringed, even unwittingly, by pharmacists and others in the supply chain. This may occur if either the pain indication or the brand Lyrica is not stated on the prescription and generic pregabalin is dispensed and used to treat pain — as opposed to epilepsy or GAD. Without information, guidance and a practical solution, Pfizer believes that multiple stakeholders may contribute to IP infringement, an unlawful act, which also runs contrary to the established policy of rewarding additional research by the granting of a second medical use patent.

The result, according to Biospace, has been "scorn" from UK physicians, while characterizing the notice as an "over-reaching legal decree."  Quoting Cory Doctorow from the Boing Boing weblog, the site complains that Pfizer wants doctors to prescribe Lyrica^® for pain instead of generic pregabilin, "even though the two drugs are identical" and the branded version "costs much more."  Quoting additionally from Boing Boing:

Weirder still is that Pfizer wants to make their stupid problem into everyone else's stupid problem.  The fact that it's hard to enforce this kind of secondary patent is Pfizer's business, not doctors'.  Doctors' duty is to science and health, not Pfizer's profit-margins.  Scientifically, there's no difference between the two compounds.  Doctors who prescribe generics leave their patients (or possibly the NHS) with more money to pursue their other health goals.

If your dumb government monopoly is hard to enforce, maybe you shouldn't be banking on it.  But in the world of corporatist sociopathy, where externalising your costs on others isn't just a good idea, it's your fiduciary duty to your shareholders, Pfizer's actions are practically inevitable.

Of course the reality is much different.  Pfizer doesn't have a problem, it has a presumptively valid patent on another, different use for its branded drug than the use for which pregabilin was initially approved.  While drug development itself is expensive, an additional, typically much greater expense is imposed by regulatory agencies, which require that the innovator drug company demonstrate that the drug is safe and effective.  While establishing safety is relatively straightforward, demonstrating effectiveness has the inherent requirement of being effective for what.  The second use in this case was likely to have been not self-evident; anxiety and epilepsy are not intrinsically associated with neuropathic pain, and Pfizer would have had to both recognize that use and establish efficacy in order to get regulatory approval for that use.  The reward for that effort and cost was patent protection for the use, which is what raises the possibility of patent infringement liability now.

In addition, while the physicians themselves will (likely) not be sued, pharmacists and hospital administrations might be (and, frankly, even if Pfizer has no intention of suing either making them aware of the legal consequences is fair and responsible exercise of their patent and regulatory exclusivity).

So why this tempest in this particular teapot?  As usual, it comes down to experience, and physicians will always want to treat as many patients as possible as effectively (and cheaply) as possible.  However, the physician's experience typically does not include any understanding regarding how medicines actually get developed, approved and marketed.  It is unfortunate that the politics of medical care provides an incentive for individuals providing care to oppose individuals providing the new drugs that improve our ability to treat and cure patients (which should be the goal for all of us).

But acting on the incentive to demonize biotech and pharmaceutical companies is self-defeating.  Generic drug companies, for all their benefits, do not invest the time and resources to produce any new drugs; without innovator biotechnology and pharmaceutical companies, generic drug makers would have nothing to copy or sell.  It would be well for physicians to consider where novel therapies will come from without companies with experience in obtaining (and financing) regulatory approval of such drugs, protecting them with patents, and having the business resources to bring such drugs to market.  It is certainly the case that these companies are for-profit (it's capitalism, after all), but the costs of R&D and regulatory approval, as well as scale-up, production, and distribution are realities that cannot be ignored.

That is where experience, specific experience with drug development, is invaluable.  Frankly, it is precisely because most physicians lack this experience that makes it easy to allude to corporate "greed" to explain outcomes they do not support.  (Similarly, in this way there are many (including apparently the Chief Justice) who attribute support of the patent system by patent attorneys as being self-serving, not realizing that efforts to complicate the system work only to our economic benefit.  Of course, that realization would prompt the thought that perhaps our motivations are not as self-serving as they may presume, leading to questions that might upset their comfortable presumptions.)

Relying on assumptions, and believing that donning a white coat relieves you of the responsibility for actually knowing something before voicing an opinion, results in the kind of uninformed outrage expressed by the UK physicians.  Ultimately this is just a waste of time and a venting of spleen that may make these doctors feel superior but does nothing to help patients or patient care.  Which is presumably supposed to be the point.

By Kevin E. Noonan —

Last Thursday, the European Court of Justice rendered a decision in International Stem Cell (ISCO) Corporation v. Comptroller General of Patents, Designs and Trademarks (UK) that significantly modified the landscape for human embryonic stem cell (hESC) patenting, by holding that prohibitions against patents on hESCs only apply to such cells derived from embryos that had the potential to develop into a human being.  This left as patent eligible in Europe hESCs produced from "parthenotes," embryos stimulated to decide (and produce hESCs) without fertilization.

The case was brought by ISCO over the UK government's rejection of these two patent applications:

• Application GB0621068.6, entitled 'Parthenogenetic activation of oocytes for the production of human embryonic stem cells', claiming methods of producing pluripotent human stem cell lines from parthenogenetically-activated oocytes and stem cell lines produced according to the claimed methods, and

• Application GB0621069.4, entitled 'Synthetic cornea from retinal stem cells', claiming methods of producing synthetic cornea or corneal tissue, which involve the isolation of pluripotent stem cells from parthenogenetically-activated oocytes, and product-by-process claims to synthetic cornea or corneal tissue produced by these methods.

ISCO appealed a decision by a Hearing Officer of the United Kingdom Intellectual Property Office, affirmed by the High Court of Justice (England and Wales), Chancery Division (Patent Court) that the claims of ISC's patent application are unpatentable under the proscription of the ECJ against hESC patenting in its earlier Brüstle (C‑34/10, EU:C:2011:669) decision.  It will be remembered that in 2011 the ECJ held that hESCs are not patent-eligible subject matter on the grounds that stem cell patents were "contrary to ethics and public policy" because they required "industrial use" of human embryos, the position originally taken by the ECJ advocate-general, Judge Yves Bot.  That case was brought by Greenpeace in German federal court over a German patent to the University of Bonn involving methods for deriving neural cells from hESCs (DE 197568664 C1).  The German federal court ruled for Greenpeace in 2006, and the university appealed to the German supreme court.  That court decided that it needed to refer the question to the ECJ, since German law was closely patterned on European Union guidelines for biotechnology patenting.  In the ECJ's decision in 2011, "human embryo" was interpreted broadly:

[A]ny human ovum must, as soon as fertilised, be regarded as a "human embryo" within the meaning and for the purposes of the application of Article 6(2)(c) of the Directive, if that fertilisation is such as to commence the process of development of a human being.

And the ECJ further decided that a "totipotent" or "pluripotent" human embryonic stem cell falls within the definition of a human embryo, deciding that these cells' capacity to develop into many or all human tissues was sufficient for them to qualify as a "human embryo."  Even the use of established hESC lines fell within the scope of that proscription, according to the ECJ, because the production of the claimed product (hESC) "necessitates the prior destruction of human embryos" by "the removal of a stem cell from a human embryo":

Accordingly, [] an invention must be regarded as unpatentable, even if the claims of the patent do not concern the use of human embryos, where the implementation of the invention requires the destruction of human embryos.  In that case too, the view must be taken that there is use of human embryos within the meaning of Article 6(2)(c) of the Directive.  The fact that destruction may occur at a stage long before the implementation of the invention, as in the case of the production of embryonic stem cells from a lineage of stem cells the mere production of which implied the destruction of human embryos is, in that regard, irrelevant.

The ECJ in the most recent action considered again the application of the meaning of the term "human embryos" in Article 6(2)(c) of Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions (OJ 1998 L 213, p. 13).  This issue arose as a Question Presented by the UK court to the ECJ, as follows:

Are unfertilised human ova whose division and further development have been stimulated by parthenogenesis, and which, in contrast to fertilised ova, contain only pluripotent cells and are incapable of developing into human beings, included in the term 'human embryos' in Article 6(2)(c) of Directive 98/44 … ?

ISCO distinguished the Brüstle decision on the grounds that the basis for the ECJ's decision in the Brüstle case was that the hESCs were "capable of commencing the process of development which leads to a human being."  ISCO argued that its cells did not satisfy that requirement, because ISCO's cells "cannot undergo such a development process."  Thus, ISCO argues that these cells should be capable of being patented under the Biotechnology Directive (Directive 98/44).

The Comptroller also identified the Brüstle decision as controlling, and maintained that "the key issue is what the Court meant in the judgment in Brüstle [] by organism 'capable of commencing the process of development of a human being just as an embryo created by fertilisation of an ovum can do so.'"  The judgment notes that the Comptroller admitted that "the written observations lodged with the Court in that case [Brüstle] may have inaccurately presented the scientific and technical background relating to parthenogenesis."

In its decision*, the ECJ set forth its understanding of the question asked by the national court to be "whether Article 6(2)(c) of Directive 98/44 must be interpreted as meaning that an unfertilised human ovum whose division and development to a certain stage have been stimulated by parthenogenesis constitutes a 'human embryo' within the meaning of that provision."  The Court concluded that the basis for the Brüstle decision was to prohibit patenting of embryos, or cells derived from embryos that are "'capable of commencing the process of development of a human being."  However, here the parthenogenetic human embryos did not have that capability (being limited to development to the blastocysts stage) and thus these embryos and hESC's derived from them did not satisfy the criterion relied upon by the Brüstle court to exclude those cells from patent eligibility.  As stated in the judgment, "where a non-fertilised human ovum does not fulfil that condition, the mere fact that that organism commences a process of development is not sufficient for it to be regarded as a 'human embryo', within the meaning and for the purposes of the application of Directive 98/44," wherein "[b]y where such an ovum does have the inherent capacity of developing into a human being, it should, in the light of Article 6(2)(c) of that directive, be treated in the same way as a fertilised human ovum, at all stages of its development."

The Court's opinion was framed as an answer to the national court's referred question:

In view of the foregoing considerations, the answer to the question referred is that Article 6(2)(c) of Directive 98/44 must be interpreted as meaning that an unfertilised human ovum whose division and further development have been stimulated by parthenogenesis does not constitute a 'human embryo', within the meaning of that provision, if, in the light of current scientific knowledge, that ovum does not, in itself, have the inherent capacity of developing into a human being, this being a matter for the national court to determine.

And its judgment, binding throughout the EU, was worded as follows:

Article 6(2)(c) of Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions must be interpreted as meaning that an unfertilised human ovum whose division and further development have been stimulated by parthenogenesis does not constitute a 'human embryo', within the meaning of that provision, if, in the light of current scientific knowledge, it does not, in itself, have the inherent capacity of developing into a human being, this being a matter for the national court to determine.

Whether parthenogeneticly produced hESCs are useful for anything other than laboratory research will determine whether this decision does anything to limit the extent to which the Brüstle decision impedes progress in hESC-dependent areas like human regenerative medicine.

*  The judgment of the Grand Chamber of the Court, made up of Judges Skouris (President), Lenaerts (Vice-President), Tizzano, Silva de Lapuerta, Ilešič and Vajda (Presidents of Chambers), Rosas, Borg Barthet, Malenovský, Toader, Safjan (Rapporteur), Šváby and Biltgen.  Also represented before the Court were representatives of the governments of Poland, France, Portugal, Sweden, the United Kingdom and the European Commission.