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You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Akebia Therapeutics Inc v Fibrogen, Inc [2020] EWHC 866 (Pat) (20 April 2020) URL: http://www.bailii.org/ew/cases/EWHC/Patents/2020/866.html Cite as: [2020] RPC 15, [2020] EWHC 866 (Pat) |
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Neutral Citation Number: [2020] EWHC
866
(
Pat)
Case Nos: HP-2018-0000036, IL-2019-000031
IN THE HIGH COURT OF JUSTICE
BUSINESS AND PROPERTY COURTS
INTELLECTUAL PROPERTY LIST (CHANCERY DIVISION)
PATENTS
COURT
Rolls Building
Fetter Lane, London, EC4A 1NLL
Date: 20 April 2020
Before :
LORD JUSTICE ARNOLD
- - - - - - - - - - - - - - - - - - - - -
Between :
|
(1) AKEBIA THERAPEUTICS INC (2) OTSUKA PHARMACEUTICAL COMPANY LIMITED |
Claimants |
|
- and - |
|
|
FIBROGEN, INC |
Defendant |
And between :
|
ASTELLAS PHARMA INC |
Claimant |
|
- and - |
|
|
(1) AKEBIA THERAPEUTICS INC (2) OTSUKA PHARMACEUTICAL COMPANY LIMITED (3) FIBROGEN, INC |
Defendants |
- - - - - - - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - - - - - - -
Justin Turner QC, Thomas Mitcheson QC, Joe Delaney and Thomas Lunt (instructed by Carpmaels & Ransford LLP) for FibroGen
Justin Turner QC, Thomas Mitcheson QC, Kathryn Pickard and Michael Conway (instructed by Potter Clarkson LLP) for Astellas
Iain Purvis QC, Piers Acland QC and Anna Edwards-Stuart (instructed by Hogan Lovells International LLP) for Akebia and Otsuka
Hearing dates: 2-6, 9-12, 17-19 March 2020
- - - - - - - - - - - - - - - - - - - - -
Approved Judgment
I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this Judgment and that copies of this version as handed down may be treated as authentic.
.............................
LORD JUSTICE ARNOLD
LORD JUSTICE ARNOLD:
Contents
Topic Paragraphs
Introduction 1-6
The witnesses 7-47
Technical background 48-106
The claims of the Family A Patents:
unconditionally amended 154-163
The claims of the Family A Patents:
conditional amendments 164
The skilled team 165-167
Common general knowledge as at the Family A Priority Date 168-203
The documents cited in the Family A Patents
204-258
Construction of Family A claims 259-303
Obviousness of Family A over Epstein 304-346
Insufficiency of EP 823 and EP 301 348-405
AgrEvo obviousness of EP 823 and EP 301 406
Infringement of Family A by vadadustat 407-462
Amendment of EP 531 463
The claims of the Family B Patents
502-518
The skilled team 519
Common general knowledge as at the Family A Priority Date 520-543
The documents cited in the Family B Patents
544-548
Construction of Family B claims 549-553
Obviousness of Family B over WO 997 554-574
Insufficiency and AgrEvo obviousness of Family B 575-578
Infringement of Family B by vadadustat 579-639
Summary of principal conclusions 640
Introduction
1. These proceedings were originally brought by Akebia Therapeutics Inc (“Akebia”) and Otsuka Pharmaceutical Co Ltd (“Otsuka”) seeking to revoke six patents
(“the
Patents”)
belonging to FibroGen, Inc (“FibroGen”) in order to clear the way for their product vadadustat. Subsequently the exclusive licensee under the
Patents,
Astellas Pharma Inc (“Astellas”), brought a cross-claim for threatened infringement. For convenience, I shall refer to Akebia and Otsuka collectively as “the Defendants” and to FibroGen and Astellas collectively as “the Claimants”. There were also parallel proceedings involving two GlaxoSmithKline companies (“GSK”) and their product daprodustat which were to be tried together with these proceedings, but those proceedings were settled on the working day before trial.
2. The Patents
concern the use of inhibitors (referred to as HIF-PHIs) of an enzyme called hypoxia inducible factor-prolyl hydroxylase (HIF-PH) for treating various types of anaemia and related conditions. Astellas obtained a marketing authorisation for the first oral HIF-PHI product, roxadustat, in Japan in September 2019, and intends to launch the product more widely, including in the UK. It hopes that the product will achieve blockbuster status by 2023. Vadadustat and daprodustat are HIF-PHI products which are both undergoing Phase III clinical trials at present.
3. The Patents
have been grouped into two families of three
patents,
each deriving from a common international application, designated “Family A” and “Family B”:
Family A Family B
WO 03/053997 (“WO 997”) WO 2004/108121 (“WO 121”)
EP (UK) No 1,463,823 (“EP 823”) EP (UK) No 1,633,333 (“EP 333”)
EP (UK) No 2,289,531 (“EP 531”) EP (UK) No 2,322,153 (“EP 153”)
EP (UK) No 2,298,301 (“EP 301”) EP (UK) No 2,322,155 (“EP 155”)
4. There is no challenge to the earliest claimed priority date of the Family A Patents,
which is 6 December 2001. It is common ground that the validity of the Family B
Patents
should be assessed as at the second claimed priority date, which is 29 April 2004. I shall refer to these dates as “the Priority Dates”.
5. It will be convenient to describe the disclosure of the Patents
by reference to the two international applications listed above (“the Applications”), in particular because WO 997, which was published on 3 July 2003, is relied upon by the Defendants as prior art against the Family B
Patents.
Nevertheless, caution is required, because there are some small, but nevertheless potentially significant, textual differences between the Applications and the respective
Patents.
I shall return to this point below.
6. The Defendants contend that the Family A Patents
are obvious over A.C.R. Epstein et al, “C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation”, Cell, 107, 43–54 (5 October 2001) (“Epstein”), that the Family B
Patents
are obvious over WO 997 and that all the
Patents
are insufficient. The Defendants also dispute that they threaten to infringe any of the
Patents.
Furthermore, FibroGen has applied to amend the
Patents
both unconditionally and conditionally. Most of the amendment applications are unopposed save on the ground that they do not cure the alleged invalidity of the
Patents,
but one is. The result is a case of considerable complexity, as indicated by the fact that the parties’ written closing submissions run to 434 paragraphs (Claimants) and 537 paragraphs (Defendants), and cross-refer to further material in their respective opening skeleton arguments.
The witnesses
Expert evidence in patent
cases
10. Before turning to consider the experts individually, it is once again necessary for me to address some general questions concerning expert evidence in patent
cases. The
Patents
Court depends on the assistance it receives from expert witnesses, many of whom are scientists of considerable distinction in their own fields. Particularly in complex cases such as this, preparing expert reports and giving oral evidence can be an arduous task in terms of the time, effort and concentration involved. It is vital that the task of the experts is not made more difficult by the lawyers than it needs to be.
11. I considered the preparation of expert reports in a passage in MedImmune Ltd v Novartis Pharmaceuticals UK Ltd [2011] EWHC
1669 (
Pat)
at [99]-[114] which is frequently cited, not least in experts’ reports. The key point I made in that passage is that “the lawyers who instruct expert witnesses bear a heavy responsibility for ensuring that an expert witness is not put in a position where he can be made to appear to have failed in his duty to the court even though he conscientiously believes that he has complied with that duty”.
12. I considered the cross-examination of experts in a passage in Merck Sharp and Dome Ltd v Shionogi & Co Ltd [2016] EWHC
2989 (
Pat)
at [87]-[93] which is perhaps less well known. The key point I made in that passage is that “too much time is spent by cross-examiners in
patent
cases on ad hominem attacks that are unfair to the witness, unhelpful to the court and waste expensive time”.
13. The present case has demonstrated that the warnings I gave in MedImmune v Novartis and MSD v Shionogi are still not being sufficiently heeded. As I shall explain, both Prof Winearls and Prof Haase were let down by those instructing them with respect to the preparation of their expert reports, and Prof Haase was in one respect cross-examined unfairly. It should not be necessary for me to say that this is unacceptable. These are matters of professional responsibility. If practitioners continue not to observe the standards required of them, the Patents
Court will have to take steps to enforce those standards.
The nephrologists
14. Prof Winearls. The Claimants’ expert was Professor Christopher Winearls. On 31 August 2019 he retired from practice as an NHS consultant nephrologist in the Oxford Kidney Unit at the Churchill Hospital, part of the Oxford University Hospital NHS Foundation Trust. Prof Winearls obtained an MBChB from the University of Cape Town in 1973 and was awarded a DPhil in transplant immunology by the University of Oxford in 1979. He undertook his training in nephrology in Oxford and then at Hammersmith Hospital. He was appointed a consultant nephrologist at the Churchill Hospital in 1988 and remained in full-time practice until 2016, after which he was part-time. He was the Clinical Director of the Oxford Kidney Unit from 1995 to 2009. He was a Lecturer, and then Senior Lecturer, at the Royal Postgraduate Medical School between 1985 and 1988, after which he became an Associate Professor of Medicine at the University of Oxford. He was an editor of Erythropoietin - Molecular, Cellular and Clinical Biology (Johns Hopkins University Press, 1991) and of the Oxford Textbook of Clinical Nephrology (now in its 4th edition), and an author of a considerable number of published papers. In addition to other professional memberships, he was formerly Secretary and later Clinical Vice President of the Renal Association (of the United Kingdom). He was on the Editorial Board of the American Journal of Kidney Diseases until 2016, and he contributed to the Standards Document produced by the Royal College of Physicians and the Renal Association and the Kidney Disease Improving Global Outcomes (“KDIGO”) Guidance on Chronic Kidney Disease (2012). He described his role in 2001 as having been “a clinician, a clinical researcher and an educator and trainer of students and doctors”. His research interests included renal anaemia. He was the nephrologist on the team which first investigated the effect of recombinant human erythropoietin in uraemic man (P.M. Cotes et al, “Characterization of the anaemia of chronic renal failure and the mode of its correction by a preparation of human erythropoietin (r-HuEpo): an investigation of the pharmacokinetics of intravenous erythropoietin and its effects on erythrokinetics”, Q J Med, 70(262), 113-37 (1989)) and he was a Principal Investigator on the PIVOTAL trial describing the effects of two dose regimens of intravenous iron in haemodialysis patients
also receiving erythropoiesis-stimulating agents (ESAs) (I.C. Macdougall et al, “Intravenous iron in
patients
undergoing maintenance hemodialysis”, N Engl J Med, 380(5), 447-458 (2019)).
15. As Prof Winearls explained in his first report, he was instructed to read EP 823 as exemplifying the Family A Patents.
Despite that, he was asked to consider the obviousness of the claims of EP 531. In paragraph 134 of his first report he identified the inventive concept of the claims of EP 531 as being “the use of HIF-PHIs to increase endogenous Epo production in prevention, pre-treatment or treatment of anaemia associated with kidney disease, CRF or CKD”. As Prof Winearls naturally accepted in cross-examination, that statement of the inventive concept is applicable to EP 823, but not to EP 531. Counsel for the Defendants rightly did not suggest that this was the fault of the witness: it is evident that, at some point in the drafting of the report, a section dealing with the obviousness of EP 823 was re-drafted to address EP 531 without all the necessary changes being made. An expert in Prof Winearls’ position cannot possibly be expected to spot points like this, and must rely on those instructing them. Fortunately, this error did not matter.
19. The second instance actually concerns a different topic to HIF. In paragraph 83 of his first report Prof Winearls referred to “the damaged kidney” being “incapable of producing Epo in renal anaemia patients
[emphasis added]”. Prof Winearls accepted that that sentence was over-stated. As counsel for the Claimants pointed out, however, elsewhere in his first report, Prof Winearls stated the position in a more nuanced manner. Thus in paragraph 136 he said that in
patients
with kidney disease “the ability of the kidneys to produce Epo was thought to be reduced because of damage to or phenotypic change in the interstitial fibroblasts [emphasis added]”, and he used very similar language at paragraph 48. It is clear that the latter statement represents the opinion that Prof Winearls was attempting to convey. Accordingly, I do not regard the poor drafting of the former statement as significant.
20. Prof Haase. The Defendants’ expert was Professor Volker Haase. He obtained an MD degree from the Johann Wolfgang Goethe University School of Medicine in 1987 and a higher research doctorate in 1990 for work on tumour immunology. His career since then has been primarily in the United States, where he held a variety of research and clinical positions in the 1990s. From 1990 to 1993 he undertook a research fellowship at the Massachusetts General Hospital and the MGH Cancer Center. From 1993 to 1996 he was an Intern and then a Resident in Internal Medicine at Emory University in Atlanta, Georgia. From 1996 to 1999 he was a Clinical and Research Fellow in the Renal Division at Beth Israel Deaconess Medical Center and Harvard Medical School, and he obtained board certification in nephrology in 1999. From 1997 to 2001 he was a Research Fellow at the Whitehead Institute for Biomedical Research at Massachusetts Institute of Technology. From 1999 to 2001 he was an Instructor in Medicine at Harvard Medical School, and from 2001 to 2008 was Assistant Professor of Medicine at the University of Pennsylvania School of Medicine. From 2008 he held various Assistant and Associate Professor roles, and in 2015 he was appointed as full Professor of Medicine, full Professor of Molecular Physiology and Biophysics and full member of the programme in Cancer Biology at Vanderbilt University School of Medicine in Nashville, Tennessee. Since 1997 his research activities have focused on the regulation of the HIF and von Hippel-Lindau (VHL) pathways
and their involvement in renal and other diseases, and he started his own laboratory group in 2001 to undertake research focused on the role of HIF signalling. He is the author of over 95 scientific publications, and he is on the editorial boards of a number of journals. Alongside his research activities, he has practised as a clinical nephrologist for over 20 years. He was an Attending Physician at the Beth Israel Deaconess Medical Center and Harvard Medical School from 1999 to 2001, and at the Hospital of the University of Pennsylvania from 2001 to 2008. Since 2010 he has served as an Attending Physician at the VA Medical Center in Nashville, and since 2011 he has served in the same capacity at the Vanderbilt University Medical Center in Nashville.
23. First, Prof Haase did not mention C. Peyssonnaux et al, “Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)”, J Clin Invest, 117, 1926–1932 (2007) (“Peyssonnaux”), of which he was a co-author, in his first report. The significance of this is that this was - apart from the Family B Patents
- the first report of a link between HIF and hepcidin (as to which, see below). Prof Haase explained in his fourth report, served in reply to Prof Winearls’ third report, which drew attention to Peyssonnaux, that there had subsequently been conflicting reports in the literature on this point. I consider that Prof Haase should have been instructed to address this in his first report, but I do not see any reason for thinking that Prof Haase is to be blamed for this failure as counsel for the Claimants submitted.
26. I turn to the cross-examination of Prof Haase. For the most part, this was exemplary: it was well-constructed, appropriately thorough and courteously conducted. It was marred, however, by one passage which should not have taken place. In paragraph 43 of his first report Prof Haase expressed the opinion that cobalt salts were well known (i) to have been used to treat anaemia from the 1930s to the 1970s, (ii) to stimulate the expression of Epo by inducing HIF-α and (iii) to mimic hypoxia by stabilising HIF and inducing Epo. In support of his opinion on the first point, Prof Haase cited H.H. Corner, “Cobalt and nutritional anaemia”, Br Med J, 2, 169-170 (1939), L. Berk et al, “Erythropoietic effect of cobalt in patients
with or without anemia”, N Engl J Med, 240, 754-61 (1949) and J.P. Kriss et al, “Hypothyroidism and thyroid hyperplasia in
patients
treated with cobalt”, J Am Med Assoc, 157, 117-21 (1955) (“Corner”, “Berk” and “Kriss”). In paragraphs 37-40 of his fourth report Prof Haase returned to this topic, explaining that he was not suggesting that Corner, Berk and Kriss were themselves common general knowledge and citing an additional publication.
“I brought this [cobalt] up. This was not something that was brought to me by the solicitors. … Then I picked papers for this expert witness report”,
counsel first mischaracterised the witness’ evidence by putting it to the witness that the papers were provided to him and then badgered the witness for a page of transcript with further questions apparently designed to try to undermine the answer the witness had given without having any material to contradict it. This is not an acceptable way in which to treat an expert witness. The cogency of Prof Haase’s opinion as to the use of cobalt salts to treat anaemia being part of the common general knowledge is a separate question to which I will return below. As I will explain, it is not even the point which matters most when it comes to the subject of cobalt.
34. Thirdly, counsel for the Claimants submitted that Prof Haase had been wrongly instructed as to, or had misunderstood, the concept of common general knowledge. I see no evidence that he was wrongly instructed. He may not have fully understood the concept, but this is a common problem for expert witnesses in patent
cases. As noted above, Prof Winearls also had some difficulty with the concept.
36. This submission illustrates why it can be advantageous to try to instruct expert witnesses in sequence, first asking them about the common general knowledge, then showing them the prior art and asking them questions such as what steps would be obvious in the light of it and only then showing them the patent
in suit. This is a procedure known as “sequential unmasking” in the psychological literature (see generally on this subject C.T. Robertson and A.S. Kesselheim (eds), Blinding as a Solution to Bias, Academic Press, 2016). The point of it is to try to avoid, or at least reduce, hindsight. In my opinion, it is desirable to try to minimise hindsight on the part of expert witnesses where possible. There is no rule or principle that experts must be instructed sequentially, however. Moreover, there are often real practical problems in doing so. To take just one obvious example, any discussion about the common general knowledge must start by identifying the skilled person or team. How is this to be done if the expert cannot be shown the
patent?
One way is to ask the expert to make an assumption, which they can check later when they see the
patent;
but that is not necessarily a perfect solution. Other problems can be caused by the pre-existing knowledge of the expert and by amendments to the parties’ cases (such as the introduction of new prior art after the expert has read the
patent).
Still further, instructing experts in this way can make their task even more burdensome, particularly when it comes to cross-examination, because they may find it difficult to recall what they knew when unless it is clearly documented. (It should be borne in mind, however, that some cross-examination as to the way in which the expert has been instructed is often justified in any event.)
37. In the present case, Prof Haase explained in his first report that he had discussed the common general knowledge with those instructing him before he had seen the Patents,
so to that extent he was instructed sequentially. Nevertheless, it appears that Prof Haase was asked to read WO 997 before commenting on Epstein because at that time the Defendants were not advancing a case of obviousness of the Family A
Patents,
but were relying upon WO 997 as prior art against the Family B
Patents.
In any event, given Prof Haase’s prior knowledge of HIF-PHIs, which he acknowledged in his first report, it would not have been possible to instruct him in a manner which was free from hindsight. Accordingly, I do not criticise the manner in which he was instructed. In evaluating his evidence, however, I accept that it is necessary to take into account that he read WO 997 before forming his opinion concerning obviousness over Epstein.
The medicinal chemists
38. The Claimants’ expert was Dr Gurdip Bhalay, who has been Team Leader, Medicinal Chemistry at the Institute of Cancer Research since 2018. He obtained a degree in chemistry and a PhD from the University of Nottingham in 1989 and 1992 respectively. From 1993 to 1995 he was a post-doctoral scientist at the University of Oxford. From 1995 to 1997 he was employed by a start-up company on drug discovery projects for Pfizer Central Research. From 1998 to 2014 he was employed by Novartis, initially as a Research Investigator (until 2008) and then as Senior Research Investigator. There his role involved co-leading drug discovery projects as the medicinal chemistry lead, as well as evaluating emerging scientific methodology. From 2014 to 2018 he was Group Leader, Medicinal Chemistry at Charles River Early Discovery. He is an author of 34 scientific publications and a named inventor on 21 patents.
40. The Defendants’ main expert was Professor Simon Ward, who has been the Sêr Cymru Professor in Translational Drug Discovery at Cardiff University and a Director at the Medicines Discovery Institute since 2017. He received an MA (natural sciences) in 1993 and a PhD (synthetic organic chemistry) in 1997 from the University of Cambridge. He then held various roles in the pharmaceutical industry as a medicinal chemist, joining GSK in 2001 as an associate/assistant director of medicinal chemistry, where he led medicinal chemistry and multi-disciplinary teams working on CNS drug discovery projects, including on enzyme inhibitors. Prof Ward left GSK in 2010 to become Professor of Medicinal Chemistry and Director of the Sussex Drug Discovery Centre at the University of Sussex. Among other things, he is Joint Editor-in-Chief of Comprehensive Medicinal Chemistry Vol III (3rd ed, Elsevier, 2017). He is an author of two books, 49 scientific publications and a named inventor on 44 published patent
applications.
41. Counsel for the Claimants criticised Prof Ward for using what counsel characterised as “invective” when he described the number of compounds covered by Formula (I) in the Patents
as “staggeringly” large. This criticism is wholly unjustified: on any objective view the number is staggeringly large, as I will explain. That is not altered by the fact that Prof Ward is a named inventor on a
patent
in respect of which the same observation might be made.
The clinical practice experts
44. The Claimants’ expert was Dr Mark Devonald, who is a consultant nephrologist at Nottingham University Hospitals NHS Trust (“NUH”). He qualified in medicine at the University of Edinburgh in 1993. He obtained specialist accreditation in 2004, and has worked as a consultant nephrologist within the NHS since then. He obtained a PhD from the University of Cambridge in 2005. He has been at NUH since 2007. He estimates that he is responsible for over 100 patients
a year who receive treatment for anaemia associated with CKD. He was a member of the guideline development group for the National Institute for Health and Care Excellence (NICE) Clinical Guidance NG8 Management of Anaemia in Chronic Kidney Disease. He was a member of NUH’s Drugs and Therapeutics Committee from 2007 to 2014.
45. Counsel for the Defendants made two criticisms of Dr Devonald’s evidence, both of which I consider well founded. First, Dr Devonald was strangely unwilling to accept that his first report was based on Prof Winearls’ evaluation of the literature, despite the fact that Dr Devonald had expressly stated in his report that he was asked to assume that Prof Winearls’ evaluation was reasonable. Dr Devonald attempted to suggest that he had undertaken his own analysis based on a review by E.K. Batchelor et al, “Iron Deficiency in Chronic Kidney Disease: Updates in Pathophysiology,
Diagnosis and Treatment”, J Am Soc Nephrol, 10 February 2020 (e-publication), but he had not seen that review at the date of his first report. Secondly, Dr Devonald was reluctant directly to answer a question he was asked as to whether a change in clinical practice was likely with HIF-PHIs. (Counsel for the Defendants submitted that Dr Devonald twice failed to answer the question, whereas counsel for the Claimants submitted that he had answered it the third time it was asked. I think counsel for the Claimants is correct, but that does not detract from the point made by counsel for the Defendants.)
46. The Defendants’ expert was Dr Neil Ashman, who is a consultant nephrologist at the Royal London Hospital, a partner hospital of Barts Health NHS Trust (“Barts”), and also the Chair of the Medicine Board at Barts. He obtained an MBChB from the University of Cape Town in 1991 and his certificate in nephrology in 2004. He obtained a PhD from Queen Mary University of London in 2008. He has managed patients
with anaemia of chronic kidney disease in the UK since at least 2004 when he became a consultant nephrologist. Barts has one of the largest renal units in the UK.
Technical background
Erythropoiesis, iron metabolism, anaemia and hypoxia
54. The main iron pathways
are shown diagrammatically in a figure from Prof Winearls’ first report which I reproduce below.
57. Absolute iron deficiency occurs when a patient
does not have enough iron in stores to supply the body’s needs. Absolute iron deficiency may be caused by a low-iron diet, reduced iron absorption and/or bleeding. Absolute iron deficiency is characterised by a low TSAT and a low level of serum ferritin, namely, a TSAT < 20% (or < 16% in more extreme cases) and serum ferritin < 50-100 ng/ml.
59. Patients
who are “iron replete” are usually defined as those with a TSAT of at least 20% and a serum ferritin level of at least 100 ng/ml; but TSAT measurements show considerable diurnal and day-to-day variation for a given
patient.
61. Though the anaemic conditions share common symptoms, their pathophysiologies
are distinct. The causes include inadequate red cell production, defective iron acquisition or availability, defective haem synthesis, red cell destruction and blood loss. Some of these causes involve Epo.
62. Anaemia of CKD. Chronic kidney disease (CKD) describes a diminution in renal function through irreversible damage to the kidneys to an extent that has negative consequences for the patient,
including an impairment of Epo production, and hence anaemia.
64. In patients
with CKD, iron deficiency is often seen, of both the absolute and functional kind.
68. Anaemia of CKD was first treated with oral iron, to see if this alone achieved the desired haemoglobin response, and if not, intravenous (IV) iron. Patients
with more severe CKD, receiving haemodialysis, were typically put straight on IV iron because this could be done easily during dialysis and because of their increased iron needs.
69. If iron supplementation did not raise haemoglobin to the target range, patients
were given an ESA. ESAs include recombinant human Epo (r-HuEpo) (such as epoetin alfa, epoetin beta) and various analogues (including darbepoetin alfa), all of which stimulate erythropoiesis in the presence of adequate iron. Anaemia of CKD was considered a treatable condition, as ESAs circumvented the damaged kidneys’ reduced Epo production by providing an exogenous source. ESAs did have certain disadvantages, however, in that they were expensive and had to be administered either intravenously or subcutaneously.
70. ESAs tend to cause (or exacerbate) iron deficiency, because they stimulate the demand for iron, and so patients
are often given supplementary iron with ESAs. The norm was to aim for a TSAT of 30% or more before starting treatment with ESAs.
71. A small number of patients
are “refractory” or “resistant” (the terms appear to be interchangeable) to ESAs. I shall consider the definition of “refractory” below. In rare cases,
patients
do not respond to ESAs at all.
72. Treatment of ACD. The primary goal of treating ACD focussed on resolving the underlying inflammation. It is common ground that ESAs were sometimes administered to patients
with ACD, but there is a dispute about the effectiveness of such treatment which I will address below.
Medicinal chemistry
77. To be robust, an SAR investigation should:
i) consider a sufficient number of molecules;
ii) generally involve making one modification at a time;
iii) involve a diverse set of modifications (conservative modifications often do not reveal much about the relationship between structure and function);
iv) involve sufficient changes to enable the medicinal chemist broadly to understand the environment around the compound (assuming it is bound into the active site of the enzyme);
v) include molecules that are both active and inactive; and
vi) be based on data that is repeated (i.e. not generated in single experiments).
i) metal ions (such as Fe2+ or Zn2+) which may assist in holding the substrate(s) in an optimal configuration and/or be involved in electron transfer reactions; and
ii) small organic molecules called co-enzymes which are transiently and loosely bound in the active site during an enzymatic reaction, and which undergo a chemical transformation as part of the enzymatic catalytic cycle. A co-enzyme may itself be considered a substrate of the enzyme (and is sometimes referred to as a co-substrate).
94. Enzyme inhibition. Compounds may inhibit the normal activity of an enzyme in a number of different ways.
102. Enzyme kinetics. Enzyme kinetics is the study of the rate of enzymatic reactions. The rate of catalysis depends on the concentration of enzyme, substrate and inhibitor present, as well as factors such as pH and temperature.
The Family A Patents
107. As noted above, I shall set out the disclosure of the Family A Patents
by reference to WO 997. I shall do so using the headings in the specification and I shall note some, but not all, of the respects in which the texts of the
Patents
differ. Before I do so, I must note two important and related points the significance of which will become apparent below.
108. The first point is that both WO 997 and the Family A Patents
which derive from it refer to a considerable number of scientific papers and books and earlier
patents
and
patent
applications. The numbers of such documents referred to in each of the four are not precisely identical, but for example EP 823 refers to 47 papers or books and 26
patents
and applications (including four prior art citations referred to in EP 823 at [0007] which are not mentioned in WO 997). I shall refer to a number of instances of such references below.
109. The second point is that, in some places, WO 997 states that the earlier publications are, or information contained in such publications is, incorporated by reference in its entirety; but that language is not present in the Family A Patents
(this is because the European
Patent
Office’s practice is to require such language to be deleted). I shall refer to some examples of this below.
Field of the invention
110. The specification begins by explaining at [0002] that the invention “relates to methods for increasing endogenous erythropoietin, ex vivo and in vivo, and to compounds that can be used in the methods”. The language in the corresponding paragraph ([0001]) of the Family A Patents
is as follows:
i) EP 823: “relates to medicaments [sic] for increasing endogenous erythropoietin in the prevention, pretreatment or treatment of anemia, and to compounds that can be used in the methods”;
ii) EP 531: “relates to compounds for use in the treatment or prevention of anemia”;
iii) EP 301: “relates to compounds for use in the treatment or prevention of anemia associated with kidney disease”.
Background of the invention
113. In [0007] reference is made to the introduction of genetically engineered Epo for the treatment of anaemia in chronic renal failure patients
and the limitations of such treatment, including cost and the need for intravenous administration. At [0008] it is explained that there remains a need for methods and compounds effective in the treatment of Epo-associated conditions such as anaemia, including anaemia associated with kidney failure, cancer and infection, and specifically a need for methods and compounds that increase endogenous Epo.
Summary of the invention
i) stabilising the alpha subunit of HIF (HIFa);
ii) inhibiting the hydroxylation of HIFa;
iii) inhibiting 2-oxoglutarate (“2-OG”) dioxygenase enzyme activity; and
iv) inhibiting HIF-PH enzyme activity.
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Brief description of the drawings
Description of the invention
“Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications cited herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing the methodologies, reagents, and tools reported in the publications which might be used in connection with the invention. …”
In the corresponding paragraph of the Family A Patents
([0037]) in EP 823) the words “incorporated herein by reference in their entirety” are replaced by the word “mentioned”.
Definitions
Invention
131. At [0064] the specification repeats that the invention provides methods of increasing endogenous Epo and further provides methods of increasing endogenous Epo levels to prevent, pre-treat or treat Epo-associated conditions including conditions associated with anaemia. Various examples of such conditions are listed, including cancer and inflammation. Various patient
groups who might benefit from an increase in endogenous Epo are discussed at [0065]-[0066].
133. At [0072] the specification states:
“The invention also contemplates increasing iron transport, processing, and utilization using the methods of the invention. (See, e.g., commonly owned, copending U.S. Patent
Application No. ____, entitled ‘Stabilization of Hypoxia Inducible Factor (HIF) Alpha,’ filed of even date, and incorporated herein by reference in its entirety.) Specifically, the methods of the invention may increase enzymes and proteins involved in iron uptake, transport, and processing. Such enzymes and proteins include, but are not limited to, transferrin and transferrin receptor, which together facilitate iron transport to and uptake by, e.g., erythroid tissue, and ceruloplasmin, a ferroxidase required to oxidize ferrous iron to ferric iron. As transferrin can only bind and transport ferric iron, ceruloplasmin is important for supply of iron to tissues. The ability of the methods of the invention to increase both endogenous erythropoietin and transport and utilization of iron in a single course of treatment provides benefits not addressed by current anemia therapeutics, such as administration of recombinant erythropoietin, in the treatment of anemic disorders including, but not limited to, rheumatoid arthritis, sideroblastic anemia, etc.”
135. The specification continues:
“[0074] As HIFa is modified by hydroxylation, a reaction requiring oxygen and Fe2+, the present invention contemplates in one aspect that the enzyme responsible for HIFa hydroxylation is a member of the 2-oxoglutarate dioxygenase family. Such enzymes include, but are not limited to, procollagen lysyl hydroxylase, procollagen prolyl 3-hydroxylase, procollagen prolyl 4-hydroxylase a(I) and a(II), thymine 7-hydroxlase, aspartyl (asparaginyl) β-hydroxylase, ε-N-trimethyllysine hydroxylase, γ-butyrobetaine hydroxylase, etc. These enzymes require Fe2+, 2-oxoglutarate, and ascorbic acid for their hydroxylase activity. (See, e.g., Majamaa et al. (1985) Biochem J 229:127-133 [‘Majamaa 1985’]; Myllyharju and Kivirikko (1997) EMBO J 16:1173-1180 [‘Myllyharju and Kivirikko 1997’]; Thornburg et al. (1993) 32:14023-14033; and Jia et al. (1994) Proc Natl Acad Sci USA 91: 7227-7231.)
[0075] Several small molecule inhibitors of prolyl 4-hydroxylase have been identified. (See, e.g., Majamaa et al., supra; Kivirikko and Myllyharju (1998) Matrix Biol 16:357-368 [‘Myllyharju and Kivirikko 1998’]; Bickel et al. (1998) Hepatology 28:404-411; Friedman et al. (2000) Proc Natl Acad Sci USA 97:4736-4741; and Franklin et al. (2001) Biochem J 353:333-338; all incorporated herein in their entirety.) The present invention contemplates the use of these compounds in the methods provided herein.
[0076] Compounds that can be used in the methods of the invention include, e.g., structural mimetics of 2-oxoglutarate. Such compounds may inhibit the target 2-oxoglutarate dioxygenase family member competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron. (Majamaa et al. (1984) Eur J Biochem 138:239-45 [‘Majamaa 1984’]; and Majamaa et al., supra.).”
136. The words “all incorporated herein in their entirety” in [0075] do not appear in the corresponding paragraphs of the Family A Patents.
In addition, the last sentence of [0075] differs in the Family A
Patents
as follows:
i) EP 823 [0068]: “The present invention contemplates the use of these compounds that are selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides.”
ii) EP 531 [0064]: “The present invention contemplates the use of these compounds that are of Formula (I) as defined herein.”
iii) EP 301 [0064]: “The present invention contemplates the use of these compounds that are of Formula (I) as defined herein.”
139. At [0078]-[0083] the specification states that “exemplary” or “additional” “compounds according to Formula (I) [or (Ia) or (Ib)]” are described in two European and nine US patents,
including US
Patent
No. 5,620,995 (“US 995”). WO 997 states that all compounds listed in these
patents
are incorporated into the application by reference, but these statements do not appear in the Family A
Patents.
A considerable number of specific examples of these compounds are also identified in these paragraphs, including certain compounds which are labelled as Compounds D, E, F, G, J, C, H, I and K. Compounds D, E, F and G are said at [0082] to be exemplary compounds according to Formula (Ia) which are described in US
Patent
No. 5,719,164 and US
Patent
No. 5,726,305 (“US 305”). Compounds J, C, H, I and K are said at [0083] to be exemplary compounds according to Formula (Ib) which are described in US
Patent
No. 6,093,730 (“US 730”).
140. At [0084] the specification states that, additionally, “compounds for use in the methods of the invention are compounds described by” five of the papers cited in [0075] and [0076], all of which are said to be incorporated by reference in their entirety (this text is not included in the Family A Patents).
It should be noted, however, that Formula (III) does not feature in EP 823 and that neither Formula (II) nor Formula (III) feature in EP 531 and EP 301.
142. At [0086] and [0088] the specification states that “exemplary” compounds of Formula (II) and Formula (III) are described in two US patents
and two international
patent
applications. Various compounds are identified in these paragraphs, including two compounds which are labelled as Compounds A and B. Compound A is said at [0086] to be an exemplary compound of Formula II which is described in US
Patent
No. 5,916,898 (“US 898”), US
Patent
No. 6,200,974 (“US 974”) and international application WO 99/21860 (“WO 860”). Compound B is said at [0088] to be an exemplary compound of Formula III which is described in international application WO 00/50390.
Examples
The claims of the Family A Patents:
unconditionally amended
154. The claims of the Family A Patents
as proposed unconditionally to be amended which were relied upon by the Claimants at trial are as follows. The numbering is a result of the fact that FibroGen made a sequence of applications to amend. As will appear, one of the claims is a Swiss-form claim while the others are EPC 2000 claims. In most cases, where dependent claims are dependent on both types of claim, I have only included the versions which are dependent on the EPC 2000 claims.
EP 823
155. Claim 8A (formerly 9) as dependent on (unconditionally amended) claim 1:
“Use of a heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity in the manufacture of a medicament for increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease,
wherein the anemia is associated with chronic kidney disease.”
156. Claim 8A (formerly 9) as dependent on (unconditionally amended) claim 2:
“A heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity for use in increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease,
wherein the anemia is associated with chronic kidney disease.”
157. Claim 19A (formerly 20) as dependent on claims 8A and (unconditionally amended) claim 2:
“A heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity for use in increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease,
wherein the anemia is associated with chronic kidney disease,
wherein the compound is a compound of Formula (I) wherein ….”
159. (New) claim 24A as dependent on (unconditionally amended) claim 2:
“A heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity for use in increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease,
wherein the compound is a structural mimetic of 2-oxoglutarate.”
160. (New) claim 24A as dependent on claim 19A, claim 8A and (unconditionally amended) claim 2:
“A heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity for use in increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease,
wherein the anemia is associated with chronic kidney disease,
wherein the compound is a compound of Formula (I) wherein …,
wherein the compound is a structural mimetic of 2-oxoglutarate.”
EP 531
161. (Unconditionally amended) claim 17A (formerly 1):
“A compound for use in the treatment or prevention of anemia associated with kidney disease, wherein the compound is a compound of formula (I) … [Compound C].”
EP 301
162. (New) claim 2 as dependent on claim 1:
“A compound for use in preventing or treating anemia associated with kidney disease in a subject, wherein the compound is a compound of [Formula (I) wherein A is (C1-C4)-alkylene],
wherein the compound inhibits HIF prolyl hydroxylase.”
163. (New) claim 4 as dependent on (new) claim 2 and claim 1:
“A compound for use in preventing or treating anemia associated with kidney disease in a subject, wherein the compound is a compound of [Formula (I) where A is (C1-C4)-alkylene but otherwise as defined previously],
wherein the compound inhibits HIF prolyl hydroxylase,
wherein the compound is a structural mimetic of 2-oxoglutarate.”
The claims of the Family A Patents:
conditional amendments
The skilled team
165. It is common ground that the Family A Patents
are addressed to a multi-disciplinary team investigating potential therapies for anaemia caused by kidney disease. The skilled team would include at minimum:
i) a pre-clinical researcher involved in the investigation of anaemia associated with renal disease;
ii) a clinical nephrologist involved in the treatment of patients
with renal disease; and
iii) a medicinal chemist involved in the development of new pharmaceuticals.
166. It is also common ground that the pre-clinical researcher and the clinical nephrologist might be the same person, which is why both sides were able to call a single expert witness to address both fields of expertise. As Prof Winearls put it in his first report, he gave evidence “from the perspective of a research scientist with knowledge of the pathophysiology
of anaemia caused by kidney disease and also as a clinician with first-hand clinical experience in the treatment of such conditions”. I shall refer to this person (or combination of persons) as “the skilled nephrologist” save where it is necessary to differentiate between the pre-clinical researcher and the clinical nephrologist.
167. There is a dispute between the parties as to the extent of the skilled nephrologist’s knowledge about HIF prior to reading the Family A Patents.
Contrary to the suggestion made at points by the Claimants, this is, as counsel for both sides agreed in oral closing submissions, not a question of the composition of the skilled team. Rather, it is a question of the skilled nephrologist’s common general knowledge, and I shall therefore address it under that head.
Common general knowledge as at the Family A Priority Date
Endogenous production of Epo by diseased kidneys
169. As noted above, there is no dispute that it was common general knowledge that in patients
with CKD the ability of the kidneys to produce Epo is reduced. This is because of a reduction in the number of Epo-producing cells. Nor is it in dispute that it was known that the amount of Epo produced in such circumstances is, although actually slightly higher than in
patients
with normal kidneys, insufficient to prevent anaemia. There is a dispute, however, as to whether the skilled nephrologist would have thought that damaged kidneys could be stimulated to produce more Epo, in particular by hypoxia.
171. Prof Haase’s evidence in his third report was that the skilled nephrologist would have appreciated from Maxwell that, even in severely damaged kidneys, it is possible to stimulate the production of significant quantities of Epo. Prof Haase added that this was consistent with observations that, in patients
with anaemia of CKD, Epo production was induced as a result of blood loss and acute hypoxia. In support of the latter point, he cited A. Kato et al, “Erythropoietin production in
patients
with chronic renal failure”, Ren Fail, 16(5), 645-51 (1994) (“Kato”) and R. P. Ross et al, “Erythropoietin response to blood loss in hemodialysis
patients
is blunted but preserved”, ASAIO J, 40(3), M880-5 (1994) (“Ross”).
“The principal finding of this study is that following renal injury a reduced number of interstitial cells expressed the Epo-TAg gene in response to anemia or hypoxia. This reduction in the number of positively staining cells was observed irrespective of the nature of the injury, and was apparent in both anemically and hypoxically stimulated animals. Several features of the response to injury were defined.
First, the reduction in the number of cells expressing Epo-TAg was regionally correlated with severity of injury. In needlestick injured kidneys the reduction in positive cells was focal. In post-ischemic kidneys, where the most severe injury was observed in the outer medulla, the most striking reduction in interstitial cells expressing the Epo-TAg gene was also in this region.
Second, even in severely injured regions occasional positive cells were observed, and there was no apparent difference in the intensity of staining in these cells when compared with those in normal kidneys.
Third, in an individual injured area there was no apparent difference between the fibroblast-like cells that did or did not express the Epo-TAg gene. In particular, the intensity of desmin staining was similar.
Fourth, although there were clear reductions in the number of positive cells in injured regions at all levels of stimulation, more intense anemic or hypoxic stimulation (as judged by the number of positive cells in the control kidney) resulted in a greater recruitment of cells in the injured kidney, so that the greatest disproportion between the injured and uninjured kidney was seen under conditions of mild stimulation.”
“Our finding that a reduced proportion of fibroblast-like cells was induced to express Epo-TAg in injured kidneys, and that more of these cells could be recruited by more severe stimulation is consistent with previous observations that rodents and humans with renal failure produce significant amounts of erythropoietin from the kidney and increase erythropoietin production in response to severe anemia or hypoxia [19—23]. It indicates that the cells are neither destroyed nor rendered completely refractory to stimulation. Rather, they have an apparently altered threshold for gene expression. …”
(It should perhaps be noted that references 19-23 do not include Kato or Ross).
174. Kato showed that Epo production could be stimulated either by hypoxia or by acute bleeding in patients
with end-stage renal disease (ESRD). Systemic hypoxia was shown to increase Epo in the blood to up to 24.6 times the normal level. As it is put in the abstract:
“These data suggest that the ability of the Epo production is well preserved in ESRD, indicating that acute hypoxic stimuli provoke a significant increase in serum Epo.”
Kato suggests that one explanation of this effect may due to enhanced production in the liver, but as Prof Haase explained, Maxwell provides direct evidence that it is due to the activity of kidney cells.
176. In cross-examination, Prof Winearls agreed that, if anyone had educated themselves in the question of the production of Epo in patients
with damaged kidneys, they would have been aware, from Maxwell and Kato, that the damaged kidneys could be stimulated to produce more Epo. Thus the evidence of both experts is consistent that this would have been common general knowledge.
177. A point was put to Prof Haase in cross-examination that had not been foreshadowed in any of Prof Winearls’ evidence (written or oral), namely that this effect was transient. Nothing in Maxwell or Ross was relied upon as supporting this, but it was pointed out that Kato reports that, out of a group of eight patients
with hypoxemia (due to pulmonary edema or pneumonia), serum Epo returned to about the normal level within 1-2 days “despite continued hypoxemia in 3
patients
whose serial blood samples were obtained (data not shown)” (page 649). Moreover, it states in the discussion section at page 650 that this is consistent with a prior report and refers to “the transient response to hypoxic stimuli”. This is not a point picked up in the abstract, however, which simply says that the serum Epo level in all eight
patients
“declined to or near the normal level after recovery from acute hypoxic stress”.
“Diseased kidneys are incapable of augmenting erythropoietin production chronically in response to an appropriate anemic hypoxic stimulus, yet an acute blood loss can transiently increase erythropoietin levels [47, 55]. The reason for the inability of diseased kidneys to sustain augmented production in response to chronic anemic ‘hypoxia’ is unknown. Although little data are available on sequential erythropoietin levels with progressive renal failure, erythropoietin production in such anemic patients
is probably also inadequate.”
(Reference 47 is Ross.)
179. Prof Haase accepted that this reflected the common general knowledge, but he pointed out that a similar transient response was observed in normal persons at high altitude. He made the same point when asked about the increase in Epo levels in the three hypoxic patients
in the Kato paper: “It is temporary, but the Epo response is temporary in the normal
patient
as well.”
HIF
181. The Claimants contend that the skilled nephrologist would not have any significant knowledge of HIF, whereas the Defendants contend that the skilled nephrologist would have a very good knowledge of the biochemistry of the HIF pathway.
182. In resolving this issue, the starting point is that I do not understand it to be in dispute that the clinical nephrologist would have little knowledge of HIF. That is evidenced by the fact that it is not mentioned in textbooks such as R.J. Johnson and J. Freehally, Comprehensive Clinical Nephrology (2nd edition, Mosby, 2003). That is beside the point, however. What matters is what the pre-clinical researcher would have known - the “research scientist with knowledge of the pathophysiology
of anaemia caused by kidney disease” in Prof Winearls’ words.
183. Prof Winearls opined in paragraph 82 of his first report that:
“Although a few nephrologists may have been working on oxygen sensing or related projects in a research setting (as was the case for example in Peter Ratcliffe’s research group), the vast majority of practising nephrologists would likely have been unaware of the HIF system and it would not have formed part of the CGK of the Skilled Clinical Nephrologist [emphasis added].”
“I remain of the opinion set out in Winearls 1. For the reasons I set out there, details concerning the molecular pathways
involved in renal anaemia were not issues that occupied the mind of the notional Skilled Clinical Nephrologist at the Priority Dates and the sort of research being carried out by the Semenza, Ratcliffe and Kaelin groups would have been seen as ‘fundamental science’ without immediate clinical application [emphasis added]”
“Clinical nephrologists concentrate on a very large number of subjects, and this was a mechanistic concept and research, which was very basic, and mostly published in scientific journals, though in that particular issue in 1997 Peter Ratcliffe described Epo as a model of oxygen-sensing. However, I think because it was in Kidney International in a single issue entitled ‘Hypoxia’ does not mean the general nephrologist would have read that. They tend to read things that are of immediate interest to them and their practice. If you were researching anaemia, you might well have read that, and, of course, because Peter Ratcliffe was a UK nephrologist originally, we had kept up with this particular story, but I do not think the ordinary nephrologists were as interested as you are implying, in the nuts and bolts of how the story had eventually been put together.”
191. The two pathways
(degradation in normoxia and functioning as a transcription factor in hypoxia) are conveniently shown in the following figure taken from the Nobel Prize website (which is of course recent, but reflects what was known at the time, and which refers to the HIF-1α isoform).
194. The role of HIF prolyl hydroxylation in the regulation of the HIF-α subunit was independently discovered by Kaelin and Ratcliffe, and published in two seminal, back-to-back papers in the 20 April 2001 edition of Science: M. Ivan et al, “HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing”, 292(5516), 464-468 (“Ivan”) and P. Jaakkola et al. “Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation” 292(5516), 468-72 (“Jaakkola”). These were accompanied by a commentary by H. Zhu and H. F. Bunn, “How do cells sense oxygen?”, 292(5516), 449-451 drawing attention to the significance of this work. It is convenient to note here that these publications were followed six months later by a further paper from the Ratcliffe group, namely Epstein.
Cobalt salts
The documents cited in the Family A Patents.
204. Before turning to consider the interpretation of the claims of the Family A Patents,
it is convenient first to consider a more general question which bears upon a number of issues in the case. This is whether, and if so to what extent, the skilled team, and in particular the skilled medicinal chemist, would read the documents cited in the Family A
Patents.
The Claimants’ case on this question evolved over time.
205. Dr Bhalay stated in his first report that FibroGen’s solicitors had asked him to review the six papers cited in [0068]-[0069] of EP 823 (corresponding to [0075]-[0076] of WO 997) and to review US 305, US 995 and US 730 (which are among the patents
cited in [0074] and [0076]-[0077] of EP 823 corresponding to [0080] and [0082]-[0083] of WO 997). He did not suggest that he would otherwise have done so, nor did he suggest that a skilled medicinal chemist reading EP 823 in December 2001 would have done so. Still less did he suggest that the skilled person would have read any of the other documents cited in the Family A
Patents.
206. Prof Ward annexed to his first report two annexes commenting on the 15 patents
and applications cited in WO 997 at [0078]-[0088] and on the six papers cited in WO 997 at [0075]-[0076]. In Annex I he explained that he had been asked to assume that the compounds of these
patents
and applications were incorporated by reference into WO 997 as appropriate and to address what, if anything, the skilled medicinal chemist would have learnt if the medicinal chemist had turned them up. In Annex III he explained that he had been asked to address what, if anything, the medicinal chemist would have learnt if the medicinal chemist had turned up the six papers. He did not suggest that a skilled person reading the Family A
Patents
in December 2001 would in fact have turned up any of these documents.
207. Dr Bhalay commented in his third report on Prof Ward’s Annex III. He also said, in the context of a discussion about Compounds C-K, that the Family A Patents
“cross-refer” to the six papers in question. He did not comment on Prof Ward’s Annex I. Nor did he say anything about whether the skilled person would follow up any of the references. In his fourth report Dr Bhalay commented further on Majamaa 1984 and Bickel, but again did not address the question of whether the skilled person would turn up these papers.
208. Prof Ward commented in his third report on what Dr Bhalay had said in his first report about the six papers and about US 305, US 995 and US 730. In the former context Prof Ward referred to what the medicinal chemist would have noted “if he had read” one of the papers. In the latter context Prof Ward noted that WO 997 provided “very little guidance or direction” as to why the 15 patents
cited at [0078]-[0088] “might be important”.
209. In their opening skeleton argument the Claimants discussed the disclosure of the Family A Patents
by reference to WO 997. In the context of insufficiency, the Claimants said that the specification “refers the Skilled Person to a series of publications describing known small-molecule inhibitors of collagen prolyl-4-hydroxylase”, which must be a reference to [0075], and that it “also refers the Skilled Person to several US
patent
applications which provide further examples of heterocyclic carboxamides that are small molecular inhibitors of prolyl-4-hydroxylase”, which seems to be a reference generally to [0078]-[0088]. The Claimants also mentioned that in [0076] “reference is made to” Majamaa 1984 and Majamaa 1985. The Claimants did not address the question of which documents cited in the Family A
Patents,
if any, the skilled team would read or why.
210. The Defendants stated in their skeleton argument that they did not accept that the skilled person would review the documents cited in the Family A Patents
considered by Dr Bhalay. They also made the point that, if the skilled person had gone beyond the lengthy specification to consider the numerous cited prior publications and
patents,
there was no basis for the selective treatment of the cited prior art undertaken by Dr Bhalay.
211. During the course of counsel for the Claimants’ oral opening submissions I was taken briefly through WO 997 as being representative of the disclosure of the Family A Patents.
When he came to [0075], counsel noted the references to the five papers cited there and said “obviously we will be … exploring these in cross-examination”. I queried whether the statement “all incorporated by reference herein in their entirety” was reproduced in the granted
Patents.
Counsel said he would check. He did not address the question of which documents cited in the Family A
Patents,
if any, the skilled team would read or why.
212. In cross-examination Dr Bhalay confirmed that the only reason why he had read the six papers cited in [0075]-[0076] of WO 997 was because he had been asked to. Furthermore, Dr Bhalay accepted that the skilled medicinal chemist would have a choice as to whether to turn up the documents referred to in [0068]-[0069] of EP 823 (corresponding to [0075]-[0076] of WO 997) and that it would be reasonable not to do so. He added, however, that “if you were doing a due diligence, I think you would be compelled to actually follow up these papers”. Similarly, Dr Bhalay confirmed that the only reason why he had read US 305, US 995 and US 730 was because he had been asked to. He also accepted that the skilled person would have a choice as to whether to turn up any of the cited patents.
When pressed as to whether it would be reasonable not to do so, Dr Bhalay said that he would do “a thorough job” and spread the work among other members of the team with (unspecified) instructions as to what to look for. He was unable to think of any reason why the skilled person would single out US 305, US 995 and US 730 for review.
213. Prof Ward’s evidence in cross-examination was that he thought that, although it depended on the time available and the information coming from the skilled nephrologist, the skilled medicinal chemist would be more likely to follow up references which were cited as disclosing particular compounds for use in the invention. Furthermore, he agreed that it would be reasonable for the medicinal chemist to read the references in [0068]-[0069] of EP 823, but focussing on the chemistry, that is to say, the compounds and their activities. No reason was put to him as to why the skilled person would single out US 305, US 995 and US 730 for review from the other cited patents
and applications.
214. In their written closing submissions the Claimants submitted that:
“.. the skilled person is deemed to read with interest the papers and patents
[to which reference is made in the specification] which are expressly advanced as being relevant to the sufficiency of the
patent.
In the alternative we contend that the skilled person would in the context of this case read those papers and
patents.”
The Claimants did not, however, identify which papers and patents
would be read on this basis, beyond making it clear that they would include the papers cited in [0075]-[0076] of WO 997.
216. During counsel for the Claimants’ oral closing submissions I asked whether it was the Claimants’ case that the skilled team would read all 47 papers and books and 26 patents
and
patent
applications cited in EP 823. After a great deal of equivocation during which he said at least twice that the answer was no, counsel’s final submission was that that the skilled team would read all the cited publications “for the purpose for which they are identified”, alternatively would read the publications cited in [0068]-[0069] and [0078] of EP 823 since those paragraphs refer to compounds for use in the invention.
217. Astonishingly, neither side referred during the course of the trial to the statement made in [0041] of WO 997, and the corresponding paragraphs of the granted Patents,
about the cited publications. I only noticed it when writing this judgment.
218. In my judgment there are two problems with the submissions advanced in the Claimants’ written closing submissions. First, there is no principle of law that the skilled team are deemed to read all documents cited in a patent.
It is a context- and fact-dependent question, and thus it depends firstly upon the wording of the specification and secondly on the evidence. Secondly, none of the documents cited in the specifications of the Family A
Patents
is “expressly advanced as relevant to the sufficiency of the
patents”.
220. As for the second submission, this appears to proceed on the assumption that the skilled team, or at least the medicinal chemist, would follow up those publications that are cited as disclosing compounds for use in the invention. But that approach does not lead one to the publications cited in [0068]-[0069] and [0078] of EP 823 (corresponding to [0075]-[0076] and [0084] of WO 997), since EP 823 also cites 15 patents
and
patent
applications as disclosing compounds for use in the invention. In my view the skilled reader would regard these references as simply providing sources of compounds which could be used if desired. In any event, no reason was identified as to why, if looking for compounds for use in the invention, the medicinal chemist would go to the cited papers and not the cited
patents
and publications.
221. My conclusion based on the texts of the granted Patents
and the evidence of the experts is that the skilled team would not necessarily follow up any of the cited publications. They would appreciate that there were a large number of them, and that the specification gives little, if any, direction as to which would be worth following up. They would also appreciate that the papers appear to be cited as providing scientific support for statements made in the specification, and that the cited papers would inevitably refer to a considerable number of other papers, leading to the question of how far they should go in reviewing such material. (Indeed, counsel for the Claimants put it to Prof Ward, and submitted in closing, that the skilled medicinal chemist would follow up a reference in Friedman even though no such suggestion was ever advanced or assumed by Dr Bhalay.) Whether they would review the cited publications would therefore depend in part on the time and resources available, which would vary between skilled teams. In my view they would be most likely to read Majamaa 1984 and Majamaa 1985, since these papers are cited in a manner that suggests that they may shed light on what is meant by “structural mimetics of 2-OG” and, as discussed below, the skilled reader would find that expression unclear. Even if the medicinal chemist did follow up all the six papers cited in [0075]-[0076] and [0084] of WO 997, what they would be looking for would be information about the chemistry and activities of specific compounds discussed in those papers, rather than for explanations of such activity. There is no basis whatsoever for thinking that the skilled team would single out US 305, US 995 and US 730 from the other cited
patents
and applications for review.
Majamaa 1984
“Pyridine 2,6-dicarboxylate differed from all the other compounds in its inhibition pattern.
This compound acts as a terdentate ligand [17] and thus cannot chelate the enzyme bound iron which provides two cis-positioned sites for co-substrate binding only (Fig. 1). Nevertheless, pyridine 2,6-dicarboxylate can interact with free Fe2+, thus competing with the enzyme for the metal.”
Majamaa 1985
Myllyharju and Kivirikko 1997
Myllyharju and Kivirikko 1998
242. Under the heading “Nonpeptide inhibitors” at page 362, the authors say:
“It has been pointed out ... that pyridine 2,5-dicarboxylate and 2-oxoglutarate may bind to P4H in different ways, and thus the data concerning modifications of this compound must be interpreted with caution (Cunliffe et al, 1992).”
Cunliffe
“… It seems very likely that oxaloglycine (3) and 2-oxoglutarate (1) bind to prolyl hydroxylase in a closely analogous way. Thus, the discovery that the structure-activity relationships in oxaloglycine series differ so completely from those in the pyridine-2,5-dicarboxylic acid series calls into question the published assumptions22 about the nature of the pyridine-2,5-dicarboxylic acid (2) binding site on prolyl hydroxylase and suggests caution in interpreting the physical reality underlying the observation of strictly competitive inhibition.”
Bickel
247. The authors state at page 408:
“The novel P4H inhibitor, S 4682, directly inhibited purified P4H, being substantially more potent than the structurally related 2,4-PDCA [pyridine 2,4-dicarboxylate] and 2-PCA [pyridine 2-carboxylic acid] at the enzyme level. Based on the IC50 values, S 4682 was 42 times more potent than 2,4-PDCA and 580 times more potent than 2-PCA (Table 1)”.
Dr Bhalay agreed that the skilled medicinal chemist would see this as very significant.
250. The authors state at page 407:
“S 4682 differs from other structural analogs of 2-oxoglutarate, such as pyridine 2-carboxylic acid (2,4-PDCA) and pyridine 2-carboxylic acid (2-PCA) by inhibiting P4H in a noncompetitive fashion with respect to the cosubstrate, 2-oxoglutarate (Fig 3A).”
Friedman
Franklin
US 730
257. Some of these compounds correspond to the exemplified isoquinolines in EP 823:
US 730 (IC50 μM) |
EP 823 |
Example 1 (0.12) |
Compound K |
Example 3 (0.79) |
Compound J |
Example 9 (2.30) |
Compound C |
Example 13 (9.30) |
Compound I |
Example 15 (0.66) |
Compound H |
Construction of Family A claims
260. Before turning to consider those issues, it is important to note a point that is common ground, which is that the claims require the therapeutic effects mentioned to be achieved. It is also common ground that the criteria for efficacy for this purpose are that indicated by the Examples in the specification, namely that the compound in question must inhibit HIF-PH in an appropriate biochemical (in vitro) assay and induce the production of endogenous Epo in vivo in a suitable animal model (such as a mouse or rat). (I would have thought that it must also increase haematocrit in a suitable animal model, but this point was not explored in closing submissions and so I shall say no more about it.) The claims obviously cover using the compounds for the treatment of human patients,
but neither side suggests that they require efficacy in humans to be demonstrated even to the level of a Phase II clinical trial.
Formula (I)
A page 34 lines 13-26:
B page 34 line 27 - page 35 line 40:
X page 35 line 41;
Q-R4 page 35 line 42 - page 36 line 34;
Y page 36 line 35;
R1, R2 and R3 page 36 line 35 - page 39 line 3 (note that Y may be N or CR3).
line 13: semi-colon before “or (C1-C4) alkylene”;
line 15: semi-colon before “(C1-C6)-alkylmercapto”;
line 19: semi-colon before “or by a substituted (C6-C12)-aryloxy”;
line 24: semi-colon before “or wherein A is -CR5R6”.
i) page 37 line 5: semi-colon before “CON(CH2)h''” - no line break;
ii) page 37 line 7: semi-colon before “a carbamoyl radical” - no line break;
iii) page 37 line 26: semi-colon before “or R* and R**”– no line break;
iv) page 37 line 29: semi-colon before “carbamoyloxy” - no line break;
v) page 37 line 50: semi-colon before “where an aryl” - no line break;
vi) page 38 line 20: semi-colon before “carbamoyloxy” - no line break;
vii) page 38 line 35: semi-colon after “(C7-C16)-aralkylsulfonyl” - line break;
viii) page 38 line 41: semi-colon after “ring” - line break;
ix) page 38 line 42: semi-colon after “ring” - line break;
x) page 38 line 41: semi-colon after “cinnoline” - line break;
xi) page 39 line 2: semi-colon after “above” - line break after “and”;
xii) page 39 line 3: semi-colon after “R3” - line break;
xiii) page 39 line 4: semi-colon after “8” - line break;
xiv) page 39 line 5: semi-colon after “(2f+1)” - line break;
xv) page 39 line 6: semi-colon after “3” - line break after “and”;
xvi) page 39 line 7: semi-colon after “7” - line break.
i) “R1, R2 and R3 are identical or different” at page 36 line 36 to page 38 line 35;
ii) “or wherein R1 and R2, or R2 and R3 form a chain” at page 38 lines 36-39;
iii) “or wherein the radicals R1 and R2, or R2 and R3” at page 38 lines 40-41;
iv) “or wherein R1 and R2, or R2 and R3 form a carbocylic” at page 38 line 42;
v) “or where R1 and R2, or R2 and R3, together with” at page 38 lines 43-45; and
vi) “or wherein the radical R1 and R2, together with the pyridine carrying them, form a compound of Formula Id” at page 38 line 46 to page 39 line 3.
275. Secondly, there is CON(CH2)hˈˈ defined at page 37 lines 5-7.
279. This takes me to the key passage of text starting “where an aryl radical may be substituted by 1 to 5 substituents” at page 37 lines 50-51. It is not obvious how this fits into the structure of the definition of R1, R2 and R3. As the Claimants point out, however, what can be seen is that the pattern
of substituents that follows repeats the
pattern
discussed above: “hydrogen, halogen, cyano, trifluoromethyl, nitro, carboxyl” (page 37 lines 51-52) followed by hydrocarbon (page 37 line 52 - page 38 line 2) followed by fluorine-containing (page 38 line 2) followed by carbonyl (page 38 lines 2-10) followed by carbamoyl (page 38 lines 10-18) followed by CON(CH2)hˈˈ (page 38 lines 18-20) followed by carbamoyloxy (page 38 lines 20-26) followed by amino (page 38 lines 26-33) followed by sulphur-containing substituents (page 38 lines 33-35). Although the
pattern
is the same, the options are not always the same: for example, the second list of sulphur-containing substituents is rather shorter than the first.
i) Type 1: instances in which the aryl group is specifically described as having a certain number and/or type of possible substitutions. See, for example, “or by a substituted (C6-C12)-aryloxy, (C7-C11)-aralkyloxy, (C6-C12)-aryl, (C7-C11)-aralkyl radical, which carries in the aryl moiety one to five identical or different substituents selected from halogen …” in A (page 34 lines 19-24) and “wherein radicals which are aryl or contain an aryl moiety, may be substituted on the aryl by one to five identical or different hydroxyl, halogen …” in B (page 35 lines 10-40).
ii) Type 2: instances where the aryl group is merely said to be “optionally substituted” without any indication as to the nature of the permitted substitution: see “optionally substituted (C7-C16)-aralkylcarbonyl, optionally substituted (C6-C12)-arylcarbonyl” in R4 (page 36 lines 32-33), “optionally substituted (C7-C16)-aralkanoyl, optionally substituted (C6-C12)-aroyl” in T (page 37 lines 25-26) and “optionally substituted (C7-C16)-aralkanoyl, or optionally substituted (C6-C12)-aroyl” in the second section of the definition of R1, R2 and R3 (page 38 line 39).
287. Before leaving this topic, however, I should mention for completeness a point which the Claimants relied upon as supporting their interpretation which I do not find persuasive. As noted above, and as discussed more fully below, EP 823 refers to 26 other patents
and applications. One such reference is in [0076]:
“Exemplary compounds according to Formula (Ia) are described in U.S. Patent
Nos, 5,719,164 and 5,726,305. All compounds listed in the foregoing
patents,
in particular, those listed in the compound claims and the final products of the working examples, may be used. Exemplary compounds according to Formula (Ia) …”
288. It is common ground that Example 16 of the first patent
(“US 164”) is a compound which falls inside Formula (I) on the Claimants’ interpretation, but outside it on the Defendants’ interpretations. The Claimants contend that this shows that the Defendants’ interpretations cannot be right. I do not accept this. Example 16 is just one of a very large number of compounds identified in
patents
cited in EP 823. Even if, contrary to the conclusion I have reached above, the skilled medicinal chemist would read at least the 15
patents
cited in [0078]-[0088] of WO 997, no reason has been given as to why the skilled person seeking to interpret Formula (I) would alight on Example 16 of US 164 as a means of checking their interpretation. US 164 is not even one of the
patents
singled out for review by Dr Bhalay. Nor has any reason been given as to why the skilled person would comb systematically through all the compounds listed in cited
patents
and applications to see which ones fell inside or outside on different interpretations, an exercise which would be a very laborious and time-consuming task indeed.
Structural mimetic of 2-OG
“Such compounds may inhibit the target 2-oxoglutarate dioxygenase family member competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron.”
“165. Claim 24 states that the compound of claim 1, 2, 19 or 20 is a ‘structural mimetic of 2-oxoglutarate’. Based on the discussion in the description of EP 823 and the prior art cited in EP 823 …, the Skilled Medicinal Chemist would understand this to be an additional mechanism-based feature by which I mean that, for a compound to fall within the claim, it needs to be one that is replicating or mimicking the key interactions of 2-oxoglutarate in the enzyme binding pocket (particularly bidentate coordination to Fe2+ via dative bonding from the lone electron pairs possessed by the aromatic nitrogen and the carbonyl oxygen of the carboxamide moiety). If a compound replicates or mimics the other two interactions of 2-oxoglutarate in the enzyme binding pocket …, this would also be expected to contribute to that compound acting as a structural mimetic of 2-oxoglutarate. ….
166. To assess whether a given compound is a ‘structural mimetic of 2-oxoglutarate’, the Skilled Medicinal Chemist would be able to make a visual assessment of its structure. In particular, the Skilled Medicinal Chemist would determine whether it is capable of replicating or mimicking the key interactions of 2-oxoglutarate with the active site of the enzyme, primarily whether it has at least two groups capable of forming dative bonds with Fe2+, for bidentate coordination in the active site. This could then be confirmed experimentally by assessing whether the compound in question competitively inhibits binding of 2-oxoglutarate.”
300. When it was put to Dr Bhalay that the medicinal chemist would be left wholly uncertain as to what that expression would be understood to mean, he had no coherent explanation. Instead his approach seemed to require the medicinal chemist to conduct enzyme kinetic experiments using isolated HIF-PH to discover whether Compounds C-K compete with respect to 2-OG. If they turned out to be competitive, then he would use similar kinetic analyses to determine whether or not other compounds were structural mimetics. This is not a criterion that is suggested anywhere in the Family A Patents.
Obviousness of Family A over Epstein
The disclosure of Epstein
306. Epstein identifies the enzyme that performs the prolyl hydroxylation of HIF-α, first in the nematode worm, C. elegans, and then as a series of homologues in mammalian cells. It investigates the biochemistry of recombinantly expressed proteins, revealing the HIF-PH enzyme to be the oxygen sensor in the hypoxia pathway.
Prof Haase’s explanation of the disclosure of Epstein in his first report was agreed by Prof Winearls in his third report. I would summarise this as follows.
308. Epstein then describes the work which the authors carried out. In summary:
i) A candidate worm version of HIF-α, termed HIF-1, was identified by database searches of the genome, and was found (like mammalian HIF-α) to encode a protein regulated by hypoxia and iron chelation.
ii) The worm version of VHL (i.e. the protein that ubiquitylates HIF-α, resulting in its destruction) was then also identified. Mutants in the gene encoding worm VHL had abnormally high levels of HIF-1 in the presence of oxygen, indicating that HIF-1 destruction was defective.
iii) The physical association between recombinantly-expressed HIF-1 and VHL was found to depend upon an activity found in worm extract, and this activity was identified (like in the mammalian system) as causing hydroxylation of a particular proline residue in a peptide found in HIF-1. This proline hydroxylation was dependent on 2-OG: it could be inhibited by an analogue of 2-OG, and the inhibition was competed with by excess 2-OG. A cell-penetrating analogue of 2-OG, DMOG, strongly induced HIF-1 in normoxic worms.
iv) Further database searches identified worm homologues of the 2-OG-dependent oxygenase superfamily. Mutants of one of these, EGL9, had high levels of HIF-1 in normoxia and showed upregulation of hypoxia-inducible transcripts (even in the absence of hypoxia).
v) The biochemical function of recombinant EGL-9 as a HIF-PH was demonstrated. It was found to depend on 2-OG, iron and oxygen, and was directly inhibited by cobalt ions.
vi) Human homologues were then identified in the sequence databases, which the authors term PHD-1, PHD-2 and PHD-3. Recombinantly-expressed versions of these proteins resulted in prolyl hydroxylation of human HIF-α, and this activity was again strongly inhibited by iron chelation, cobalt ions, and by the 2-OG analogue NOG, and to depend upon oxygen concentration.
310. In its discussion section Epstein states (at page 51-52) that:
“… the classical features of HIF induction by hypoxia, cobaltous ions, and iron chelators can be explained, at least qualitatively, by the properties of recombinant HIF-PH enzymes.”
311. It goes on to say (at 52):
“In mammals, the HIF system regulates not only cellular responses to oxygen, but also a range of systemic functions such as regulation of angiogenesis, erythropoiesis, and vasomotor control. …”
312. The paper concludes (at 52):
“Finally, the identification of the HIF-PHIs also raises therapeutic possibilities. Inhibitors of HIF-PHs might be used to activate HIF and enhance angiogenesis in ischemic/hypoxic disease. Application of the 2-oxoglutarate analog dimethyloxalylglycine to tissue culture cells strongly induces HIF target genes (D.R.M., unpublished observations). Though this compound is not specific for the HIF-PHs and inhibits other 2-oxoglutarate dioxygenases, structural and mechanistic studies of the defined enzymes may now permit design of more specific inhibitors for therapeutic development.”
The differences between Epstein and claim 17A of EP 531
315. The differences between Epstein and claim 17A of EP 531 are as follows:
i) Epstein makes no reference to the treatment or prevention of anaemia associated with kidney disease, or even to enhancing endogenous Epo. Epstein mentions possible therapeutic uses of HIF-PHIs to activate HIF and enhance angiogenesis in ischaemic/hypoxic disease, but does not refer to erythropoiesis in this context.
ii) Although Epstein discloses the use of inhibitors of HIF-PH to stabilise HIF, it discloses only one inhibitor, namely DMOG, and provides no results beyond stating that it “strongly induces HIF target genes” in tissue culture cells. It is not disclosed that DMOG induces the production of endogenous Epo in an animal model. Thus Epstein does not show that DMOG satisfies the second of the two criteria for therapeutic efficacy discussed in paragraph 260 above.
iii) Epstein does not disclose Compound C.
Is claim 17A of EP 531 obvious?
i) Would it be obvious to consider using a HIF-PHI to treat or prevent anaemia associated with CKD?
ii) If so, would the skilled person have a reasonable expectation of success, in the sense of satisfying the criteria for therapeutic efficacy discussed above?
iii) If so, would it be obvious to search for other compounds in addition to DMOG to test?
iv) If so, would a routine search lead to Compound C?
323. Secondly, counsel for the Claimants put to Prof Haase a series of 10 papers about HIF, including Ivan and Jaakkola, published in the period from 2000 to 2003 which do not mention the treatment of anaemia as a possible application of HIF-PHIs, whereas there are a number of mentions of ischaemia and a couple of mentions of stroke and cancer. Again, counsel for the Claimants submitted that, if the treatment of anaemia had been obvious, at least some of these papers would have been bound to mention it. Again, Prof Haase did not accept this, and nor do I. The evidence relied upon is a dog that did not bark in the night; but it is only probative if there is some reason why the dog should have barked. I am not persuaded that there is. One of the papers (Jaakkola) does not discuss clinical applications at all. More importantly, it was not established, or even put to Prof Haase, that the authors of all the papers included one or more persons corresponding to the skilled nephrologist: although some did, it appears that some did not (such as a review written by at least two oncologists). Even in the case of papers which do satisfy that criterion, the point remains that a perfectly good explanation why cancer, heart disease and stroke are mentioned is to draw attention to the significance of HIF, particularly in journals not aimed at nephrologists. Furthermore, an alternative explanation for the failure to mention the potential application of HIF-PHIs to induction of Epo is that it was considered by many to be unremarkable in the light of Epstein. Yet further, as Prof Haase pointed out in his third report, two review articles, one by Ratcliffe and one by Patrick
Maxwell, were published during the same period (in September 2002 and 2003 respectively) which cited Epstein and which did expressly mention “erythropoietin deficiency” and “promot[ing] erythropoiesis” as potential therapeutic applications for HIF-PHIs.
324. Thirdly, the Claimants pointed out that on 21 March 2002 Isis Innovation Ltd (“Isis”) filed a priority patent
application in the UK (0206711.4) naming a number of inventors, including Ratcliffe, for an invention relating to HIF-PHIs which mentioned a number of potential therapeutic applications but not anaemia, although it did mention the “critical” role of HIF in (among other things) erythropoiesis. When Isis came to file an international application (WO 03/080566) claiming priority from the UK filing on 21 March 2003, additional applications were included, including “the treatment of anaemia”. Counsel for the Claimants suggested that this showed this application had not occurred to the Ratcliffe group by March 2002, but only later. This does not necessarily follow. They might, for example, have thought that it went without saying. They did not need to mention this specific application, because the claims in the priority document did not include any claims directed to specific applications, but did include a general claim directed to “treatment of a condition associated with increased or decreased HIF levels or activity”.
“… we know that the damaged kidneys can produce extra Epo. What we would have been concerned about is, if the original stimulus to the HIF system was not working adequately in these patients,
why would an alternative work?”
330. After it was put to Prof Winearls that the answer to this question was that a HIF-PHI would artificially stimulate the system rather than relying upon the natural hypoxia, he accepted that this would obviously be well worth testing to see if it worked, but not that it was obvious that it would do so. As he put it, “… I would have said, ‘It could work, but I am not sure that it will’.” He went on to accept that it would be obvious in particular to test compounds in rats with cisplatin (as in Example 4 in the Family A Patents).
331. Although Prof Winearls was clear and consistent throughout his evidence that, in his opinion, the skilled nephrologist would be sceptical as to the ability of damaged kidneys to produce sufficient Epo to alleviate the patients’
anaemia, not once did he suggest that the skilled nephrologist would think that HIF-PHIs were unlikely to work because the enhanced production of Epo in response to hypoxia was thought to be transient. Despite this, the case that was put to Prof Haase in cross-examination was that the skilled nephrologist would think that the effect on damaged kidneys would be both insufficient and transient. Given that it was never mentioned by Prof Winearls, I do not accept that transience would have been a factor in the skilled nephrologist’s thinking. In any event, Prof Haase did not agree that either factor meant that it was not obvious to try using HIF-PHIs to treat anaemia.
332. Turning to Prof Winearls’ second concern, this was that there could be a problem due to the fact that HIF turns on other genes as well as Epo. This is not a concern he had raised in his written evidence, however. Moreover, as he accepted, it is not something that is addressed in the Family A Patents.
Nor was it put to Prof Haase as being something that would deter the skilled nephrologist from testing HIF-PHIs for anaemia.
342. Dr Bhalay noted in his third report that SW3 included Majamaa 1985, Bickel, Franklin, and the two European patents
cited in WO 997. It also includes US 974. More importantly, it includes German
patent
application No. 197 46 287 (“DE 287”). It can be seen from US 730 (which, as noted above, is WO 997’s source for Compound C) that this was the priority document for US 730. As is common ground, US 730 contains both in vitro and in vivo results demonstrating the efficacy of Compound C as a P4H inhibitor. The same data are contained in DE 287; but the skilled team would have to obtain a translation of DE 287 to find that out.
345. I therefore conclude that claim 17A of EP 531 is not obvious over Epstein.
Other claims
346. Given that claim 17A is not obvious over Epstein, and the way in which the Defendants put their case, it follows that nor are the other claims of the Family A Patents
in issue. If claim 17A was obvious, the Claimants did not identify any reason why the other claims would be independently valid. The validity of the other claims would be saved, however, by the conditional amendments proposed by FibroGen.
Insufficiency of EP 823 and EP 301
347. A patent
is invalid if “the specification does not disclose the invention clearly and completely enough for it to be performed by a person skilled in the art” (section 72(1)(c) of the
Patents
Act 1977 giving effect to Article 138(1)(b) EPC). As I have observed in a number of previous judgments, although insufficiency is a single ground of invalidity, it embraces three distinct types of objection: where the invention cannot be performed at all without undue burden (sometimes called “classical insufficiency”); where the invention cannot be performed across the breadth of the claim without undue burden (sometimes called “Biogen insufficiency” and also referred to as “excessive claim breadth”); and where the claim does not enable the skilled person to know whether they are within the claim or outside (previously called “ambiguity” and recently re-named “uncertainty”). In the present case the Defendants advance both of the latter types of objection against EP 823 and EP 301, but not the first.
Excessive claim breadth
349. In Eli Lilly & Co v Human Genome Sciences Inc [2012] EWCA Civ 1185, [2013] RPC 22 at [11] Sir Robin Jacob, and in Idenix Pharmaceuticals Inc v Gilead Sciences Inc [2016] EWCA Civ 1089 at [133] Kitchin LJ, cited with approval the following summary of the basic principles given by Kitchin J (as he then was) at first instance in the former case [2008] EWHC
1903 (
Pat),
[2008] RPC 29 at [239]:
“The specification must disclose the invention clearly and completely enough for it to be performed by a person skilled in the art. The key elements of this requirement which bear on the present case are these:
(i) the first step is to identify the invention and that is to be done by reading and construing the claims;
(ii) in the case of a product claim that means making or otherwise obtaining the product;
(iii) in the case of a process claim, it means working the process;
(iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims;
(v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification;
(vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim;
(vii) the specification must be sufficient to allow the invention to be so performed without undue burden.”
350. As Kitchin LJ added in Idenix v Gilead at [135]:
“The extent of the disclosure necessary to make the patent
sufficient depends on the nature of the invention, the scope of the claims and the art in which the invention is made …”
352. It is well established that it is permissible for a claim to describe an invention in general terms provided it is plausible in the light of the disclosure and the common general knowledge that the invention will work with anything falling within the scope of those terms. As Kitchin LJ explained in Regeneron Pharmaceuticals Inc v Genentech Inc [2013] EWCA Civ 93, [2013] RPC 28:
“98. … it is permissible to define an invention using general terms provided the patent
discloses a principle of general application in the sense that it can reasonably be expected the invention will work with anything falling within the claim. As Lord Hoffmann said in Biogen Inc. v Medeva plc [1977] R.P.C. 1 at pp.48–49:
‘If the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. The patentee
need not show that he has proved its application in every individual instance. On the other hand, if the claims include a number of discrete methods or products, the
patentee
must enable the invention to be performed in respect of each of them.
Thus if the patent
has hit upon a new product which has a beneficial effect but cannot demonstrate that there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a
patent
for that product but not for the class, even though some may subsequently turn out to have the same beneficial effect: see May & Baker Ltd v Boots Pure Drug Co. Ltd. (1950) 67 R.P.C. 23, 50. On the other hand, if he has disclosed a beneficial property which is common to the class, he will be entitled to a
patent
for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.’
99. In Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2004] UKHL 46, [2005] RPC 9 Lord Hoffmann further explained the concept of a principle of general application in this way:
‘112. In my opinion there is nothing difficult or mysterious about [a principle of general application]. It simply means an element of the claim which is stated in general terms. Such a claim is sufficiently enabled if one can reasonably expect the invention to work with anything which falls within the general term. For example, in Genentech I/Polypeptide expression (T 292/85) [1989] O.J. EPO 275, the patentee
claimed in general terms a plasmid suitable for transforming a bacterial host which included an expression control sequence to enable the expression of exogenous DNA as a recoverable polypeptide. The
patentee
had obviously not tried the invention on every plasmid, every bacterial host or every sequence of exogenous DNA. But the Technical Board of Appeal found that the invention was fully enabled because it could reasonably be expected to work with any of them.
113. This is an example of an invention of striking breadth and originality. But the notion of a “principle of general application”' applies to any element of the claim, however humble, which is stated in general terms. A reference to a requirement of “connecting means” is enabled if the invention can reasonably be expected to work with any means of connection. The patentee
does not have to have experimented with all of them.’
100. It must therefore be possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim or, put another way, the assertion that the invention will work across the scope of the claim must be plausible or credible. The products and methods within the claim are then tied together by a unifying characteristic or a common principle. If it is possible to make such a prediction then it cannot be said the claim is insufficient simply because the patentee
has not demonstrated the invention works in every case.
101. On the other hand, if it is not possible to make such a prediction or if it is shown the prediction is wrong and the invention does not work with substantially all the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution the patentee
has made to the art and the claim will be insufficient. It may also be invalid for obviousness, there being no invention in simply providing a class of products or methods which have no technically useful properties or purpose.”
353. Accordingly, the authorities establish that the court must undertake a two-stage enquiry. The first stage is to determine whether the disclosure of the patent,
read in the light of the common general knowledge of the skilled team, makes it plausible that the invention will work across the scope of the claim. At this stage, it is not permissible for either the
patentee
or the party attacking the
patent
to rely upon evidence which post-dates the
patent.
If the disclosure does make it plausible, the second stage is to consider whether the evidence establishes that in fact the invention cannot be performed across the scope of the claim without undue burden. At this stage, evidence which post-dates the
patent
is admissible.
354. The criterion of plausibility has received the most detailed consideration by the courts in the context of claims involving medical applications. The authoritative statement of the law is that of the majority of the Supreme Court in Warner-Lambert Co LLC v Generics (UK) Ltd [2018] UKSC 56, [2019] Bus LR 360, which was given by Lord Sumption. That case was concerned with a second medical use claim in Swiss form of a known pharmaceutical. This part of the present case is concerned with a first medical use of (largely) known compounds, even though there are claims framed as second medical use claims both in Swiss form and in EPC 2000 form. There is no dispute that the guidance given by Lord Sumption is applicable, although the Claimants contend that, for the reasons explained below, it is not the whole story. (To avoid returning to this subject later, I would add that the claims in the Family B Patents
are true second medical use claims, and thus Lord Sumption’s guidance is directly applicable.)
355. Lord Sumption began at [17] with the fundamental principle that, as it was put by the Board of Appeal of the European Patent
Office in T 409/91 Exxon/Fuel oils [1994] OJ EPO 63 at [3.3] and [3.4], “the extent of the
patent
monopoly, as defined by the claims, should correspond to the technical contribution to the art”, that is to say, “the
patent
monopoly should be justified by the actual technical contribution to the art”. As he observed, the requirements of novelty, inventive step, industrial applicability and sufficiency are all, in one way or another, directed to ensuring that this principle is satisfied.
356. At [19]-[20] Lord Sumption noted that the problem with interpreting the requirement of sufficiency in the context of a second medical use claim as merely requiring the disclosure of the new purpose was that “it would enable a patent
to be obtained on a wholly speculative basis”. Importantly for the present context, he said at [22]:
“The Court of Appeal's reference to ‘armchair inventors’ suggests that what they meant by speculative claiming was claiming by persons who had done nothing new or inventive at all but had simply sought to patent
abstract possibilities. That may well be a particular risk in the case of
patents
for new uses of known compounds, especially when they are commercially successful in their existing use. In reality, however, speculative claiming of this kind is simply one of a number of ways in which a
patentee
may attempt to claim a monopoly more extensive than anything which is justified by his contribution to the art. Other ways in which this can happen include claiming a monopoly wider than the disclosure in the
patent
can support. An over-broad claim will not necessarily be speculative. The inventor may really have invented something corresponding to the full breadth of the claim. Research may subsequently demonstrate this. But the claim will still exceed his contribution to the art if that contribution is not sufficiently disclosed in the
patent.”
“The principle is that the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true. Plausibility is not a distinct condition of validity with a life of its own, but a standard against which that must be demonstrated. Its adoption is a mitigation of the principle in favour of patentability.
It reflects the practical difficulty of demonstrating therapeutic efficacy to any higher standard at the stage when the
patent
application must in practice be made. The test is relatively undemanding. But it cannot be deprived of all meaning or reduced … to little more than a test of good faith.”
359. Lord Sumption went on at [37] (emphases and line breaks added):
First, the proposition that a product is efficacious for the treatment of a given condition must be plausible.
Second, it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion. ….
But, third, the claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason, ie not just because there was an abstract possibility that it would work but because reasonable scientific grounds were disclosed for expecting that it might well work. The disclosure of those grounds marks the difference between a speculation and a contribution to the art. This is in substance what the Technical Board of Appeal has held in the context of article 56, when addressing the sufficiency of disclosure made in support of claims extending beyond the teaching of the patent.
In my opinion, there is no reason to apply a lower standard of plausibility when the sufficiency of disclosure arises in the context of EPC articles 83 and 84 and their analogues in section 14 of the
Patents
Act. In both contexts, the test has the same purpose.
Fourth, although the disclosure need not definitively prove the assertion that the product works for the designated purpose, there must be something that would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true.
Fifth, that reasonable prospect must be based on what the TBA in SALK (para 9) called ‘a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent
per se.’
Sixth, in SALK, this point was made in the context of experimental data. But the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning. For example, and it is no more than an example, the specification may point to some property of the product which would lead the skilled person to expect that it might well produce the claimed therapeutic effect; or to some unifying principle that relates the product or the proposed use to something else which would suggest as much to the skilled person.
Seventh, sufficiency is a characteristic of the disclosure, and these matters must appear from the patent.
The disclosure may be supplemented or explained by the common general knowledge of the skilled person. But it is not enough that the
patentee
can prove that the product can reasonably be expected to work in the designated use, if the skilled person would not derive this from the teaching of the
patent.”
360. At [40] Lord Sumption added:
“The question is not whether [the medicament] works but whether the contribution to the art consisting in the discovery that it can be expected to work has been sufficiently disclosed in the patent.
The inherent difficulty of demonstrating this before clinical trials is taken into account in the modest standard (ie plausibility) which is applied to test it. … This does not mean that subsequent data is never admissible in a dispute about sufficiency, but the purpose for which it is admitted is strictly limited. Where the asserted therapeutic effect is plausible in the light of the disclosure in the
patent,
subsequent data may sometimes be admissible either to confirm that or else to refute a challenger's contention that it does not actually work… But it cannot be a substitute for sufficient disclosure in the specification.”
“Whether the specification discloses an invention clearly and completely enough for it to be performed by a person skilled in the art involves a question of degree. It is impossible to lay down any precise rule because the degree of clarity and completeness required will vary depending on the nature of the invention and of the art in which it is made. On the one hand, the specification need not set out every detail necessary for performance. The skilled person must be prepared to display a reasonable degree of skill and use the common general knowledge of the art in making routine trials and to correct obvious errors in the specification, if a means of correcting them can readily be found. Further, he may need to carry out ordinary methods of trial and error, which involve no inventive step and generally are necessary in applying the particular discovery to produce a practical result. On the other hand, he should not be required to carry out any prolonged research, enquiry or experiment: Mentor Corporation v Hollister Inc. [1993] R.P.C. 7.”
“102. … patentees
not infrequently seek to avoid the possibility that a claim covers products or methods which do not work by inserting a functional limitation. Such a claim may be allowed by the EPO if the invention can only be defined in such terms or cannot otherwise be defined more precisely without unduly restricting its scope. But, it must still be possible to perform the invention across the scope of the claim without undue effort. As I said in Novartis v Johnson & Johnson at [244]:
‘… In the case of a claim limited by function, it must still be possible to perform the invention across the scope of the scope of the claim without undue effort. That will involve a question of degree and depend upon all the circumstances including the nature of the invention and the art in which it is made. Such circumstances may include a consideration of whether the claims embrace products other than those specifically described for achieving the claimed purpose and, if they do, what those other products may be and how easily they may be found or made; whether it is possible to make a reasonable prediction as to whether any particular product satisfies the requirements of the claims; and the nature and extent of any testing which must be carried out to confirm any such prediction.’
103. … the Boards of Appeal of the EPO have recognised that in the case of a claim to the use of a product to make a medicine for a particular therapeutic purpose it would impose too great a burden on the patentee
to require him to provide absolute proof that the compound has approval as a medicine. Further, it is not always necessary to report the results of clinical trials or even animal testing. Nevertheless, he must show, for example by appropriate experiments, that the product has an effect on a disease process so as to make the claimed therapeutic effect plausible. It was put this way in T609/02 Salk at [9]:
‘… It is a well-known fact that proving the suitability of a given compound as an active ingredient in a pharmaceutical composition might require years and very high developmental costs which will only be borne by the industry if it has some form of protective rights. Nonetheless, variously formulated claims to pharmaceutical products have been granted under the EPC, all through the years. The patent
system takes account of the intrinsic difficulties for a compound to be officially certified as a drug by not requiring an absolute proof that the compound is approved as a drug before it may be claimed as such. The boards of appeal have accepted that for a sufficient disclosure of a therapeutic application, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement in a
patent
specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the
patent
provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the
patent
per se. Showing a pharmaceutical effect in vitro may be sufficient if for the skilled person this observed effect directly and unambiguously reflects such a therapeutic application (T 241/95, OJ EPO 2001, 103, point 4.1.2 of the reasons, see also T 158/96 of 28 October 1998, point 3.5.2 of the reasons) or, as decision T 158/96 also put it, if there is a “clear and accepted established relationship” between the shown physiological activities and the disease (loc. cit.). Once this evidence is available from the
patent
application, then post-published (so-called) expert evidence (if any) may be taken into account, but only to back-up the findings in the
patent
application in relation to the use of the ingredient as a pharmaceutical, and not to establish sufficiency of disclosure on their own.’”
363. Consistently with this statement of the law, it has been held in a number of cases that a patent
will be insufficient if the specification requires the skilled person to undertake a substantial research project in order to perform the invention (either at all or across the breadth of the claim) and claims the results: see e.g. American Home Products Corp v Novartis Pharmaceuticals UK Ltd [2001] RPC 8 at [41]-[47] (Aldous LJ), Halliburton Energy Services Inc v Smith International (North Sea) Ltd [2006] EWCA Civ 1715 at [18] (Jacob LJ), Novartis AG v Johnson & Johnson Medical Ltd [2010] EWCA Civ 1039, [2011] ECC 10 at [50]-[92] (Jacob LJ) and Idenix v Gilead at [197] (Kitchin LJ).
364. Kitchin LJ returned to the question of the extent to which an invention must be enabled across the whole scope of the claim in Regeneron Pharmaceuticals Inc v Kymab Ltd [2018] EWCA Civ 671, [2018] RPC 14. Having reviewed a number of decisions of Boards of Appeal of the EPO, he concluded:
“231. First, it is not the law that a specification must necessarily enable the skilled person to make or perform all of the embodiments of a claimed invention. Were it otherwise, claims would be insufficient if they covered inventive improvements. But, as the decision in GENENTECH I/Polypeptide expression makes clear, in appropriate cases, a claim may embrace variants which may be provided or invented in the future and which achieve the same effect in a manner which could not have been envisaged without the invention.
232. Secondly, the assessment of insufficiency must be sensitive to the nature of the invention and the facts of the particular case. If the character of the invention is one of general methodology or is such that the invention is of general application then it may be permissible to claim it in general terms, even though the specification does not enable every way of arriving at its subject matter. Otherwise, as the Board explained in Modifying plant cells/MYCOGEN , no dominant patent
could ever exist and each developer of a new method of arriving at that subject matter would be free of earlier
patents.
In many cases in the field of biotechnology,
patent
protection would then become illusory.
233. Thirdly, it is a general principle that the protection afforded by the claims must correspond to the technical contribution to the art made by the disclosure of the invention. The patentee
is entitled to fair protection having regard to the nature and character of the invention he has described.
…
248. Th[e] exposition [of the law in Regeneron v Genentech at [173]] is, we believe, entirely consistent with the principles we have identified. A claim is not insufficient simply because it encompasses inventive embodiments provided they embody the technical contribution the disclosure of invention has made to the art.”
365. A particular issue which arises in this case concerns the sufficiency of claims which combine both broad structural and functional features. Counsel for the Claimants submitted that such a claim was valid if the skilled person or team could identify, without undue burden, some compounds having the claimed structural features which also fulfilled the claimed functional requirements. In my judgment this is not the law. Rather, the law is correctly stated in Case Law of the Boards of Appeal of the European Patent
Office (9th edition, 2019) at page 368 (emphasis added):
“In T 544/12 the board confirmed that a definition of a group of compounds in a claim by both structural and functional features is generally acceptable under Article 83 EPC as long as the skilled person is able to identify, without undue burden, those compounds out of the host of compounds defined by the structural feature(s) in the claim which also fulfil the claimed functional requirements (following T 435/91 and T 1063/06).”
The statement of principle in T 544/12 Princeton University/Very High Efficiency Organic LEDs (22 November 2013) at [4.2] has subsequently been followed in other Board of Appeal decisions which counsel for the Claimants cited and relied on, such as T 555/12 Cytec Technology/Flexible Polymer Element (30 July 2015) at [5.1] and T 323/13 Princeton University/L2MX Complexes (5 March 2015) at [7.1.1].
369. Plausibility. For the reasons explained above, the first question to consider is whether the disclosure of the Family A Patents,
read in the light of the skilled team’s common general knowledge, makes it plausible that the invention will work across the scope of the claims in issue. As the Claimants emphasise, the Defendants do not contend that claim 17A of EP 531 is insufficient. Accordingly, there is no dispute that the specification makes it plausible that Compound C is effective in the treatment or prevention of anaemia associated with CKD. Indeed, it fully demonstrates that Compound C satisfies the criteria for efficacy discussed in paragraph 260 above. It is convenient to note here that it is common ground that the specification also adequately demonstrates efficacy for Compounds E, F, J and K.
373. I do not accept this argument. In my judgment it is precluded by the decision of the Court of Appeal in Idenix v Gilead, which is binding on this Court. In that case claim 1 of the patent
was, on its face, a pure compound claim based on a Markush formula which embraced a very large number of compounds. The parties agreed at trial, however, that the validity of claim 1 should be assessed on the basis that it was to be construed as a claim to compounds which had anti-Flaviviridae activity (see [2014]
EWHC
3916 (
Pat)
at [306]). I concluded that claim 1 was invalid for lack of inventive step on AgrEvo grounds because it covered compounds which the skilled team would not have considered plausible had anti-Flaviviridae activity and which therefore did not plausibly solve the technical problem of providing compounds which did have such activity, and thus the claim covered compounds which made no technical contribution to the art (see [449]-[450)]). For the same reasons, I concluded that the disclosure of the
patent,
read in the light of the common general knowledge of the skilled team, did not make it plausible that the invention would work across the scope of the claim, and therefore the claim was insufficient (see [469]).
374. The Court of Appeal upheld the conclusion that the claim lacked an inventive step for want of plausibility (see [2016] EWCA Civ 1089 at [129]), and held that it inevitably followed that it was also insufficient for the same reasons (see [140]). Importantly, when considering the question of plausibility for the purposes of inventive step, Kitchin LJ referred in his judgment not once but twice to the fact that it was agreed that the claim should be construed as a claim to compounds which had anti-Flaviviridae activity (see [116] and [124]).
375. It is fair to say that counsel for the appellant do not appear to have submitted that, because the claim was limited to compounds which had anti-Flaviviridae activity, it necessarily followed that it was plausible that all compounds covered by the claim would work. Nor, consequently, did Kitchin LJ reject any such submission. It is not hard to see, however, why the very experienced team of specialist counsel who represented the appellant did not make that submission, and why neither of the two very experienced specialist judges (the other being Floyd LJ) who sat on the appeal thought that it was an answer to the objection of lack of plausibility. The reason is that it was implicit in the agreed construction of the claim that the patent
was promising that substantially all compounds having the defined structure did have anti-Flaviviridae activity. Otherwise the
patentee
would have been saying, in effect, “I claim those compounds which are among the billions covered by the structural definition which happen to have anti-Flaviviridae activity, but I make no promise that any of them do, and you, dear reader, can go and find out which if any do have such activity”. That would not have involved an inventive step, because it would not have solved the technical problem of providing compounds which did have anti-Flaviviridae activity. Equally, it would have meant that the specification did not sufficiently disclose the invention, because it was leaving the task of finding compounds which had anti-Flaviviridae activity to the reader. As Lord Sumption pointed out in Warner-Lambert, the underlying consideration in both contexts is the same: what actual technical contribution has the
patentee
made to the art which justifies the scope of the monopoly claimed?
376. Turning to the present case, the patent
is implicitly promising that substantially all compounds which satisfy the structural definitions in the claims in issue will have the claimed therapeutic efficacy. Otherwise, the skilled team would be faced with a situation where the structural definition covers around 10183 compounds (or a little less or even more), but the specification only demonstrates that five compounds, namely Compounds C, E, F, J and K, satisfy the criteria for therapeutic efficacy. That would amount to no more than an invitation to the skilled team to find the other compounds covered by the claim which work. It would not involve an inventive step, because it would not solve the technical problem of identifying compounds which have the desired activity, and it would not sufficiently disclose the invention, because it would leave most of the work to the reader.
378. Instead, the Claimants argue that the technical contribution of the Family A Patents
is the teaching that “heterocyclic carboxamides, being prolyl hydroxylase inhibitors, can be used to treat anaemia associated with kidney disease by inhibiting HIF-PH”, and that they are entitled to claims commensurate with that technical contribution. As I understand it, what the Claimants mean by this statement is that some heterocyclic carboxamides (i.e. Carboxamides as I have defined that term) can be used to treat anaemia. They do not mean that all, or even substantially all, heterocyclic carboxamides can be used for that purpose.
388. Dr Bhalay’s evidence in paragraph 168 of his first report was that, having read the six papers and the three US patents,
it would be straightforward and routine for the skilled medicinal chemist “to identify compounds other than those tested in the specific examples which exhibit similar activity and have potential use in therapy”. It is clear from what he said both in this paragraph and elsewhere in his first report that what he meant by this was some compounds. The same goes for his third report.
389. It is clear from Dr Bhalay’s evidence that this would require a substantial amount of work. The medicinal chemist would start by making Compounds C-K in order to verify the teaching of the Family A Patents
and for benchmarking purposes. The medicinal chemist would then synthesise and test other compounds using the same or similar assays to those disclosed in EP 823. The medicinal chemist would make sensible choices (e.g. avoiding excessively and unnecessarily bulky substitutions). Relatively large numbers of compounds could be tested in vitro and those that which showed activity could be tested further in vivo.
390. Just making the compounds is not simple. The Family A Patents
do not teach how to make any of the compounds that they describe. There is a dispute as to how useful the information contained in the cited
patents
would be in synthesising new compounds, and the extent to which combinatorial synthesis could assist. Prof Ward thought that a single skilled medicinal chemist could make approximately 150 compounds a year, while Dr Bhalay said that using combinatorial or parallel synthesis it would have been feasible to make “many thousands of compounds in a year”. It does not matter who is right about this, and I will assume Dr Bhalay is, at least if “many” is interpreted as being low single digits.
392. Dr Bhalay clarified the nature of this exercise in cross-examination:
i) the medicinal chemist would start with an SAR analysis, involving tens, hundreds or even thousands of compounds to see what kind of changes are tolerated, testing for activity in an enzyme assay;
ii) depending on the strategy, there might be “spot checks” to see whether the compounds were competitive with respect to 2-OG;
iii) compounds which looked promising would be progressed to cell-based Epo induction assays;
iv) after that, promising compounds would go on to in vivo Epo induction assays, but not before completion of some initial pharmacokinetic studies.
394. In summary, the search for active compounds beyond Compounds C-K would be a very substantial undertaking, even for a well-resourced company. By its very nature, it would be a research programme, as Dr Bhalay accepted. Moreover, the difficulty of making any reliable prediction of what would work is vividly illustrated by Dr Bhalay’s comment that, even having read the six papers and three patents,
it would be “a leap of faith” to conclude that (as the Claimants contend) useful guidance could be obtained from the information they provided about collagen prolyl hydroxylases given the absence of information that the three-dimensional shape of the active site of HIF-PH was the same.
396. In addition to the opinion evidence of the experts summarised above, there is a certain amount of evidence that post-dates the Family A Patents
from the parties’ disclosure. This consists of results from various assays in respect of compounds which qualify as Carboxamides even if they do not fall within Formula (I). Leaving aside the fact that there is no witness evidence concerning this work, as the Defendants point out, some caution is required because it is evident that some of it was carried out after the publication of a crystal structure of HIF-PH and Compound C in 2006 (see N.C. Warshakoon et al, “Design and synthesis of substituted pyridine derivatives as HIF-1α prolyl hydroxylase inhibitors”, Bioorg Med Chem Lett, 16, 5616-5620 (2006) (“Warshakoon”) at 5616 and references 9 and 20). That is information which obviously was not available at the Family A Priority Date, and as explained above would have made it easier to design active compounds.
Uncertainty
400. The law. In Generics (UK) Ltd v Yeda Research & Developments Co Ltd [2012] EWHC
1848 (
Pat)
I said at [193]:
“… it is necessary to distinguish between claims that are difficult to construe or that have a ‘fuzzy boundary’ (in the words of Lord Hoffmann in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2004] UKHL 46 [2005] RPC 9 at [126]) on the one hand from claims that are truly ambiguous on the other. It is regrettably common for claims to be difficult to construe, but the court will nevertheless strive to give such claims a sensible meaning having regard to the inventor's purpose. It is also common for claims to have a fuzzy boundary, because an integer of the claim involves some question of degree or an imprecise functional limitation. It is well established that is not itself objectionable. If a claim is truly ambiguous, so that it is unclear what is the correct test to determine whether or not a product or process infringes, however, then the claim is insufficient…”
That statement of the law was approved by the Court of Appeal in the same case: [2013] EWCA Civ 925, [2014] RPC 4 at [78] (Floyd LJ).
401. In Anan Kasei Co. Ltd v Neo Chemicals and Oxides Ltd [2019] EWCA Civ 1646, [2020] FSR 8 at [24]-[25] (Floyd LJ) and [101]-[104] (Lewison LJ) the Court of Appeal held that this type of insufficiency is better described as “uncertainty” rather than ambiguity. At [26]-[27] Floyd LJ rejected in the following terms a submission that such insufficiency was only available where it was impossible to tell in any case whether a product infringed:
AgrEvo obviousness of EP 823 and EP 301
Infringement of Family A by vadadustat
407. There are a number of issues as to whether vadadustat infringes the claims of the Family A Patents.
There is no dispute, however, that vadadustat is a Carboxamide which is suitable for use in the treatment of anaemia associated with CKD in that it meets the criteria for efficacy discussed in paragraph 260 above. Nor is there any issue concerning the intention requirements in claims 1 and 2 of EP 823. Accordingly, if it was valid, vadadustat would infringe claim 8A of EP 823.
Infringement on a normal interpretation of the claims
Infringement by equivalence
414. The law. In Actavis UK Ltd v Eli Lilly and Co [2017] UKSC 48, [2017] Bus LR 1731 the Supreme Court held that a patent
may be infringed by virtue of this doctrine even if the product or process does not fall within the relevant claim(s) as a matter of interpretation. In order to determine this, Lord Neuberger said at [66] that the court should generally ask itself the following three questions:
“(i) Notwithstanding that it is not within the literal meaning of the relevant claim(s) of the patent,
does the variant achieve substantially the same result in substantially the same way as the invention, i.e. the inventive concept revealed by the
patent?
(ii) Would it be obvious to the person skilled in the art, reading the patent
at the priority date, but knowing that the variant achieves substantially the same result as the invention, that it does so in substantially the same way as the invention?
(iii) Would such a reader of the patent
have concluded that the
patentee
nonetheless intended that strict compliance with the literal meaning of the relevant claim(s) of the
patent
was an essential requirement of the invention?
In order to establish infringement in a case where there is no literal infringement, a patentee
would have to establish that the answer to the first two questions was ‘yes’ and that the answer to the third question was ‘no’.”
416. Although the questions are framed to begin from the “literal” meaning of claim(s), it has since been clarified by the Court of Appeal that this means the “normal” or purposive meaning: Icescape v Ice-World International [2018] EWCA Civ 2219, [2019] FSR 5 at [60] (Lord Kitchin).
419. Assessment: question (i). The Claimants put their case on question (i) in three alternative ways with increasing levels of particularity. I will consider these in turn. Before doing so, it is pertinent to observe that question (i) is partly a question of interpretation of the specification (what is the inventive concept revealed by (the relevant claim(s) of) the patent?)
and partly a question of fact (does the variant achieve substantially the same result in substantially the same way?). In so far as it is a question of fact, it is clear that the burden of proof must lie on the
patentee.
424. Vadadustat also differs from the commonality between Compounds C-K in other ways. It has:
i) a hydroxyl group at the Q-R4 position of Formula (I), which Compound D does not have;
ii) a hydrogen at R3, which is found only in Compounds H and I; and
iii) a hydrogen at R1, which is only found in Compounds D, E, F and G.
439. As Dr Bhalay agreed, this motif is plainly not satisfied by vadadustat.
441. Fifthly, if the claim language is ignored entirely and the skilled medicinal chemist is told to extract some core structural features from the description as a whole that the patentee
has indicated as being of importance, I agree with the Defendants that they would look to Formula (I). There at least the
patentee
has identified structural features of the compounds considered to be important for activity. Formula (I) is very broad in some respects, but narrow in others. This can be demonstrated by reference to the following version of Formula (I) in which the ring positions have been labelled a-f.
i) the heterocyclic ring has a mandatory nitrogen at position (a), so this is not just a feature of Compounds C-K but of all the huge number of compounds covered by Formula (I);
ii) the mandatory nitrogen at position (a) of the heterocyclic ring cannot be substituted;
iii) Y cannot be a substituted nitrogen;
iv) R2 cannot be oxygen (so as to form a carbonyl group);
v) the ring atom at position (d) must be carbon; and
vi) the heterocyclic ring must be aromatic.
448. In the present case I consider that it is clear that the skilled team would conclude that the patentee
intended that strict compliance with the normal meaning of “Compound C” was an essential requirement of the invention of claim 17A for a number of reasons.
451. Thirdly, Compound C would be understood to be the most promising and best-explored of the exemplified compounds in EP 531. The skilled team would realise that the patentee
had limited the claims accordingly, and was not claiming different or untested compounds. In other words, a technical choice had been made.
“If the description discloses a plurality of possibilities for achieving a specific technical effect, but only one of those possibilities is catered for in the patent
claim, the utilisation of any of the other possibilities properly does not constitute infringement of the
patent
with equivalent means.”
455. Fifthly, the skilled team would recognise that vadadustat is less structurally similar to Compound C than Compounds D to K of EP 531. Accordingly, the skilled team would conclude that, having disclaimed Compounds D to K of EP 531, it was not the patentee’s
intention that a claim to Compound C of EP 531 would extend to a product such as vadadustat.
459. Eighthly, there is the prosecution history. FibroGen chose to limit the scope of claim 1 of EP 531 to compounds of Formula (I) in order to overcome an objection from the examiner that the previous claims, which were directed to “a heterocyclic carboxamide compound”, lacked novelty over prior art referred to as D11. FibroGen thereby represented that it was not seeking to contend that the patent,
if granted, would have a scope that extended to heterocyclic carboxamides beyond the confines of Formula (I). Yet extending the scope of claim 17A in this way is precisely what the Claimants are now seeking to do. In those circumstances, this is one of those cases referred to by Lord Neuberger in Actavis v Lilly at [88] where it would be contrary to the public interest for the contents of the prosecution file to be ignored.
460. Contrary to the Claimants’ submission, I do not accept that it is an answer to this objection that, in its response, FibroGen stated that “Any deleted subject matter is not abandoned” and that “Although the applicant maintains that the previous claims were patentable,
the applicant has amended the claims to simplify the outstanding issues in the hope of progressing the applicant to grant”. FibroGen cannot have it both ways. If it wanted a broader claim, it should have maintained its position in the face of the examiner’s objection and, if necessary, appealed to the Board of Appeal (as was its right). It did not do so, but accepted a narrower claim. It is inconsistent with that acceptance for it now to say that the claim extends beyond that. (The fact that the Claimants have subsequently further limited the claim to Compound C does not detract from this, but simply makes it even worse.)
461. If, finally, one cross-checks the foregoing conclusion with the Protocol on the Interpretation of Article 69 of the European Patent
Convention, I consider that it is manifest that extending the scope of protection of claim 17A in the manner contended for by the Claimants would go well beyond fair protection for the
patentee
and would not afford a reasonable degree of legal certainty for third parties.
462. Accordingly, I conclude that claim 17A of EP 531 is not infringed by vadadustat.
Amendment of EP 531
The Family B Patents
464. As noted above, I shall set out the disclosure of the Family B Patents
by reference to WO 121. Again, I shall do so using the headings in the specification. The same caveats apply as in the case of the Family A
Patents.
Quite a lot of the specification of WO 121 is repeated from WO 997.
Field of the invention
465. This is identified at [0002] in the following terms:
“The present invention relates to methods and compounds for regulating or enhancing erthropoiesis [sic] and iron metabolism, and for treating or preventing iron deficiency and anemia of chronic disease.”
This statement is repeated in the corresponding paragraph ([0001]) of the Family B Patents.
Background of the invention
466. At [0003]-[0004] the specification refers to anaemia associated with chronic disease of inflammation (ACD), and points out that ACD is often associated with absolute or functional iron deficiency. At [0005] it notes that numerous physiological deficiencies are observed in patients
with ACD, including reduced Epo production and impaired iron metabolism, which contributes to impaired erythropoiesis.
Summary of the invention
470. The specification states at [0015]:
“The present invention relates to methods and compounds for inducing enhanced or complete erythropoiesis in a subject. In particular, the methods comprise inducing enhanced or complete erythropoiesis by stabilizing HIFα in a subject. Methods of inducing enhanced erythropoiesis by inhibiting HIF prolyl hydroxylase are specifically contemplated. In specific embodiments, the methods comprise administering to a subject a compound of the invention. In various embodiments, the subject can be a cell, tissue, organ, organ system, or whole organism.”
“The invention provides various methods of regulating/enhancing iron processing and iron metabolism. In one aspect, the invention provides methods for increasing iron transport, uptake, utilization, and absorption in a subject, each of the methods comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). In particular embodiments, the invention provides methods for increasing transferrin expression, transferrin receptor expression, IRP-2 expression, ferritin expression, ceruloplasmin expression, NRAMP2 expression, sproutin expression, and ALAS-2 expression in a subject, each method comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). In other embodiments, the invention provides methods for decreasing hepcidin expression, the method comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). Methods for increasing heme synthesis in a subject by administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF) are also provided.”
Brief description of the drawings
Description of the invention
Definitions
477. At [0122] the specification states:
“In particular embodiments, the present invention provides for use of structural mimetics of 2-oxoglutarate. Such compounds may inhibit the target 2-oxoglutarate dioxygenase family member competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron. (Majamaa et al. (1984) Eur J Biochem 138:239-45 [‘Majamaa 1984’]; and Majamaa et al. (1985) Biochem J 229:127-133 [‘Majamaa 1985’].) …”
No further explanation is provided, however.
Invention
478. At [0123] the specification repeats the statement of the invention made in [0015].
“… Reduced or ineffective erythropoiesis is a common pathology
in
patients
with anemia of chronic disease. Reduced or ineffective erythropoiesis can result from various metabolic abnormalities in the erythropoietic
pathway
including, for example, …abnormal iron processing including for example abnormal or ineffective iron uptake, mobilization, storage, and absorption.”
481. At [0127] the specification states:
“The present invention provides advantages over existing therapies for anemia of chronic disease, such as, for example, recombinant EPO administration. Reduced EPO production is only one aspect of decreased erythropoiesis and it is recognized that administration of recombinant EPO does not address other deficiencies associated with reduced erythropoiesis that exist in patients
with anemia of chronic disease. These deficiencies include, for example, reduced EPO responsiveness of the bone marrow, as well as numerous aspects of iron metabolism that contribute to complete or total erythropoiesis including iron absorption from the gut, transenterocyte transport, oxidation of the iron to the ferric state by hephaestin or ceruloplasmin, binding and uptake of iron by transferrin and transferrin receptor and iron transport to the marrow where iron utilisation occurs, including heme synthesis. Many
patients
are refractory to administration of recombinant EPO for the reasons described above, in which responses to recombinant EPO administration are reduced or absent, even at high doses of recombinant EPO.”
482. At [0129] the specification states:
“Anemia of chronic disease is associated with increased levels of ferritin. Despite high levels of ferritin, subjects with anemia of chronic disease are not able to utilize iron effectively. High levels of ferritin are indicative of reduced iron recycling to the marrow and enhanced iron storage, a functional iron deficiency often associated with anemia of chronic disease and a pseudo-inflammatory state often existing in uremic chronic kidney disease patients.
By decreasing ferritin levels, methods and compounds of the present invention decrease stored iron and enhance iron recycling through transferrin and transferrin receptor. Reduced serum ferritin levels would be indicative of enhanced iron utilization and enhanced iron recycling to the marrow, thus increasing iron availability for heme production and erythropoiesis.”
“Iron is not available at a rate sufficient to allow normal hemoglobinization of erythrocytes, leading to reduced reticulocyte and erythrocyte cellular hemoglobin content. Functional iron deficiency is often seen in healthy individuals with apparently normal or even increased iron stores but with impaired iron availability, as measured, e.g., by low levels of percent transferrin saturation. This type of iron deficiency is frequently associated with acute or with chronic inflammation.”
484. At [0140]-[0141] the specification states:
“[0140] Numerous proteins mediate iron metabolism, including proteins such as … transferrin, transferrin receptor, iron transporters …, ceruloplasmin etc. Increases in transferrin and transferrin receptor expression stimulate iron uptake by erythroid progenitors and transport to marrow by macrophage ... Ceruloplasmin increases the oxidation of ferrous iron to ferric so that binding to transferrin occurs … In certain aspects, methods of the present invention increase iron metabolism by increasing expression or activity of proteins involved in iron metabolism including… transferrin, transferrin receptor… In other aspects, methods disclosed increase iron metabolism by decreasing expression or activity hepcidin and by modulating expression of ferritin.
[0141] In one embodiment, the disclosure provides methods and compounds for increasing expression of genes whose products are involved in iron metabolism and processing including iron uptake, storage, transport, absorption etc. Such genes include but are not limited to transferrin receptor, ceruloplasmin … Therapeutic upregulation of genes involved in iron metabolism and processing will effectively increase iron availability and, thereby produce a beneficial effect in patients
with anemia of chronic disease, anemia of iron deficiency, functional iron deficiency etc. In another embodiment, the disclosure provides methods and compounds for decreasing expression of hepcidin, a protein associated with iron regulation.”
486. A subsection of the specification headed “Compounds” at [0156]-[0177] discloses compounds for use in the invention in similar, but not identical, terms to WO 997. This subsection begins by stating that exemplary compounds that stabilise HIFα are disclosed in WO 03/049686 (“WO 686”) and WO 997 (in WO 121 these are said to be incorporated by reference in their entirety, but that wording is missing from the granted Family B Patents).
487. [0160]-[0162] are in almost identical terms to [0074]-[0076] of WO 997.
489. At [0165]-[0169] and [0172] the specification identifies “exemplary” or “additional” compounds within Formula (I), Formula (Ia), Formula (Ib) or Formula (III) by reference to 12 patents
and
patent
applications. The same
patents
and applications are cited as in WO 997 at [0078]-[0088] save for US 898, US 974 and WO 860 which relate to Formula II. Each paragraph identifies a number of specific compounds. [0169] identifies Compound A as an example of Formula (Ib). [0170] identifies additional compounds for use in the invention without referring to any prior art, including Compounds B and C. [0172] identifies Compound D as an example of Formula (III).
490. Pharmaceutical Formulations and Routes of Administration are dealt with at [0178] onwards.
Examples
“Therefore, compounds of the present invention are useful for increasing transferrin receptor expression in various cell types. In addition, increased transferrin receptor expression would result in increased transferrin receptor-mediated endocytosis of ferric transferrin, thereby increasing iron transport, utilization, storage, and metabolism Therefore, compounds of the present invention are useful for enhancing erythropoiesis by increasing iron transport, utilization, storage, and metabolism.”
496. Example 17 ([0240]-[0254] shows the effect of expression of genes encoding iron-processing proteins in mice in vivo when treated with Compound A. Ceruloplasmin expression was increased in mouse kidneys over a period up to 72 hours, as shown in Table 3. Table 4 shows down-regulation of hepcidin expression over a period up to 16 hours. The figures reported do not appear to show a clear trend, however, and there is no statistical information. As Prof Haase explained, and Prof Winearls accepted, there is nothing to demonstrate that this effect is independent of erythropoiesis, although both witnesses considered that this was a possibility. Data are also provided showing upregulation of expression of the transferrin receptor (Figure 6A), the gut duodenal transporter NRAMP2 (Figure 6A; Figure 6B) and the first enzyme in the haem synthetic pathway
ALAS-2 (Figure 6C).
499. In Example 20 ([0259]-[0278]) an animal model of ACD was used in two series of experiments in which various measurements taken to ascertain the efficacy of Compound A, namely reticulocyte count, haematocrit, haemoglobin, red blood cell count, mean corpuscular volume and mean corpuscular haemoglobin. The same model was also used to measure serum iron and transferrin saturation, which are both reduced in patients
with ACD. As shown in Figures 18A and 18B, administration of 40 mg/kg of Compound A resulted in a significant increase in both serum iron and TSAT in non-anaemic control animals. This increase was not observed to the same extent in anaemic animals, however, although administration of 40 mg/kg of Compound A produced lower levels of serum iron and TSAT than 20 mg/kg. Compound A was also found to increase expression of NRAMP2 and sproutin in the intestine (Figure 19), suggesting a beneficial effect on iron absorption.
501. It should be noted, for reasons that will appear, that the Family B Patents
do not contain any data comparing the effects of HIF-PHIs to those of ESAs, and in particular no data showing that any of Compounds A-D have superior effects on iron mobilisation to ESAs.
The claims of the Family B Patents
502. The claims of the Family B Patents
as proposed unconditionally to be amended which were relied upon by the Claimants at trial are as follows. All of these claims are EPC 2000 claims.
EP 333
“A compound of formula (I) that stabilizes HIFα for use in treating anemia of chronic disease in a subject … wherein the subject has a percent transferrin saturation of less than 20%.”
“The compound of claim 1 for the use of that claim, wherein the subject has a percent transferrin saturation of less than 16% in adults.”
“A compound of formula (I) that stabilizes HIFα for use in treating anemia that is refractory to treatment with exogenously administered erythropoietin (EPO) in a subject wherein A, B, Q, R1, R2, R4, Y and X are as defined in claim 1.”
506. (Unconditionally amended) claim 22A (formerly 15):
“A compound of formula (I) that stabilizes HIFα for use in treating functional iron deficiency in a subject, and wherein the functional iron deficiency is associated with anemia wherein A, B, Q, R1, R2, R4, Y and X are as defined in claim 1.”
507. (Unconditionally amended) Claim 31A (formerly 24):
“The compound for use according to any of the preceding claims 1, 2, 7, 8, 9, 15, 16, 17, 20, 21, 22, 27 and 28 wherein the compound is for decreasing hepcidin expression in a subject.”
“The compound for use according to any of claims 102, 7-9, 15-17, 20-23, 27, 28, 31 and 32, wherein the compound is a structural mimetic of 2-oxoglutarate.”
“The compound for use according to any of the preceding claims wherein the compound is [Compound A].”
EP 153
510. (Unconditionally amended) claim 1A:
“A compound that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase activity for use in treating or preventing functional iron deficiency associated with anemia in a subject, wherein the compound is a structural mimetic of 2-oxoglutarate.”
“The compound according to claim 1, where the compound is of Formula (I) …”
“The compounds of claim 1, 2 or 3 for the use of that claim, wherein the compound is for decreasing hepcidin expression.”
EP 155
“A structural mimetic of 2-oxoglutarate that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase activity for use in treating anemia in a subject having a percent transferring saturation of less than 20%.”
“The mimetic of claim 1 for the use of that claim, wherein the subject has a percent transferrin saturation of less than 16% in adults.”
515. (Unconditionally amended) claim 3B (formerly 2):
“The mimetic of claim 1 3A for the use of that claim, wherein the anemia is anemia of chronic disease is associated with a condition selected from the group consisting of an inflammation, an infection, an immunodeficiency disorder, and a neoplastic disorder.”
“The mimetic of claim 1 or 2 for the use of that claim, wherein the anemia is associated with iron deficiency,
wherein the iron deficiency is functional iron deficiency”
517. (Unconditionally amended) claim 8A (formerly 7:
“The mimetic of any one of claims 1, to 4, 5 or 6 for the use of that claim, wherein the mimetic is a compound of Formula I …”
“The mimetic of any preceding claim for the use of that claim, wherein the mimetic is for decreasing hepcidin expression.”
The skilled team
519. It is common ground that the Family B Patents
are addressed to the same skilled team as the Family A
Patents.
Common general knowledge as at the Family B Priority Date
Treatment of ACD with ESAs
521. As noted above, there is no dispute that patients
with ACD were sometimes treated with ESAs, but there is a minor dispute as to the effectiveness of such treatment. ACD was not an approved indication for ESAs, and so such treatment was “off-label” (i.e. prescribed by the responsible clinician on the basis of their own clinical judgment of the potential of the treatment to meet the needs of a specific
patient).
Prof Winearls agreed that this use of ESAs was conventional (although he later contradicted himself by saying that it was not conventional, but was done on an ad hoc basis). He said that in his view it was “somewhat misguided”, but nevertheless volunteered that it was an obvious thing to try because it was hoped to compensate for reduced Epo production by the kidneys and reduced responsiveness to Epo by the bone marrow. His opinion was that the treatment was generally ineffective, but he accepted that it worked in some
patients.
522. Prof Haase’s opinion was that ESAs were effective in the treatment of ACD in some patients,
particularly when used at higher doses. As he pointed out, that view is supported by several contemporaneous textbooks, such as E. Beutler et al (eds), Williams Hematology (6th ed, McGraw-Hill, 2001) at pages 484-485. Prof Haase agreed that it was thought that ESAs achieved such therapeutic effect as they did by compensating for reduced Epo production and responsiveness to Epo, and that ESAs were not thought to act by unblocking iron. Thus there was little difference between the experts.
Anaemia that is resistant to exogenous Epo
524. The 2002 UK Renal Association Guidelines defined “resistance” to Epo as failure to reach target haemoglobin or the need for doses of Epo above 300 IU/kg/week. Dr Ashman agreed this was a recognised definition of Epo resistance in 2001/2, and that this group of patients
was a recognised
patient
cohort.
525. The US guidelines suggested that there was no point in giving Epo to patients
who had stopped responding to it. Similarly, UpToDate, a multi-volume treatise published in the USA in CD-ROM form in 2001 states in volume 9 number 2 (edited by Schrier) that “It is not worthwhile to continue Epo in
patients
who do not have a clinically meaningful response by 12 weeks”. Prof Haase accepted that this reflected the common general knowledge, although his personal view was that completely stopping Epo would be a mistake.
Hepcidin
530. Furthermore, Prof Winearls accepted in cross-examination that it was known by 2003 that Epo was involved in transcriptional down-regulation of hepcidin, adding “if you give erythropoietin to a dialysis patient
the hepcidin comes down”.
“A speculative scheme in the regulation of iron balance by hepcidin is proposed in Figure 7. When anemia/hypoxia occurs, e.g., following severe bleeding or after PHZ [phenylhydrazine] treatment, erythropoietin expression increases, leading to a stimulation of the erythropoietic activity. In parallel, hepcidin gene expression is decreased, inducing a rapid mobilization of iron from reticuloendothelial cells to supply sufficient amounts of iron for the erythropoietic activity. Indeed, we demonstrated previously that a deficiency in hepcidin gene expression results in a dramatic decrease in iron stores in reticuloendothelial cells (6). At the moment, we cannot specify whether erythropoietin is involved in hepcidin downregulation or whether hepcidin and erythropoietin responses to hypoxia are independent.”
534. Nicolas goes on, however, to say (at 1043):
“These results [namely those reported in two prior papers] reinforce our hypothesis that hepcidin per se is a key component of the erythropoietic regulator of intestinal iron absorption.”
Counsel for the Claimants himself put it to Prof Haase that this was the understanding that a reader of the paper would take away from it, and Prof Haase agreed.
“Therapeutic implications of hepcidin
…
Elucidation of the receptor and its transduction pathways
should lead to the development of hepcidin antagonists, some of which could be useful in treatment of anemia of inflammation, a condition often resistant to erythropoietin therapy45.
….
Conclusions
Hepcidin may be the principal iron-regulatory hormone, the key mediator of anemia of inflammation, and a bridge between innate immunity and iron metabolism (Figure 2). Studies of the molecular mechanisms of hepcidin activity could transform our understanding of the regulation of iron transport and should lead to new therapies for hemochromatosis and anemia of inflammation.”
“Induction of hepcidin by infection and inflammation
…
[reference to Nicolas]
…
In the aggregate, the increase of hepcidin production by inflammation and the ability of transgenic or tumor-derived hepcidin to suppress erythropoiesis by iron starvation strongly suggest that hepcidin is the key mediator of anemia of inflammation. However, it still remains to be shown that hepcidin peptide administration to mice or humans will cause iron sequestration and iron-limited erythropoiesis.
Suppression of hepcidin by anemia or hypoxia
In addition to iron stores and inflammation, anemia and hypoxia also affect iron metabolism. These stimuli would be expected to decrease hepcidin production and remove the inhibitory effect on iron absorption and iron release from macrophages so that more iron is available for compensatory erythropoiesis. Weinstein et al21 and Nicolas et al23 confirmed that these effects indeed take place.”
“Evidence from transgenic mice expressing mRNA for hepcidin suggests that it reduces iron absorption and iron release from macrophages. In inflammation, hepcidin production may increase substantially, so that it is possible that this substance plays an important role in EPO resistance.”
“To date, the relevance of hepcidin for the effectiveness of erythropoietin in chronic kidney disease patients
is unclear.”
540. The next sentence states, however:
“Absolute iron deficiency rapidly develops during therapy with exogenous erythropoietin, and persistently high levels of hepatic hepcidin expression might explain why duodenum iron absorption remains inadequately low.”
Moreover, these statements follow immediately on from the preceding section of the review, headed “Hepcidin: a target for erythropoietin?”.
The documents cited in the Family B Patents
544. Like the Family A Patents,
the Family B
Patents
refer to a considerable number of papers, books,
patents
and
patent
applications. EP 333, for example, refers to 64 papers and books and 20
patents
and
patent
applications. Again, the question arises as to which, if any, of these documents the skilled team, and in particular the medicinal chemist, would read. There was less evidence on this topic than in relation to the Family A
Patents.
545. In his first report Dr Bhalay reviewed WO 686. Although he did not say so in terms, it is clear from what he said that this was because he was asked to do so. He also noted that EP 333 cited the same (six) papers that he had been asked to read in relation to EP 823 and cited at [0138]-[0142] the same (11) patent
documents as sources of Formula (I) compounds as EP 823 at [0072]-[0077]. Prof Ward in his first report simply referred to his previous comments on the cited documents.
546. In cross-examination Dr Bhalay said that the skilled medicinal chemist would read all six cited papers and all 11 cited patent
documents when reading EP 333, but gave no reason for taking a different approach than in relation to EP 823.
547. In my judgment the skilled team is most likely to read Majamaa 1984 and Majamaa 1985 for the same reason as in the case of the Family A Patents.
Given that the Family B
Patents
refer to even more papers and
patent
documents than the Family A
Patents,
they would be even less likely to read the other documents.
Construction of Family B claims
Formula (I) and structural mimetic of 2-oxoglutarate
550. The same issues arise in relation to these features as in the context of the Family A Patents,
and it is common ground that they should be resolved in the same way.
For use in treating anaemia of chronic disease
For use in treating anaemia that is refractory to treatment with exogenously administered erythropoietin
552. It is common ground that the relevant claims are to be interpreted as covering use of a HIF-PHI for the purpose of treating anaemia in circumstances where the patient’s
anaemia has already been established to be refractory to treatment with exogenous Epo. It is also common ground that “refractory” covers both a complete absence of response and hyporesponsiveness, i.e. a lowered response, to Epo. Although there was at earlier stages a dispute as to what criterion the skilled nephrologist would apply for this purpose, by closing submissions it was not disputed that they would apply the criterion for resistance set out in paragraph 524 above.
For use in treating functional iron deficiency associated with anaemia
Obviousness of Family B over WO 997
554. The Defendants contend that all the Family B claims in issue are obvious over WO 997. It is common ground that this is essentially a question of whether it would be obvious to use the compounds disclosed in WO 997 for the purposes claimed in the Family B Patents.
Although claim 36A of EP 333 is limited to Compound A, corresponding to Compound C of WO 997, the Claimants do not suggest that there would be any invention in choosing that compound given that it is the one that is the subject of the most experimental data in WO 997.
WO 997
The differences between WO 997 and the claims in issue
557. Before doing so, however, I should address the Claimants’ over-arching point that the obvious way forward for the skilled team reading WO 997 in April 2004 would be to investigate the use of HIF-PHIs for the treatment of anaemia of CKD, and that in order properly to test that they would want to exclude co-morbidities and ensure that patients
were iron replete. Unsurprisingly, Prof Haase agreed that that would be an obvious course to adopt. It simply does not follow, however, that other possibilities were not obvious.
For use in treating ACD in subjects with TSAT less than 20%/16% in adults
560. It is common ground that, in the case of patients
with ACD, the standard of care in 2004 was (in addition to treating the underlying disease) to administer supplemental iron either orally or intravenously. Prof Haase’s evidence was that there were a small number of
patients
for whom this treatment was not effective. The Claimants suggest that this means that there was no need to treat
patients
with a TSAT of less than 20% or 16% with anything else, but that would mean that there was no technical problem to solve. In any event, the evidence is clear that it is precisely because supplemental iron was not always effective that ESAs were used to treat ACD, as discussed above. (The Claimants also rely upon Dr Ashman’s evidence that, in CKD
patients
being treated with ESAs, IV iron would almost always correct any absolute iron deficiency; but this is irrelevant to the present issue.)
561. Prof Winearls explained in his first report that TSAT < 16% was the cut-off for iron deficiency in the normal population, while TSAT < 20% was the cut-off for iron deficiency in the CKD population. He also explained that (based on the disclosure of the Family B Patents)
one would expect administration of HIF-PHIs to increase TSAT and to treat iron deficiency anaemia, including anaemia associated with ACD, in both populations.
562. The Defendants contend that, given that it was obvious from WO 997 to use the disclosed HIF-PHIs to treat ACD, then it follows that the skilled team would inevitably be treating at least some subjects with a TSAT at the claimed levels. I accept this. In any event, Prof Haase’s evidence was that patients
with a TSAT of less than 20% or 16% were treated with ESAs, including some
patients
whose TSAT dipped below those levels due to diurnal or periodic variation. Given that HIF-PHIs are disclosed by WO 997 as an alternative to ESAs, they would be administered to
patients
with the relevant TSAT levels.
563. As the Defendants point out, the Family B Patents
do not show, or even attempt to show, that HIF-PHIs confer any benefit over ESAs in terms of iron delivery. If and in so far as there is such a benefit, however, the Defendants contend that this would have been discovered by the skilled team by taking obvious steps. As Prof Winearls accepted, the skilled team would have been motivated by WO 997 to do some relatively straightforward tests. These would have included the transferrin and transferrin receptor tests in animal cells in WO 121, which would (if WO 121 is correct in its assertions) have shown an “enhancement” of erythropoiesis through increasing iron transport etc. This would have led to the other tests done in WO 121 to measure iron uptake, including measuring haemoglobin levels, and then ultimately comparative tests on iron uptake over ESAs. The Defendants submit, and I agree, that, taken as a whole, Prof Haase’s evidence was also consistent with this.
For use in treating anaemia that is refractory to treatment with exogenous Epo
565. The Defendants contend that, given the disclosure of WO 997 of HIF-PHIs for the treatment of anaemia explicitly as alternatives to ESA treatment with potential benefits, it would be entirely obvious to administer a HIF-PHI as a replacement therapy for a patient
who had proved refractory to ESAs. Indeed, there would be a huge motivation to do so, and no reason not to do so. As the Defendants submit, this is supported by the evidence of Dr Devonald, which although given in relation to a latter point in time is equally applicable to April 2004.
566. The Claimants rely upon evidence that, if a patient
was found to be refractory to Epo, treatment with Epo should cease, such as the statement in UpToDate that “it is not worthwhile to continue EPO in
patients
who do not have a clinical meaningful response by 12 weeks”. Counsel for the Claimants submitted that this showed that Epo should not be given to such
patients
at all, but it shows no such thing. What it shows is that Epo was discontinued where the
patient’s
anaemia was found to be refractory precisely for that reason. This supports, rather than undermines, the Defendants’ case.
567. Accordingly, I conclude that claims 9 and 36A of EP 333 are obvious over WO 997.
For use in treating functional iron deficiency associated with anaemia
568. [0018] of WO 997 expressly teaches use of the compounds of the invention for the treatment of anaemia “associated with defects in iron transport, processing or utilisation” i.e. functional iron deficiency. The same message appears from [0072]. Yet further, as discussed above, ACD involves functional iron deficiency. The Claimants do not suggest that the mode, format or dosage involved in treating functional iron deficiency in accordance with the Family B Patents
is any different to those involved in treating ACD. Nor, as discussed above, is it a requirement of the relevant claims that there should be any increase in iron parameters. It follows that WO 997 also makes it obvious to use the compounds for the treatment of functional iron deficiency associated with anaemia.
569. The Claimants submitted that the relevant claims require the HIF-PHIs to act “by overcoming the reticuloendothelial block which prevents the release of iron from stores”. This is not a feature of the claims, however. Nor is there is any evidence in the Family B Patents
that HIF-PHIs achieve this. In any event, even if it did happen, it would be an inherent effect of administering the compounds of WO 997 to an ACD
patient.
For decreasing hepcidin expression
Insufficiency and AgrEvo obviousness of Family B
575. The issues on insufficiency in relation to the Family B Patents
are the same as in relation to the Family A
Patents.
Accordingly, I can deal with them briefly.
Infringement of Family B by vadadustat
579. For the purposes of the Family B Patents,
it is necessary to explain the basis of the Claimants’ infringement case more fully than I did in relation to the Family A
Patents.
As noted at the outset of this judgment, vadadustat is presently undergoing Phase III trials. It follows that it has not yet received a marketing authorisation. It is common ground, however, that, if and when vadadustat is authorised, the Defendants intend to market it in the UK. Moreover, the Defendants have given evidence (by way of a Product and Process Description) as to the scope of the marketing authorisation that they presently intend to seek. The therapeutic indications for which authorisation will be sought are “treatment of anaemia associated with chronic kidney disease (CKD) in adults who are non-dialysis-dependent (NDD) and those who are dialysis-dependent (DD)”.
580. The Claimants contend that the Defendants thereby threaten to infringe the Family B Patents
despite the fact that the proposed marketing authorisation does not on its face include any of the uses claimed in the Family B
Patents,
but only the use taught by WO 997 and claimed in the Family A
Patents,
and that the proposed Summary of Product Characteristics (“SmPC”) states that “[TSAT] and serum ferritin should be evaluated per standard of care”, alternatively “prior to and during treatment with vadadustat”, and “Administration of supplementary iron therapy is recommended as needed”.
The law
582. Infringement of medical use claims. As noted above, most of the claims in issue are in EPC 2000 form, whereas claim 1 of EP 823 is in Swiss form. The difference between the two is that a Swiss-form claim is a purpose-limited process claim (see Generics (UK) Ltd v Warner-Lambert Co LLC [2018] UKSC 56, [2019] Bus LR 360 at [2], [63]), whereas an EPC 2000-form claim is a purpose-limited product claim. As such, they have a different scope of protection: see T 1373/11 GENZYME/Treatment of Pompe’s Disease [2016] EPOR 33 at [21] cited in Case Law of the Boards of Appeal of the European Patent
Office at page 522. In particular, direct infringement of EPC 2000 claims falls to be determined under section 60(1)(a) of the
Patents
Act 1977, whereas direct infringement of Swiss-form claims falls to be determined under section 60(1)(c). Furthermore, whereas claims for indirect infringement of Swiss-form claims by downstream dealings in the product of the manufacturing step are unsustainable for the reasons explained by Lord Sumption (with whom all the other members of the Supreme Court agreed on in this issue) in Generics v Warner-Lambert at [87]-[88], no such problem arises in the case of EPC 2000 claims.
584. Indirect infringement. Under section 60(2) of the 1977 Act a person infringes if:
“while the patent
is in force and without the consent of the proprietor, he supplies or offers to supply in the United Kingdom a person other than a licensee or other person entitled to work the invention with any of the means, relating to an essential element of the invention, for putting the invention into effect when he knows, or it is obvious to a reasonable person in the circumstances, that those means are suitable for putting and are intended to put, the invention into effect in the United Kingdom.”
585. The background to Article 26 CPC, and hence section 60(2) of the 1977 Act, was explained by Jacob and Etherton LJJ, with whom Sir David Keene agreed, in Grimme Landmaschinenfabrik GmbH v Scott [2010] EWCA Civ 1110, [2011] FSR 7 at [82]-[98]. They went on at [105]-[131] to consider the requirements of knowledge and intention in section 60(2). They found helpful guidance in relation to these questions in a number of decisions of the Bundesgerichtshof (Federal Court of Justice) on the corresponding German provision, which also derives from Art 26 CPC. In KCI Licensing Inc v Smith & Nephew plc [2010] EWCA Civ 1260, [2011] FSR 8 at [53] Jacob LJ delivering the judgment of the Court of Appeal summarised the key parts of Grimme v Scott with regard to the requirements of knowledge and intention as follows:
“i) The required intention is to put the invention into effect. The question is what the supplier knows or ought to know about the intention of the person who is in a position to put the invention into effect - the person at the end of the supply chain, [109].
ii) It is enough if the supplier knows (or it is obvious to a reasonable person in the circumstances) that some ultimate users will intend to use or adapt the ‘means’ so as to infringe, [107(i)] and [114].
iii) There is no requirement that the intention of the individual ultimate user must be known to the defendant at the moment of the alleged infringement, [124].
iv) Whilst it is the intention of the ultimate user which matters, a future intention of a future ultimate user is enough if that is what one would expect in all the circumstances, [125].
v) The knowledge and intention requirements are satisfied if, at the time of supply or offer to supply, the supplier knows, or it is obvious to a reasonable person in the circumstances, that ultimate users will intend to put the invention into effect. This has to be proved on the usual standard of the balance of probabilities. It is not enough merely that the means are suitable for putting the invention into effect (for that is a separate requirement), but it is likely to be the case where the supplier proposes or recommends or even indicates the possibility of such use in his promotional material, [131]”
587. I considered what is meant by the term “means relating to an essential element of the invention” in Nestec SA v Dualit Ltd [2013] EWHC
923 (
Pat),
[2013] RPC 32 at [168]-[175], and held that it must be “something that … contribute[s] to the technical teaching of the invention”.
588. Quia timet claims for infringement. Having reviewed the relevant authorities, Birss J summarised the relevant principles in Merck Sharp Dohme Corp v Teva Pharma BV [2013] EWHC
1958 (
Pat),
[2014] FSR 13 as follows:
“56. The principle I derive from these authorities is that the question the court is asking in every case is whether, viewed in all the relevant circumstances, there was a sufficiently strong probability that an injunction would be required to prevent the harm to the claimant to justify bringing the proceedings. In adding the word sufficiently to the word strong I do not mean to put a gloss on the words of Chadwick LJ, rather I am seeking to encapsulate the idea that the degree of probability required will vary from case to case depending on all the circumstances but that mere possibilities are never enough. To justify coming to court requires there to be a concrete, strong and tangible risk that an injunction is required in order to do justice in all the circumstances”
57. If a defendant really does, at the date of the proceedings, have no intention to do the act then in the majority of cases that will be conclusive of the question whether there was a sufficiently strong probability to justify proceedings. (e.g. London Borough of Islington). However it seems to me that the question is not confined to the defendant's subjective intentions. A defendant's overt acts must be capable of being relevant. To take an extreme case, if a man began taking actual preparatory steps to commit some unlawful act seriously damaging to the claimant and in infringement of the claimant's rights and did so in full view of the claimant and well aware that the claimant could see them, he could hardly complain if the claimant started proceedings and the court decided to grant a final injunction to prevent it. A statement at trial that he had never intended to go through with it would get short shrift.
58. I bear in mind that intentions are not necessarily simple. A state of mind need not merely be either one thing or another. Also in this case the defendants are corporate entities to whom an intention can only be imputed.
59. The way the matter is put in the Particulars of Claim contains the allegation that the defendant ‘threatens and intends’ to infringe. I think this is a useful expression in that it encompasses both the defendant's intentions and also the idea that the court should look from the outside at what the defendant is threatening to do. Both are relevant.”
Assessment
592. This situation has come about because the Claimants have chosen to bring an infringement claim now, rather than wait and see what happens if and when vadadustat is marketed. Counsel for the Claimants recognised, however, that the Court might conclude that it is not possible to form a view as to infringement at this stage because there are too many uncertainties. Counsel submitted that, in that event, the appropriate course would be for the Court to stay the cross-claim and give the parties permission to apply in the event of a change of circumstances. In my judgment, that would not be appropriate. If the evidence before the Court does not establish that the Defendants are presently threatening to infringe the Family B Patents,
then the cross-claim should be dismissed. Given that there is no claim by the Defendants for a declaration of non-infringement, there would be nothing to prevent the Claimants from bringing a further claim for infringement if the circumstances change in the future.
593. As to whether vadadustat is suitable and intended for the uses claimed in the Family B Patents,
as both sides recognised, for practical purposes the question which matters is whether vadadustat has advantages compared to ESAs with respect to such uses, since it is only likely to be prescribed by clinicians if it does have such advantages.
594. As is common ground, there has not yet been any Phase III trial comparing vadadustat to ESAs with respect to its effect on ACD in patients
with TSAT < 16% or 20%, or its effect on
patients
with anaemia that is refractory to treatment with ESAs or its effect in
patients
with functional iron deficiency; nor is there any evidence that such a trial is presently planned. (Indeed, although there are quite a lot of Phase III trials underway in which HIF-PHIs are being compared with ESAs, there is no evidence that iron parameters are a primary end point in any of them.) The Claimants do not dispute that it follows that at present there is no foreseeable prospect of vadadustat receiving a marketing authorisation for such uses. The Claimants nevertheless contend that it is foreseeable that clinicians will prescribe vadadustat for such uses off-label because there is a growing body of clinical evidence that HIF-PHIs have advantages over ESAs in terms of their effects on increasing iron mobilisation. This contention requires me to consider two questions. First, what is the current state of the clinical evidence? Second, is it foreseeable that clinicians will prescribe vadadustat off-label for such uses?
595. The current clinical evidence. As Prof Winearls explained in his second report, in seeking further evidence of the claimed therapeutic effects of HIF- PHIs on iron parameters as promised by the Family B Patents,
the most relevant experiments would be those in which:
i) HIF-PHIs and ESAs were compared so as to investigate whether the effects of HIF-PHIs are additional to those provided by ESAs; and
ii) the treatment of patients
was conducted irrespective of their iron status and without pre-treatment with iron, such that the response of low iron
patients
could be compared to that of iron replete
patients.
“The primary endpoint of a clinical trial is the endpoint for which the subjects are randomised and for which the trial is powered. While iron metabolism parameters such as serum iron, TSAT and hepcidin may have been secondary endpoints, it is more difficult to draw any conclusions about the effect of the compounds on these parameters without an appropriately powered trial designed to investigate them. Interpretation of the results is further complicated by the fact that between different studies (and in some cases within the same study) some patients
were provided with iron supplementation and some were not.”
597. For the reasons given by Prof Winearls, the debate centres on a small subset of these studies that came closest to meeting one or other of the two criteria mentioned in paragraph 595 above, namely three trials of roxadustat sponsored by FibroGen: R. Provenzano et al, “Oral Hypoxia–Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients
with CKD”, Clin J Am Soc Nephrol, 11, 982–991 (2016) (“Provenzano 1”); R. Provenzano et al, “Roxadustat (FG-54920 Versus Epoeitin Alfa for Anemia in
Patients
Receiving Maintenance Hemodialysis: A Phase 2, Randomised, 6- to 19-week, Open-Label, Active Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study”, Am J Kidney Dis, 67(6), 912-924 (2016) (“Provenzano 2”); and N. Chen et al, “Roxadustat Treatment for Anemia in
Patients
Undergoing Long-Term Dialysis”, N Engl J Med, 381, 1011-1022 (2019) (“Chen”).
598. Provenzano 1 was not a study comparing HIF PHIs with ESAs. In his second report, Prof Winearls relied on the authors’ observation (at page 989) that “Hb response in patients
who were not iron replete and not on oral iron at baseline was as good as those who were iron replete and on oral iron”. As Prof Haase pointed out in his fourth report, however, supplemental iron was made available to the
patients
and the paper does not identify those
patients
who received the supplemental iron or whether or not those
patients
who received supplemental iron were iron replete at the outset or not. Accordingly, as Prof Winearls accepted, it is not possible to conclude whether the reported effects of increased iron availability for erythropoiesis was the result of exogenous iron or the administration of the HIF-PHI (roxadustat). Furthermore, as a matter of common sense, it is likely that those who were not iron replete at the start of the trial were the most likely
patients
to receive oral iron.
599. Ultimately, Prof Winearls accepted that in the absence of a comparative study between roxadustat and ESAs, Provenzano 1 could not provide any real clinical evidence that roxadustat had an effect on iron metabolism over and above that of ESAs. He described it as a “weak paper” in which the authors had “mined the data” in a manner that amounted to “speculation”. Even though patients
with TSATs of <20% were included in the study, it was well known that such
patients
may also respond to ESAs.
600. Provenzano 2 did seek to compare roxadustat with an ESA, epoetin alpha. As Prof Winearls accepted, however, because all the patients
were iron replete at baseline, the paper provides no clinical evidence about whether
patients
could be safely treated with roxadustat at lower TSAT levels. Furthermore, whilst
patient
cohorts were administered different doses of roxadustat, only one dose of Epo was used. The study did not therefore seek to compare
patient
cohorts who were experiencing the same degree of erythropoiesis (from roxadustat and Epo), and so the effects of roxadustat and Epo other than stimulating erythropoiesis could not be ascertained.
601. Chen was another trial (described by the authors as a Phase III trial, although it was in some ways closer in design to a Phase II trial) in which roxadustat and epoetin alpha patients
were compared, the primary endpoint being haemoglobin level. Although
patients
were included in both groups with TSATs at baseline above and below 20%, the proportion of
patients
with low TSAT levels was less in the roxadustat group and the results were not stratified according to TSAT at baseline. As such, Prof Winearls accepted that it was not possible to conclude that
patients
with a TSAT below 20% would benefit more from roxadustat than epoetin alpha.
“Regarding patients
with low baseline iron, it is hard to draw any firm conclusions from the studies given that the
patients
in the relevant studies were permitted to take oral iron during the treatment period notwithstanding low baseline parameters. Furthermore, none of the studies provide support for HIF prolyl hydroxylase inhibitors being suitable for the treatment of iron deficiency or any other condition for which ESAs are not also suitable.”
605. The sentence in Sanghani refers to the authors’ finding in part 1 of the study that, as shown in Figure 4B, there was a statistically significant difference in the patients
given 2 mg/kg roxadustat (but not 1 mg/kg or 1.5 mg/kg) compared to epoetin alpha at 2 weeks and at 5 weeks 4 days. This is a thoroughly dubious result, however, since Figure 4B shows that there was no statistically significant difference even in the 2 mg/kg group at 6 weeks. It is therefore understandable that Prof Haase was unimpressed by this when writing his report.
607. Thus the real point is not one of inconsistency on the part of Prof Haase, but that, upon analysis, the data in Provenzano 2 support a different conclusion to that which he drew in his report with respect to hepcidin. The primary endpoint in Provenzano 2 for both parts of the study, however, was the patients’
haemoglobin level. The hepcidin level was merely an “exploratory analysis” (meaning that, as explained by Prof Winearls in the passage quoted above, the study was not designed to produce statistically meaningful results in that respect). Moreover, it was, as the title indicates, an open-label (i.e. unblinded) study. In those circumstances the finding with respect to hepcidin is indicative rather than properly substantiated.
“Another major advantage of HIF-PHI therapy would be the suppression of hepatic hepcidin production and its negative effects on iron mobilisation. Hepcidin plays a central role in the pathogenesis
of functional iron deficiency as it inhibits gastrointestinal iron uptake and iron release from internal stores by down-regulating the surface expression of ferroportin, the only known cellular iron exporter. Clinical data from phase II studies have consistently shown ‘positive’ effects on iron metabolism as manifested by a reduction in plasma ferritin and hepcidin and simultaneous increase in plasma transferrin and TIBC … These results are consistent with experimental data from animal and cell culture studies, which demonstrated that the PHD/HIF axis coordinates iron metabolism with erythropoiesis via transcriptional regulation of genes involved in iron uptake, iron release and transport. … The observed effects on plasma hepcidin levels in CKD
patients
receiving HIF-PHIs are most likely indirect, as hepcidin is not a direct transcriptional target of HIF. Transcriptional suppression of hepcidin in the context of HIF activation requires erythropoietic activity and is mediated by bone-marrow derived factors such as erythroferrone. It is unclear, however, whether the effects of oral HIF-PHI therapy on iron metabolism are primarily mediated via the hepcidin-ferroportin axis (increase in erythropoietic activity with subsequent suppression of hepcidin and increased ferroportin-mediated iron release) or through direct transcriptional regulation of iron metabolism gene expression. Although several iron metabolism genes … are bona fide HIF-regulated genes and can be upregulated by oral prolyl hydroxylase inhibition, it has not been examined whether HIF-PHI doses currently used in clinical trials are sufficient to induce the expression of these genes in CKD
patients.
Nevertheless, the added HIF-PHI effect on iron mobilisation has the potential to reduce the need for IV iron supplementation in
patients
with renal anemia as suggested by Besarab and colleagues.”
610. The matter does not end there, however, because the real question is not whether HIF-PHIs have an effect on hepcidin, but whether any such effect is a clinical useful one with respect to iron mobilisation, in particular compared to ESAs. It can be seen that in the last sentence of the passage from Sanghani quoted in paragraph 608 above, Prof Haase referred to a paper by A. Besesarab et al, namely “Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients”,
J Am Soc Nephrol, 27, 1225–1233 (2016) (“Besarab”).
611. Prof Haase discussed Besarab in paragraphs 74-77 of his second report. As he explained, this is the only study to stratify subjects by reference to exogenous iron supplementation. It was a Phase IIb study of roxadustat in correcting anaemia in newly initiated dialysis patients
naïve to ESAs, randomly assigned to different iron supplementation regimens (oral iron, IV iron and no iron). One group of 24
patients
received no iron, and that group showed a statistically significant decrease in levels of both serum iron and TSAT. The authors noted (at page 1228) that “Neither transferrin saturation (TSAT) levels nor reticulocyte Hb content changed significantly in the groups receiving oral or IV iron, but both decreased in those not receiving iron”. The iron parameters were not primary endpoints in this study, however, and so, consistently with his other evidence, Prof Haase said that further studies were needed to form a definitive view.
613. Prof Winearls stated in paragraph 11 of his fourth report that he did not disagree with what Prof Haase had said in his second report about Besarab. Consistently with that, Prof Haase’s evidence about Besarab was not challenged in cross-examination. (I should take this opportunity to apologise to Prof Haase for the fact that, having forgotten Prof Winearls’ concession and having lost patience
due to some long answers Prof Haase had given, I cut him off when he raised Besarab during the course of his cross-examination, saying “We will come to that in due course”. Contrary to my expectation at that moment, counsel for the Claimants did not come to Besarab. The witness did return to the topic in a later answer, however.)
619. Current clinical practice in the treatment of CKD. There was substantial agreement between Dr Ashman and Dr Devonald as to the current practice. It was common ground between the experts that where a patient
presents with CKD, nephrologists will follow the relevant guidelines (i.e. the Renal Association’s Clinical Practice Guideline Anaemia of Chronic Kidney Disease and NICE Guideline NG8), which provide as follows.
620. The patient
will be assessed. That assessment will include a consideration of any underlying cause of the anaemia and an assessment of the
patient’s
iron status, typically by measuring a combination of serum ferritin and TSAT. If iron deficiency is detected, it is corrected with oral or intravenous iron supplementation. Iron repletion alone may result in adequate improvement in haemoglobin levels and symptoms.
621. Where iron repletion is insufficient to improve haemoglobin levels and symptoms, the clinician will then consider whether exogenous Epo (i.e. an ESA) is appropriate. ESAs are not prescribed before iron status is replete (recognised, for example, by evidence of both ferritin greater than 200 mg/L and TSAT > 20%). Haemoglobin, ferritin and TSAT are monitored regularly in any patients
receiving ongoing treatment with iron and/or an ESA. These results are used to adjust doses of iron and/or the ESA, in general with the aim of keeping haemoglobin between 100-120 g/L (for
patients
receiving ESAs), ferritin at 200-800 mg/L and TSAT > 20%.
622. Guideline 2.1 of the Renal Association Guidelines provides as follows:
“Guideline 2.1 - Treatment of Anaemia with Iron therapy - Iron repletion
We recommend that patients
should be iron replete to achieve and maintain target Hb whether receiving ESAs or not. (1B)
Iron repletion is usually defined as:
• %HRC <6% / CHr >29 pg / ferritin and TSAT (>100 microgram/L and >20%)
• For children, aim for a target ferritin level greater than 100 microgram/L for CKD patients
on dialysis as well as CKD
patients
not on ESA therapy. (ungraded)”
623. It is clear from this guideline that CKD patients
should be iron replete to achieve and maintain target haemoglobin whether receiving ESAs or not. Unless there is a change in the Guidelines, there is no reason to believe that nephrologists would depart from their usual practice of assessing a
patient’s
iron status and correcting iron deficiency if it exists.
624. Unsurprisingly, it was common ground between the experts that, in accordance with the RA Guidelines, patients
with anaemia of CKD will first be administered iron. As Dr Devonald put it:
“[ESAs] would not be offered until the patient’s
iron status is considered replete. In our unit we would consider this to be when serum ferritin is greater than 200 micrograms per litre and TSAT greater than 20% … For
patients
with anaemia related to CKD who are not iron replete according to these criteria, a clinical nephrologist would offer oral or intravenous iron until their iron status was replete.”
As Dr Devonald explained, iron repletion alone may be effective.
625. The current tendency in clinical practice in respect of iron is to administer higher levels of iron than formerly (albeit still within the RA Guidelines range). This tendency is due to the influential PIVOTAL study published in 2019. This was one of the largest renal clinical trials ever undertaken exclusively in the UK, and was designed to investigate the optimum amount of intravenous iron that can be given to patients
on dialysis to treat anaemia effectively and safely. Previously it was thought that giving high doses of IV iron might lead to a greater risk of infection, but the PIVOTAL trial showed that a high dose regime is safe and more effective than the (more commonly used) low dose regime, and leads to a reduction in the dose of ESAs required, which is both clinically and financially advantageous. The PIVOTAL study therefore provides a basis for nephrologists to use iron supplementation more liberally in haemodialysis
patients
in order to achieve better
patient
outcomes, and Dr Ashman explained that Barts (one of the leading renal units in the UK) has already changed to a high-iron regime.
626. Dr Ashman summarised the position as follows:
“For nearly a century the management of iron deficiency anaemia has included the use of iron supplementation; there is a level of comfort with the use of iron supplementation. Furthermore, iron is cheap and, as explained above, the results from the PIVOTAL study provide a basis for nephrologists to use iron supplementation more liberally in haemodialysis patients
in order to achieve better
patient
outcomes. I therefore cannot see any motivation for nephrologists to move away from the use of iron therapy to treat iron deficiency anaemia.”
628. Expected clinical practice with respect to vadadustat for CKD. The Claimants contend that it is foreseeable that at least some clinicians will at some point approach iron supplementation differently with vadadustat compared to what they do currently with ESAs. The suggestion is that HIF-PHIs may start to be used without iron repletion. This relies on the theory that the hepcidin effects of HIF-PHIs may have a clinically beneficial effect on iron mobilisation, such that patients
may be given HIF-PHIs without first being made iron replete, i.e. when they have a TSAT <16% or even <20%.
630. The highest that Dr Devonald put it was that, if the effects referred to in the clinical trial papers (for which he relied on Prof Winearls’ assessment of the literature in his second report) continued to be observed in Phase III clinical trials and subsequent studies, then there was a reasonable expectation that clinical guidelines would consider it acceptable to administer these drugs to patients
with ferritin and TSAT levels below current guideline levels for epoetin ESA prescription. In terms of prescribing to
patients
with TSAT <20%, he suggested that the label “would be unlikely to deter nephrologists from taking this approach if they obtained adequate reassurance, from relevant academic publications, that this approach is safe and effective”. But on the evidence, it is clear there is no such reassurance to be found in the existing clinical trials.
631. If matters were to change, and a substantial body of evidence were to emerge to support administering HIF-PHIs to patients
with TSAT <20%, it is likely that it would take several years before this were to trickle down into clinical practice. Dr Ashman gave the example of the PIVOTAL results, where it took 12 years from the generation of the hypothesis in 2007 to the publication of definitive
patient
outcome results in 2019, which only now is resulting in changes in clinical practice. As he pointed out, even where robust clinical data is available, clinicians may not change their practice, particularly in circumstances where to do so would be against guidelines or contrary to regulatory authorisation.
632. Furthermore, it would appear to be against the goal of achieving clinical benefits for patients
and against the mechanism of action of HIF-PHIs to treat non-iron-replete
patients
with vadadustat. As the mechanism of action of HIF-PHIs involves stimulating erythropoiesis (which uses iron), it is only logical to achieve iron repletion first to ensure sufficient iron levels to be used in making red blood cells to allow the HIF-PHIs to achieve their best therapeutic effects for the
patients.
There is no apparent clinical justification for a doctor to avoid iron repletion of the
patient
before the administration of HIF-PHIs, particularly given that iron is cheap and easy to administer.
633. Expected clinical practice with respect to vadadustat for ACD/anaemia refractory to ESAs/functional iron deficiency. The wording of the SmPC for vadadustat is not within the Defendants’ control and has not been finalised. With one exception, all of the options proposed by the Defendants include the following text in section 4.2, Posology and method of administration:
“All other causes of anaemia (e.g. iron deficiency, vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) should be evaluated and treated prior to initiating therapy with [vadadustat]. The management of anaemia due to chronic renal failure should be individualized.”
635. Treatment of ACD. Whilst there was some suggestion that HIF-PHIs might be of benefit to patients
with (for example) raised inflammation (as in ACD) and that HIF-PHIs might, in the future, prove to be suitable for the treatment of
patients
with conditions such as ACD, there is no evidence at all that vadadustat might actually be prescribed to treat
patients
with indications (such as ACD) for which it is not licensed. The evidence of Dr Ashman was to the contrary.
636. Treatment of anaemia that is refractory to exogenous EPO. Dr Ashman acknowledged that there were small groups of patients
who are difficult to treat and for whom the existing treatment options are limited (e.g. those who are hyporesponsive and those who are blocked within the reticuloendothelial system). Dr Ashman also acknowledged that HIF-PHIs may be an attractive drug for these
patients,
but only if the clinical benefits could be established and it was a cost-effective agent. Since the clinical benefits have not yet been established and the cost of vadadustat is unknown, however, there is no current indication that vadadustat will be used for treating such
patients.
638. Treatment of functional iron deficiency. A nephrologist treats a patient’s
anaemia, not their functional iron deficiency. As explained above, at the outset of such treatment the
patient’s
iron status is assessed and any iron deficiency corrected with supplemental iron. If the
patient
is still showing symptoms of anaemia once iron replete, additional lines of treatment will be considered. In these circumstances, the
patient’s
iron deficiency having been corrected, I agree with the Defendants that the administration of HIF-PHIs to treat the continuing anaemia could not sensibly be said to be for “treating” the functional iron deficiency, particularly where appropriate TSAT levels will be maintained through the course of the treatment.
639. Conclusion. On the evidence available to this Court, the Defendants are not threatening to market vadadustat in circumstances where they will know, or it would be obvious to a reasonable person in the circumstances, that vadadustat is suitable for putting and intended to put the claimed inventions into effect in the United Kingdom. Accordingly, even if the claims in issue are valid, there is no threat by the Defendants to infringe the Family B Patents.
Summary of principal conclusions
640. For the reasons given above, I conclude that:
i) the Family A Patents
are not obvious over Epstein, and since this is the only attack on the validity of claim 17A of EP 531 that claim is valid (subject to the allowability of the amendment);
ii) all the claims in issue of EP 823 and EP 301 both lack plausibility and cannot be performed across their scope without undue burden, and therefore are invalid for insufficiency;
iii) claim 24A of EP 823 and claim 4 of EP 301 are uncertain, and therefore invalid for insufficiency;
iv) all the Family A claims in issue other than claim 17A of EP 531 would be infringed by vadadustat if they were valid;
v) claim 17A of EP 531 is not infringed by vadadustat on the basis of equivalence, and the same goes for claim 36A of EP 333;
vi) the amendments to produce claim 17A of EP 531 are permissible;
vii) all the claims in issue of the Family B Patents
are obvious over WO 997;
viii) all the claims in issue of the Family B Patents
except for claim 36A of EP 333 are invalid on the grounds of insufficiency for the same reasons as the Family A
Patents;
and
ix) even if the claims in issue are valid, there is no threat by the Defendants to infringe the Family B Patents.
Annex