American Intellectual Property Law Association
Biotechnology Committee
Biotechnology in the Courts Subcommittee
Report
Summaries of Recent Decisions of Interest to the Biotechnology Community
Prepared for the AIPLA Biotechnology Committee
April 29, 2012
Edited By:
Melanie Szweras
Subcommittee Chair
Bereskin & Parr LLP
E-mail: mszweras@bereskinparr.com
Nicholas Landau
Subcommittee Vice Chair
Bradley Arant Boult Cummings LLP
E-mail: nlandau@babc.com
CONTRIBUTORS
Oliver Kingsbury
Paul Cole
The AIPLA Biotechnology in the Courts Subcommittee Report is a forum for members of the
subcommittee to present summaries and commentary on recent judicial decisions of interest to
the biotechnology community. Any view of a contributor expressed in a summary should be
understood to reflect only the present consideration and views of the contributor, and should not
be attributed to the AIPLA or any of its committees, the contributor’s firm, employer, or past or
present clients, to other contributors, or to the editor. To request an electronic copy of the
Report, or if you are interested in summarizing a case for a future edition, please contact Melanie
Szweras at mszweras@bereskinparr.com.
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CONTRIBUTORS:
Dr Oliver Kingsbury read chemistry at Oxford University, obtaining his doctorate in
organic chemistry in 1997. He qualified as a UK and European Patent Attorney in 2002
and has spent most of his career working in the pharmaceutical industry including a
period on secondment to GSK followed by full-time roles at Lilly and Pfizer. In
November 2011, Oliver left Pfizer to join Elkington and Fife LLP.
Paul Cole is a UK and European patent and trademark attorney and is additionally
authorized to conduct intellectual property litigation before the UK courts. He received
an MA in chemistry from Oxford University and an LLM from Nottingham Trent
University and has been a partner at Lucas & Co since 1999. His prosecution experience
has focused on chemical and pharmaceutical inventions but has extended into a wide
range of other technologies, e.g., optics, photocopiers and OLED and liquid crystal
display devices. He has also served as an editor of the 6th and 7th Editions of the CIPA
Guide to the Patents Acts and is a visiting professor in IP law at Bournemouth University.
Lynn C. Tyler is a partner and registered patent attorney in the Intellectual Property
Department of Barnes & Thornburg LLP in Indianapolis. He concentrates his practice in
litigation of intellectual property matters, representing clients at all stages of the process.
Mr. Tyler has been listed in Best Lawyers in America® since 2009, more recently in
multiple categories. He is the author of several published articles on issues of intellectual
property or federal procedure in a variety of peer-reviewed publications. In 2010, one of
his articles won the prestigious Burton Award for Legal Achievement. The first of his
two articles on inequitable conduct has been cited by two Federal Circuit Judges in
published opinions.
Mr. Tyler graduated summa cum laude in 1981 from the University of Notre Dame and in
1984 received his J.D. magna cum laude from the University of Michigan Law School. In
2007, he received a M.S. in Biology from Purdue University (Indianapolis campus).
Mr. Tyler’s civic activities include being a co-founder, past president, and volunteer for
the Neighborhood Christian Legal Clinic. For his work on behalf of the Clinic, he
received the Indianapolis Bar Association's Pro Bono Award in 2002 and was a corecipient of the firm's inaugural Joseph A. Maley Pro Bono Award in 2009.
Jennifer L. Schuster is an associate in Barnes & Thornburg LLP’s Indianapolis, Indiana
office, where she is a member of the firm’s Intellectual Property and Litigation
Departments.
Ms. Schuster completed her undergraduate and graduate work at Purdue University,
where she was a recipient of the Steven C. Beering Scholarship and Fellowship. She
received her B.S. in molecular biology with honors in research and B.A. in creative
writing in 2004, both with highest distinction, and her M.S. in genetics in 2005. While at
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Purdue, she was selected as an outstanding senior in the School of Science and was a
member of Phi Beta Kappa.
Ms. Schuster received her J.D. magna cum laude from Indiana University School of Law
– Bloomington in 2008, where she was awarded the Chancellor’s Fellowship. She was an
Executive Competition Coordinator for the Sherman Minton Moot Court Board and a
Notes and Comments Editor for the Indiana Law Journal. Upon graduation, she was
elected to the Order of the Barristers and Order of the Coif.
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TABLE OF CONTENTS
I.
Regeneron & Bayer v. Genentech, UK Patents Court, March 22,
2012…………5
II.
Prometheus v Mayo – A European view………10
III.
Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc., Case No. 09-11340-FDS,
slip op. (D. Mass. Mar. 9, 2012)…………15
415
Case Summaries
I.
Regeneron & Bayer v. Genentech, High Court of Justice, Chancery
Division, Patents Court, London, UK, 22 March 2012, [2012] EWHC
657 (Pat)
Reported by: Oliver Kingsbury
Summary
On 22 March 2012, the UK Patents Court rejected applications by Regeneron
Pharmaceuticals Inc. and Bayer Pharma AG for revocation of European Patent (UK) No.
1 238 986 (“the Patent”), which belongs to Genentech Inc. Furthermore, the Court ruled
that a product called VEGF Trap Eye (“VTE”) which Regeneron and Bayer are planning
to market for the treatment of age-related macular degeneration of the eye would infringe
the Patent.
The decision confirms the European standard for anticipation of a therapeutic use claim
and also illustrates the importance of “expectation of success” as a key restraint in an
“obvious to try” assessment of inventive step. However, it is perhaps most remarkable
because the Patent in suit was held to meet the requirements for sufficient disclosure even
though it claimed a therapeutic use wherein not only were the therapeutic agents merely
functionally defined, but also the diseases to be treated were only defined by reference to
a common biological effect. For this reason, the present report is restricted to a review of
the Court’s rejection of the numerous insufficiency attacks.
The Patent
Claim 14 of the Patent is exemplary and reads as follows:
An hVEGF antagonist for use in the treatment of a non-neoplastic disease or
disorder characterised by undesirable excessive neovascularisation, wherein the
hVEGF antagonist is:
(a) an anti-VEGF antibody or antibody fragment;
(b) an anti-VEGF receptor antibody or antibody fragment; or
(c) an isolated hVEGF receptor.
Despite its potential breadth, the experimental support for this claim lies within just three
examples (Examples 4-6), one of which is described by way of background because it
relates to inhibition of tumour growth which is outside the scope of the claims. The
disclosure of these examples is summarised below.
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In Example 4, three different tumour cell lines were injected into nude mice and, after
tumour nodules formed, the anti-VEGF antibody A4.6.1 or controls were administered.
A4.6.1 caused a significant decrease in the rate of tumour growth in one of the cell lines
and the size and weight of the tumours at the end of the 5 week experiment were
substantially lower in mice treated with the antibody when compared to the negative
controls. Tumour weights from the other two cell lines were also significantly lower in
the antibody treated mice compared to the negative controls.
In Example 5, cells from two of the tumour cell lines in culture were exposed to a range
of A4.6.1 concentrations and found to grow similarly to those exposed to negative
controls, thus demonstrating that antibody A4.6.1 is not cytotoxic per se.
In Example 6, the effect of A4.6.1 on endothelial cell chemotaxis stimulated by synovial
fluid from rheumatoid arthritis (RA) patients is shown. Synovial fluid of the RA patients
contained an activity which caused endothelial cells to migrate - which is required as part
of the angiogenic process. This chemotactic activity was significantly and reproducibly
inhibited by the A4.6.1 antibody. By contrast, it had little effect on endothelial cell
chemotaxis induced by synovial fluid from patients with osteoarthritis (in which the
angiogenesis observed in RA does not occur).
The Decision
Regeneron and Bayer argued that the limited experimental data did not provide adequate
basis to support the prediction that anti-VEGF therapy would be effective over the whole
range of diseases claimed nor that all hVEGF antagonists covered by the claims would be
effective. The patentee on the other hand argued that the effects observed in the
Examples, coupled with what the skilled person already knew about the biological role of
VEGF, presented the skilled reader with a “concept fit for generalisation” which
therefore deserved broad protection. In their view, the breadth of the claims did not
exceed the technical contribution to the art made by the invention. Both parties relied on
the evidence of their expert witnesses to support their positions and this evidence was
crucial to the court’s final decision as to who was correct - sufficiency of disclosure being
a fact-based enquiry into the ability of the skilled person to work the invention across its
full scope.
Claim breadth – Diseases to be treated
On the issue of claim breadth for the disease definition, the expert for the Patentee took
the position that, as early as the mid-1980s, the general view in the art was that both
tumour and non-tumour neovascular diseases were linked by a common thread, namely
angiogenesis, and that if you could suppress tumour growth you would expect to be able
to use the same anti-angiogenic strategy to treat non-neoplastic diseases. He went on to
say that the data in the patent (Example 4) provided the first proof-of-concept that a
VEGF antagonist can be used to reduce tumour angiogenesis and the rate of tumour
growth, and would have provided the skilled team with significant confidence that such
an antagonist can also be used in non-tumor neovascular settings.
615
The claimants’ expert, on the other hand, disagreed that one could extrapolate from the
cancer data of the Patent to conclude that VEGF antagonism would be effective in the
treatment of all other angiogenic diseases. However, the court found this view hard to
reconcile with the same expert’s testimony in relation to the issue of obviousness where
he had expressed a more expansive view of what the skilled person would have learnt
from the prior art. Furthermore, the expert’s apparent enthusiasm for the case he was
presenting led the court to approach his evidence with considerable caution.
In the end, whilst recognising that it would not be possible to make a fair prediction if the
evidence had shown that angiogenesis was significantly different in character from
disease to disease, the court decided that the evidence did not show this at all. Once the
inventors had shown that blockade of VEGF was sufficient to prevent pathological
angiogenesis in tumours, it was reasonable to predict that it would be sufficient in other
diseases. The patent did not need to prove that this was in fact the case.
Claim breadth – Antagonist definition
On the issue of claim breadth for the definition of the antagonists of use in the invention,
the claimants took the position that the claim was insufficient if the group (c) antagonist
(i.e. “an isolated hVEGF receptor”) extended to cover their own VTE product which is a
recombinant chimeric homodimer, each monomer comprising:
• the immunoglobulin-like domain 2 of the VEGF-R1 receptor; and
• the immunoglobulin-like domain 3 of the VEGF-R2 receptor; fused to
• the constant region (Fc) of human immunoglobulin G1.
715
Although the Patent disclosed how to make “an isolated hVEGF receptor” comprising the
full extracellular domain (ECD) of a VEGF receptor fused to human IgG1 heavy chain,
the claimants contended that it amounted to an undue burden for the skilled person to
discover more limited sections of the isolated VEGF receptor which would also function
as VEGF antagonists. Their evidential support came from papers published after the
priority date which illustrated the different results obtained by contemporaneous research
teams and highlighted the pitfalls involved in this task. They also relied on the
considerable amount of work which had been done to produce their own (infringing)
VTE product which was clearly not taught by the Patent.
The court recognised the theoretical force in these points, but decided that they did not
lead to a finding of insufficiency noting that:
“Firstly, one has to bear in mind that the industry in question is one where
careful experimentation with a degree of trial and error, sometimes extending
over months and years, is entirely normal. Secondly, it is not necessary, in order
to work the invention to identify the minimum binding domain of the receptor. The
fact that one can continue to refine one’s receptor beyond the point at which one
has a viable construct does not, as it seems to me, matter. A patent is not
insufficient because it may take much work to develop the most elegant or refined
embodiment of its inventive concept. If one were to carry on with the refinement,
one would still be making use of the principle disclosed in the patent, working
towards an improved embodiment of it.”
Claim breadth - Non-working embodiments
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Finally, the claimants also alleged that there were non-working embodiments which fell
within the scope of the claims, either because there were certain diseases which did not
respond to treatment with a VEGF antagonist, or because there were certain antagonists
which did not deliver the claimed therapeutic effect. However, the court ruled that the
evidence provided to support these allegations fell short of that required for a finding of
insufficiency.
Commentary
This case illustrates a number of important considerations for litigants seeking to attack a
patent on the basis of insufficient disclosure in Europe.
The first is one that will be familiar to attorneys who have been involved in European
opposition proceedings, that is, it is hard to win with an insufficiency attack in Europe!
The evidential burden on claimants/opponents is high and is made more difficult by the
fact that one is often required to ‘prove a negative’ – i.e. that the skilled person could not
perform the invention across its scope without undue burden. In the present case the court
appeared to accept that months, or even years of experimentation may not amount to
undue burden in this field. As an aside, one has to wonder whether this is proportionate
with what must be demonstrated by Patentees to obtain such broad claims in the first
place? Perhaps this case will be helpful to the patent attorney in obtaining claims with
broader scope.
The second is the reinforcement of the importance of objective expert evidence for factbased enquiries such as obviousness and enablement. Had the claimants’ expert been a
little less extreme in some of his views, the court might have been inclined to afford
greater weight to his evidence. It also illustrates the potential dangers of contradictory
positions being exposed when running attacks under both obviousness and insufficiency.
Finally, US practitioners should note that European law does not provide any equivalent
to the US “written description” requirement. Although similar policy considerations (i.e.
that the scope of a patent should not exceed the patentee’s technical contribution to the
art) underlie both the insufficiency test in Europe and the written description test in the
US, the need to show “possession” of the invention to satisfy the latter test appears to lay
down a stricter requirement for US applicants. As a result, it is perhaps true to say that
claims which define an invention by function rather than structure are more likely to be
granted and to withstand a subsequent validity challenge in Europe than in the US.
915
II.
Prometheus v Mayo – A European view
Reported by: Paul Cole, European Patent Attorney, Lucas & Co.
How is the Prometheus invention viewed by the European Patent Office (“EPO”),
and what are the differences between the reasoning of EPO appeal boards and of the US
Supreme Court concerning patent eligibility?
An indication is that the EPO granted EP-B-1114403 (Seidman-the ‘403) which
corresponds to US 6,355,623 (the ‘623) and has a main claim that reads:
An in vitro method for determining efficacy of treatment of a subject
having an immune-mediated gastrointestinal disorder or a non-inflammatory
bowel disease (non-IBD) autoimmune disease by administration of a 6mercaptopurine drug, comprising
determining in vitro a level of 6-thioguanine in a sample from said subject
having said immune-mediated gastrointestinal disorder or said non-inflammatory
bowel disease (non-IBD) autoimmune disease,
wherein said treatment is considered efficient if the level of 6-thioguanine
is in the range of about 230 pmol per 8x108 red blood cells to about 400 pmol per
8x108 red blood cells.
The above claim is not an outlier. The forward references of the ‘623 patent
include US 7,524,851, whose equivalent EP-B-1695092 has a main claim that reads:
A method for monitoring azathioprine therapy in an individual, said
method comprising
measuring the level of 6-thioguanosine diphosphate and 6-thioguanosine
triphosphate in a sample from said individual, and
calculating a concentration ratio of 6-thioguanosine triphosphate to 6thioguanosine triphosphate and 6-thioguanosine diphosphate,
wherein a concentration ratio greater than 0.85 is indicative of superior
clinical responsiveness to azathioprine therapy, and wherein a concentration ratio
less than 0.85 is indicative of inferior clinical responsiveness to azathioprine
therapy.
In a communication dated 26 October 2007, and available in the EPO’s online
file, the Examining Division decided that the ‘851 claim was novel and inventive based
on the technical effect of improved therapeutic efficiency. In accordance with EPO
practice, from that effect a technical problem based on the Seidman disclosure as starting
point could be reconstructed which was to provide an improved method of monitoring
azopurine therapy.
If the ‘403 patent had been challenged e.g. in an opposition the EPO would have
been bound to follow established case law and hold that the claimed method was patenteligible firstly because it is carried out on a sample from the subjects and secondly
1015
because an in vitro measurement is made (see the Enlarged Appeal Board decision in G
3/08 PRESIDENT’S REFERENCE in which the long-standing practice of the Appeal
Boards was approved.) It was pointed out that a computer-readable data storage medium
had the technical effects of being computer-readable and of being capable of storing data
and is patent-eligible under EPC Articles 52(2) and (3). On that basis it could not become
ineligible merely because it was storing computer program X, any more than a cup which
was a technical article could become ineligible merely because it was decorated with
picture X. There was no case-law to support the view that a claim to “a computerreadable storage medium with program X written on it” should lose its technical
character merely because it was too generic or functionally defined. As is well-known,
that is not the whole story. The UK Court of Appeal has described this approach as: “The
Lord giveth, the Lord taketh away” and has objected that treating ineligible features as
part of the prior art is “simply not intellectually honest”, see Aerotel v Telco [2006]
EWCA Civ 1371. UK courts treat eligibility as a matter of substance and not mere form.
In the present case, however, an argument that the “wherein” features should be
disregarded for assessment of novelty or inventive step taking into account the exclusions
under Article 52 EPC as a mere discovery or mere presentation of information would
have been likely to fail because, as seen above, improvement in therapeutic efficiency is
treated at least at first instance as a technical effect.
The U.S. Court of Appeals for the Federal Circuit (“CAFC”) in its opinion on
remand of 17 December 2010 reasoned in broadly similar terms to what would be
expected from an EPO Appeal Board dealing with patent-eligibility. It held that treatment
and optimisation formed part of an inherently patent-eligible treatment protocol (opinion,
page 20) and continued:
“We agree with the district court that the final “wherein” clauses are
mental steps and thus not patent-eligible per se. However, although they alone are
not patent-eligible, the claims are not simply to the mental steps. A subsequent
mental step does not, by itself, negate the transformative nature of prior steps.
Thus, when viewed in the proper context, the final step of providing a warning
based on the results of the prior steps does not detract from the patentability of
Prometheus’s claimed methods as a whole. The data that the administering and
determining steps provide for use in the mental steps are obtained by steps well
within the realm of patentable subject matter; the addition of the mental steps to
the claimed methods thus does not remove the prior two steps from that realm.”
As to the overall significance of the “wherein” clauses in the context of the claim
as a whole, the CAFC appears to have accepted that they helped define a technical result
(opinion at pp. 22-23):
“Although the wherein clauses describe the mental processes used to
determine the need to change the dosage levels of the drugs, each asserted claim
as a whole is drawn to patentable subject matter. Although a physician is not
required to make any upward or downward adjustment in dosage during the
“warning” step, the prior steps provide useful information for possible dosage
1115
adjustments to the method of treatment using thiopurine drugs for a particular
subject. Viewing the treatment methods as a whole, Prometheus has claimed
therapeutic methods that determine the optimal dosage level for a course of
treatment. In other words, when asked the critical question, “What did the
applicant invent?,” Grams, 888 F.2d at 839 (citation omitted), the answer is a
series of transformative steps that optimizes efficacy and reduces toxicity of a
method of treatment for particular diseases using particular drugs.”
From a European standpoint the key ruling of the Supreme Court is that the
reasoning of the CAFC and the EPO Appeal Boards should not be followed. Its reasons
are set out in the slip opinion pp. 20-21:
“Third, the Government argues that virtually any step beyond a statement
of a law of nature itself should transform an unpatentable law of nature into a
potentially patentable application sufficient to satisfy §101’s demands… The
Government does not necessarily believe that claims that (like the claims before
us) extend just minimally beyond a law of nature should receive patents. But in its
view, other statutory provisions—those that insist that a claimed process be novel,
35 U. S. C. §102, that it not be “obvious in light of prior art,” §103, and that it be
“full[y], clear[ly], concise[ly], and exact[ly]” described, §112—can perform this
screening function.
This approach, however, would make the “law of nature” exception to
§101 patentability a dead letter …
What role would laws of nature, including newly discovered (and “novel”)
laws of nature, play in the Government’s suggested “novelty” inquiry? Intuitively,
one would suppose that a newly discovered law of nature is novel. The
Government, however, suggests in effect that the novelty of a component law of
nature may be disregarded when evaluating the novelty of the whole… But §§102
and 103 say nothing about treating laws of nature as if they were part of the prior
art when applying those sections. Cf. Diehr, 450 U. S., at 188 (patent claims
“must be considered as a whole”).”
If the CAFC/EPO approach is to be abandoned, what is the alternative? The rule
followed by the Supreme Court is that the claimed combination of features must amount
to significantly more than the natural law itself and that limiting the law to a particular
technological environment or adding insignificant post-solution activity does not suffice.
The Court was aware of the need for caution and warns in its opinion:
“The Court has recognized, however, that too broad an interpretation of this
exclusionary principle could eviscerate patent law. For all inventions at some
level embody, use, reflect, rest upon, or apply laws of nature, natural phenomena,
or abstract ideas.”
In effect the Mayo rule corresponds to the “contribution approach” suggested at
first instance in the UK in Merrill Lynch’s Application [1988] R.P.C. 1 which was to
consider whether the inventive contribution resided only in excluded matter. That
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approach also has its difficulties and it was rejected by the UK Court of Appeal in
Genentech’s patent [1989] R.P.C. 147 where it was observed that:
“Such a conclusion, when applied to a discovery, would seem to mean that the
application of the discovery is only patentable if the application is itself novel and
not obvious, altogether apart from the novelty of the discovery. That would have a
very drastic effect on the patenting of new drugs and medicinal or microbiological
processes.”
The Supreme Court acknowledges that the rule ought not to be interpreted to
cover newly discovered first or subsequent medical indications for a known substance
(slip opinion at page 18):
Unlike, say, a typical patent on a new drug or a new way of using an existing
drug, the patent claims do not confine their reach to particular applications of
those laws.
It is, however, less than clear by what logic new drugs escape the rule in Mayo,
but the Prometheus test is caught by that rule. For example, nitroglycerin was first
synthesized in 1847 and was used as an explosive. In 1878 it was introduced as a
treatment for angina by Dr. William Murrell. Suppose Dr. Murrell had claimed a
pharmaceutical composition for the treatment of angina or other heart conditions
comprising nitroglycerin and a pharmaceutically acceptable carrier or diluent. The antiangina activity of nitroglycerin could be regarded as a mere phenomenon of nature
“though just discovered”, the reference to treatment of cardiac disorder could be a mere
limitation to a particular technological environment and formulation into tablets or other
forms for convenient administration to the patient could be regarded as an insignificant
post-solution activity since the incorporation of active ingredients into tablets or other
dosage forms was well known long before 1878. The pharmaceutical composition claim
which is in standard form for a first medical indication would block research into further
formulations and further medical indications for nitroglycerin. Indeed, blocking further
development was an objection raised in the 1790’s to James Watt’s patent for a steam
engine. It might be said that the hypothetical Murrell claim confines the reach of what has
been discovered to the particular application of pharmaceuticals but it might equally be
said that the Prometheus claim confines the reach of what has discovered to the particular
application of a blood test for metabolites of drugs of a particular family. If there is a
distinction, arguably it is no more than pragmatism.
Such a conclusion is consistent with the arguments of Robert Sachs in Part III of a
April 2012 Guest Post, where he singles out relative terminology and conclusory
statements. A question expressed as “doing significantly more” or “adding enough” is a
matter of degree rather than of kind, and provides no unequivocal forward guidance.
Indeed the Supreme Court accepted the limitations of its guidance (slip opinion at page
24) where it said:
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“In consequence, we must hesitate before departing from established
general legal rules lest a new protective rule that seems to suit the needs of one
field produce unforeseen results in another.”
Perhaps the wisest course is to take the opinion at its word and accept that beyond
disapproving the CAFC/EPO approach Mayo makes no new rule and does nothing
positive to explain what is patent-eligible and what is not.
On the particular facts, the Supreme Court objects (slip opinion at page 18) that:
“The ‘determining’ step too is set forth in highly general language covering all processes
that make use of the correlations after measuring metabolites, including later discovered
processes that measure metabolite levels in new ways.” However, that generality is
arguably broader than the construction of the relevant claim mandated by §112(6). The
second step is to “determining the level of 6-thioguanine…” Self-evidently that is a step
for performing the function of level determination without recital of acts in support
thereof. It is therefore to be construed to cover the corresponding acts described in the
specification and equivalents thereof. The disclosed acts (‘623 at columns 9 and 10) all
involve collecting erythrocytes (red blood cells), leucocytes (white blood cells) or cells
from the oral mucosa. Thiobases are extracted from the cells and analysed by highpressure liquid chromatography or by one of several specified fluorometric assays. The
claim is therefore not of indefinite scope but instead is confined to those acts and their
equivalents. If Judge Breyer had more clearly appreciated how the application of the
alleged natural law is confined by §112(6) there might have been a different outcome in
this finely-balanced case.
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III. Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc., Case No. 0911340-FDS, slip op. (D. Mass. Mar. 9, 2012)
Reported by: Lynn C. Tyler and Jennifer L. Schuster
Summary
Regular readers of these summaries are familiar with the ongoing patent war
between various Abbott entities and certain Johnson & Johnson affiliates ("Centocor")
over various antibody patents. As previously reported, Centocor won the largest
judgment in the history of patent litigation in a dispute with Abbott over an antibody to
TNF-alpha, represented by the competing blockbuster drugs, Humira from Abbott and
Remicade from Centocor, only to see that judgment reversed by the Federal Circuit.
Abbott now has a suit pending against Centocor over another TNF-alpha patent.
Another battle in this multi-front war is currently raging over an antibody to IL-12
and IL-23. Centocor's product, Stelara, is projected to have sales of over $500 million in
2013. Abbott's product, briakinumab, is in late stage clinical trials. In this battle, most
recently the district court entered summary judgment in favor of Abbott that Stelara
infringes several claims of U.S. Patent No. 6,914,128 (“the ‘128 patent”) and U.S. Patent
No. 7,504,485 (“the ‘485 patent”). The court also entered summary judgment against
Centocor on certain invalidity defenses (indefiniteness and whether certain Abbott work
constituted prior art) and denied Centocor’s motion for summary judgment on invalidity
defenses (written description and whether certain Centocor work was prior art).
Invention
Abbott’s ‘128 and‘485 patent include claims to antibodies to the cytokines IL-12
and IL-23. These cytokines are involved in certain autoimmune diseases, such as
psoriasis, and antibodies against them can be effective treatments. Claim 29 of the ‘128
patent, which was found to be infringed as a matter of law, reads:
29. A neutralizing isolated human antibody, or antigen-binding portion
thereof that binds to human IL-12 and disassociates from human IL-12
with a Koff rate constant of 1×10-2 s-1 or less, as determined by surface
plasmon resonance.
Claim 1 of the ‘485 patent, also found to be infringed as a matter of law, reads:
1. A pharmaceutical composition comprising an isolated human antibody, or
antigen-binding portion thereof, which is capable of binding to an epitope of the
p40 subunit of IL-12, and further comprising an additional agent.
Procedural History
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On December 12, 2007, the BPAI declared an interference between Abbott’s ‘128
patent and Centocor’s still-pending U.S. Patent Application 10/912,994 (“Centocor ‘994
application”). The BPAI instituted a proceeding to determine priority under Section
102(g), obviousness under Section 103, and patent validity under the written description,
enablement, and definiteness requirements of Section 112. The interference included a
single count, which the PTO defined as “[a]n isolated human antibody according to claim
1 of U.S. Application 10/912,994 or claim 1 of U.S. Patent 6,914,128.” Abbott prevailed
in that interference, and Centocor sought review in a district court pursuant to 35 U.S.C.
§ 146 and also sought a declaration of non-infringement and invalidity of the ‘128 and
‘485 patents.
On August 10, 2009, Abbott sued Centocor for infringement of the ‘128 and ‘145
patent. Eventually, Centocor’s suit was transferred to the District of Massachusetts,
where Abbott’s case was pending, and the cases were consolidated.
Following a claim construction ruling, the parties filed motions for summary
judgment on various issues. Abbott sought summary judgment that Centocor was
collaterally estopped from challenging the validity of the patents, at least on the same
grounds as presented to the BPAI, that the asserted claims were not indefinite, that the
work of some of the inventors was not prior art under § 102(g)(2) or § 102(f), and that
Stelara infringed certain claims. Centocor sought summary judgment that certain claims
were indefinite, that all the asserted claims lacked an adequate written description, that
the work of some inventors was prior art, that Centocor’s work had priority and
anticipated the claims, and that Stelara did not infringe certain or all asserted claims.
Decision
Factual summary
In July, 1993, three Abbott scientists determined that an antibody to IL-12 could
have medical use and later than same year Abbott began collaborating with two other
companies to develop such an antibody. In late 1995 and early 1996, researchers
working on the project identified several antibodies with the ability to bind to IL-12.
These antibodies, one of which was known as the Joe 9 antibody, were subsequently used
to develop antibodies for IL-12 with higher affinity and neutralizing effect. After further
work, the researchers discovered an antibody known as J695, which binds to and
neutralizes IL-12 to a degree that makes it effective for treatment.
On March 25, 1999, Abbott filed a provisional application for a patent on human
antibodies that specifically bind to human IL-12. On March 24, 2000, it filed a related
application, U.S. Patent Application 09/534,717, that described 50 antibodies that bind to
an epitope located on the p40 subunit of IL-12. The application set forth 74 claims
covering antibodies that share with the disclosed antibodies particular binding properties
in relation to IL12.
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Eventually, Abbott became aware that the IL-12 antibodies also bind to IL-23.
IL-23 includes the same p40 subunit as IL-12, but in IL-23 the p40 subunit is combined
with a p19 subunit and in IL-12 the p40 subunit is combined with a p35 subunit. Some of
the disclosed antibodies that bind to an epitope located on the p40 subunit of IL-12 also
bind to that subunit of IL-23.
On July 1, 2004, Abbott filed U.S. Patent Application 10/884,830 as a divisional
of the
09/534,717 application. Abbott’s ‘830 application claimed antibodies that bind to the p40
subunit of IL-12 both when it binds to a p35 subunit to form IL-12 and when it binds to a
p19 subunit to
form IL-23. The PTO granted the application as the ‘485 patent on March 17, 2009.
In approximately March 1997, Centocor scientists began work on developing a
fully human neutralizing antibody to IL-12. On September 4, 1997, one scientist on the
team identified a hybridoma that produced an antibody that binds to IL-12; that antibody
was later named ustekinumab. By February 25, 1998, Centocor scientists had created a
pharmaceutical composition of ustekinumab. No later than April 30, 1998, Centocor
confirmed that the antibody had the desired binding and neutralizing characteristics. Like
J695 and other antibodies described in the ‘128 and ‘485 patents, ustekinumab binds to
the p40 subunit of IL-12. Ustekinumab became Stelara.
On August 7 and September 29, 2000, Centocor filed provisional patent
applications claiming human, neutralizing antibodies to IL-12. It filed a non-provisional
application on the subject matter on August 1, 2001. On August 6, 2004, it filed the
Centocor ‘994 application as a divisional of the 2001 application.
Court’s Analysis
1. Collateral estoppel
The court first addressed Abbott’s motion for summary judgment that Centocor
was collaterally estopped, based on the BPAI proceedings, from challenging the validity
of the ‘128 and ‘485 patents, if not completely, then at least based on the same arguments
that Centocor had presented to the BPAI. The court denied this motion because Centocor
had sought review of the BPAI decision pursuant to § 146. The Court ruled that there had
not been a final decision yet because the § 146 proceeding is a mixture of an appeal and a
de novo trial and it was not concluded. The district court also exercised its discretion not
to resolve the § 146 proceeding first and then apply collateral estoppel against Centocor
based on the outcome. The court concluded that such a procedure would improperly deny
Centocor its right to a jury trial on its validity defenses.
2. Definiteness
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The first substantive motions addressed by the court were Centocor’s motion that
certain claims, dubbed the Kd claims, were indefinite as a matter of law and Abbott’s
cross-motion that the claims were not indefinite, again as a matter of law. Claim 1 of the
‘128 patent was taken as representative of the Kd claims and describes “[a]n isolated
human antibody, or antigen-binding portion thereof that binds to human IL-12 and
dissociates from human IL-12 with a K4 of 1×10-10M or less and a Koff rate constant of
1×10-3 s-1 or less, as determined by surface plasmon resonance.” (‘128 patent, col. 385,
ll.11-15).
Centocor argued that a person reasonably skilled in the art would not be able to
measure the Kd value of an antibody using surface plasmon resonance (SPR) without
information on at least two experimental conditions, surface density and flow rate. The
district court rejected Centocor’s argument, and granted Abbott’s cross-motion, for
several reasons. First, one of Abbott’s experts testified that a person of ordinary skill in
the art would have known to conduct pilot experiments to determine appropriate surface
density and flow rate values. Although Centocor had an expert also, its expert did not
dispute this key point. Second, Abbott’s patent disclosed instruments for performing the
test made by BIAcore and BIAcore’s handbooks on the use of those instruments issued
prior to the filing of the application that led to the ‘128 patent showed that appropriate
methods for conducting SPR experiments were known at the time of the application.
Third, other scientific literature that predated Abbott’s application proved that
how to conduct the SPR tests was known. Finally, the court noted that Abbott had
identified 36 other patents, including 3 owned by Centocor, that contained similar claim
language, which satisfied the district court that a person of ordinary skill in the art must
understand the terminology.
3. Written description
a. ‘128 patent
Centocor argued that the asserted claims, all of which defined a genus of
antibodies based on their ability to bind and neutralize IL-12, were invalid because the
patent did not disclose enough examples within each family to support the genus claims.
The court stated that there are no bright line rules concerning the number of species that
must be disclosed to support a genus, citing cases for the proposition that one species was
insufficient, e.g., In re Alonso, 545 F.3d
1015, 1021 (Fed. Cir. 2008), and one case for the proposition that disclosure of even a
single species may, in some circumstances, be sufficient to describe a functionallydefined genus, Invitrogen Corp. v. Clontech Labs., Inc., 429 F.3d 1052, 1073 (Fed. Cir.
2005). The court noted that the ‘128 patent disclosed 50 species and ruled that the
number of species required to support a functionally-defined genus was too fact-intensive
an inquiry to decide on summary judgment.
b. ‘485 patent
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Centocor argued that the asserted claims of the ‘485 patent to binding IL-23
lacked written description because the patent had only a single mention of the p19
subunit and did not disclose its protein structure. The court stated that the patent did not
have to disclose the protein structure because it claimed antibodies to IL-23, not IL-23
itself. Because the antibodies bonded with the p40 subunit of both IL-12 and IL-23,
however, the court found that a reasonable finder of fact could infer that this reference
establishes a “descriptive link” between the disclosure and the IL-23 claims.
Further, the court stated that whether the disclosed antibodies sufficiently describe
a genus of IL-23 antibodies may depend on the state of knowledge in the art about IL-23
at the time of filing. The state of the art was a factual issue disputed by the parties,
however, so summary judgment was inappropriate.
4. 102/103
a. Abbott’s own work
Centocor argued that the work by the three Abbott scientists who first decided to
research IL-12 was work by a different inventive entity than the 22 scientists named on
the ‘128 and ‘485 patents and thus prior art. The court rejected the argument as
inconsistent with the broad joint inventorship provision of 35 U.S.C. § 116, which
provides:
Inventors may apply for a patent jointly even though (1) they did not physically
work together or at the same time, (2) each did not make the same type or amount
of contribution, or (3) each did not make a contribution to the subject matter of
every claim of the patent.
Abbott’s three scientists had not pursued their own patent and could contribute their work
to the joint invention represented by the ‘128 and ‘485 patents.
b. Centocor’s development of Stelara
Centocor argued that its development of Stelara was prior art to Abbott’s patents.
The parties agreed that Centocor had a priority date of April 30, 1998, and Abbott’s filing
date was March 25, 1999. Abbott presented evidence, however, that antibodies falling
within the scope of its claims were reduced to practice in 1995, 1996, and 1997. The
BPAI had found that the Joe antibodies were reduced to practice in 1995. This evidence
was sufficient to create a factual dispute on priority.
With respect to the composition claims, Centocor argued that one of the named
inventors (Freidrich) on Abbott’s patents had not joined the team until August, 1998, so
the invention could not have taken place prior to that time. The court rejected this
argument, noting that the Federal Circuit has held that proof of priority to a genus claim
requires less than what is required to establish adequate written description of that claim.
In re Zletz, 893 F.2d 319, 323 (Fed. Cir. 1989); see also In re Stempel, 44 C.C.P.A. 820,
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826 (1957). Thus, Abbott could have invented a species of pharmaceutical composition
within the scope of its claims before Centocor’s priority date of April 30, 1998, but
required contributions from Friedrich after that date to satisfy § 112 for Abbott’s genus
claims. The Court noted that there was other evidence that Abbott had invented
antibodies to IL-12 before Centocor’s priority date, so Freidrich may have been
misjoined.
5. Infringement
a. Human antibody
The parties filed cross-motions for summary judgment on whether Stelara was a
“human antibody” within the meaning of all the asserted claims. The district court had
construed “human antibody” to mean “an antibody that is derived from human DNA and
not from the DNA of any non-human species.” Centocor argued that Stelara is not a
“human antibody” within the court’s construction because the DNA that encodes the
antibody is likely to contain nucleotide sequences that were inserted through Nnucleotide addition by the B cell of a transgenic mouse. The district court rejected this
argument, however, noting that its construction referred to germline DNA, all of which
was human, and the likely addition of murine DNA was simply one way in which the
human germline DNA could be altered or mutated. As this was Centocor’s only noninfringement argument on three claims of the ‘128 patent and twenty claims of the ‘485
patent, the court found that Stelara infringed those claims as a matter of law.
b. Kd limitation
Centocor’s expert found that Stelara did not have a Kd value within the scope of
the claims, so Centocor sought summary judgment of non-infringement on this ground.
Abbott presented expert testimony challenging both the methods and results of
Centocor’s expert, however, so the court denied summary judgment.
c. Receptor binding assay
Claim 61 of the ‘128 patent contains a limitation that the claimed antibody must
“inhibit[] IL-12 binding to its receptor in an IL-12 receptor binding assay (RBA) with an
IC50 of 1×10-11 M or less.” (’128 patent col. 388, ll. 64-67). The IL-12 receptor consists of
two subunits, called β1 and β2, and Centocor argued that to prove infringement the
evidence had to consist only of assays that test the ability of an antibody to bind both
subunits simultaneously. Abbott relied on tests done by a Centocor scientist to show
infringement. In its claim construction order, the district court ruled that this element
could be shown using any test known at the time of the application. Thus, the issue was
whether the test used by the Centocor scientist was known at the relevant time, and the
court found a factual dispute on this issue. Accordingly, summary judgment was denied.
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Commentary
Judge Saylor’s 76-page opinion is quite thorough and in some sections includes
far more discussion of relevant case law than we can present in a summary. Interested
readers may wish to consult the full opinion.
Because the denials of summary judgment simply mean the case will go to trial on
those issues, perhaps the most interesting aspects of the opinion are those where the court
granted summary judgment. As to infringement, readers with experience in patent
litigation will recognize the familiar pattern of fighting over the proper construction of
the claim terms, “human antibody” here, followed by fighting over the proper
construction of the court’s construction of the claim terms. Depending on the outcome of
the trial and barring a settlement, this fight is likely to continue on to the Federal Circuit.
On the definiteness ruling, assuming the court’s description of the evidence is
accurate (and there is no reason to think otherwise), the opinion is persuasive. Similarly,
given the flexibility of § 116, the conclusion that the prior work of the three Abbott
scientists was not prior art appears sound. In light of the summary judgment standard and
standard of review on appeal, however, this is not to say that these rulings may not be
reversed some day.
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