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2 Genentech's UK patent 2,119,904 on Tissue Plasminogen Activator (t-PA)

2 Genentech's UK patent 2,119,904 on Tissue Plasminogen Activator (t-PA)

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Patent Law f o r Biopharmaceuticals


data to support the author‘s conclusions. But for European patent law,

sufficiency and support are now coming to be considered as two sides of the

same coin, since both have to be assessed in relation to the patent claims,

which determine the scope of the legal protection. Both investigations

converge on the effectiveness of the patent description to teach the skilled

person how to put the invention to use. What the inventor has actually done

in the laboratory is, in a sense, less important than the ability to write a recipe

for others to follow.

For biotechnology, patent law first grappled with t h s problem in relation

to inventions in classical microbiology, especially those involving the use of

newly isolated or developed strains of micro-organism to produce some

useful product. The repeatability problem was solved by using culture

collections as official patent depositories of such strains as a substitute for the

well-nigh impossible task of providing an adequate written description both

of the new organism and how to obtain it. This became formalised in an

international convention (the Budapest Convention) whereby deposit in any

one such depository was recogtllsed by all member countries as complying

with their own national requirements. Thls convention now extends beyond

micro-organisms to any biologxal material that cannot be adequately

described by the written word. It follows that this principle must apply to

many of the materials referred to in gene cloning and monoclonal antibody

protocols whch are not available ‘off the shelf to the skilled person wishing

to repeat the prescribed procedure.


Erythropoietin in the European Patent Ofice

(Appeal case T412/93)

European patent No.148 605 was opposed by six Opponents. The case

has assumed considerable legal and t e c h c a l complexity, includmg

consideration of over 500 cited documents, and is not concluded at the time

of this writing. The following remarks are therefore limited to what can be

determined from published accounts.

Thls patent was issued with claims to certain specified DNA sequences

coding for expression of a polypeptide product having at least part of the

primary structural conformation of erythropoietin. The claim covers (i)

specific tabulated sequences, (ii) sequences which hybridize to them , and (iii)

those “whch but for the degeneracy of the genetic code would hybridize to

any of (i) or (ii)”. There are also claims to the polypeptide expression

product of an exogenous DNA sequence. The polypeptide claims are skilfully

worded product-by-process claims which do not cover the polypeptide as

formed in nature.

R Stephen Crespi


A considerable part of the t e c h c a l arguments of expert witnesses

revolved around whether the description was adequate to enable the

preparation of erythropoietin cDNA. This particular enquiry always involves

deciding who is the typical “skilled person” who has to repeat the described

method. The EPO Appeal Board decided that the notional skilled person is “a

Ph.D researcher with several years of experience and two laboratory

assistants having the necessary manual dexterity and lack of fatigue”. The

matter was heavily contested by the scientific experts for all sides. The end

result is that the cDNA claim has not survived but the broader DNA claim is

still intact.

As to whether the claims to the recombinant polypeptide (r-Epo) were

permissible, the question was whether the product was new in the s&se of

being different from erythropoietin obtained from urine (u-Epo). As indicated

previously t l u s is crucial to the allowability of product claims. The scientific

experts were much exercised on this point also. The claim was finally

amended to specify that the product has greater molecular weight than uEpo.

Another decision of the Appeal Board on this issue is awaited on certain

procedural points following whch the matter will be concluded in the EPO. It

may of course resurface in national courts.


Recombinant Factor VII patent

In view of the inventiveness issues that appeared in the t-PA and epo

cases, it is instructive to note how these problems were anticipated by the

writer of the Factor W patents (US 4,784,950 and EP 0 200,421).

The patent points out that Factor W is a trace plasma protein and the

mRNA encoding it is rare. Purification without degradation was also

problematical. Consequently Factor W was poorly characterised and was

hfficult to obtain in quantities sufficient for sequence analysis.

It was nevertheless necessary to expand on tlus argument to persuade the

EPO examiner to withdraw her objection that, at the priority date of this

patent application (April 1985), it was obvious to clone this particular gene

and how it could be acheved. The applicant pointed out in detailed manner

the uncertainty of malung a cDNA library, the inadequacies of sequence

information for oligonucleotide screening, the uncertainty of antibody tools

then available, and the lack of success of other groups working on the

problem. The EPO examiners are open to t h l s lund of reasonable persuasion

and will concede in the face of such impressive arguments.

For reasons mentioned above, these patents do not have a product claim to

the naked recombinant protein. The claims are mostly directed to the DNA

constructs, recombinant plasmids, transfected cells and methods of

Patent Law for Biopharmaceuticals

26 1

production. However, the European Factor W patent has a commercially

very valuable claim to “a pharmaceutical preparation for the treatment of

bleedmg disorders containing a protein having an amino acid sequence as

shown in Figure 1b and free of contaminating human proteins”.


Recombinant Factor IX

In some countries, the Factor IX gene and the protein are covered in

separate patents. The recombinant Factor IX is covered in US 5,171,569

wherein it is claimed as a plasma-free preparation containing the

recombinantly-derived Factor IX protein defined, inter alia, as derived from a

single individual, free of pox viruses and other plasma constituents, and

having a specific activity (as defined in a certain way) of at least 90% of

average normal human plasma.

In Europe the gene for the Factor IX precursor polypeptide (convertible in

vivo into human Factor D( ) is the subject of EP 107,278 wherein it is claimed

as a specified 129 nucleotide sequence.


Hepatitis B patent (Biogen v Medeva)

Thls case is an even more strikmg example of different outcomes obtained

on equivalent patents in different jurisdictions. This patent covers

recombinant DNA molecules having sequences coding for polypeptides

displaymg HBV antigen specificity (claim 1) and HBV antigenicity (claim 2).

There are specific claims to the coding for HBV core antigen and HBV

surface antigen and product-by-process claims to the expression products of

these. Biogen’s European patent 182,442 survived opposition but its British

counterpart underwent the whole rigour of litigation in the UK courts.

Questions of adequacy of description and support for the broad claims figured

prominently throughout h s case ,the most remarkable feature of whch was

the divergmg opinions expressed on these issues by the various judges en

route to the final decision. Finally the UK House of Lords decided that its

claims were too broad. The complexities of h s case have been described in

detail elsewhere (8).



The patent literature is replete with inventions in the field of monoclonal

antibodies. Most of the early development of h s technology, as reflected in

patents, has been directed to the use of monoclonals for the separation and


R Stephen Crespi

purification of bio-molecules and for diagnostic applications. One example of

an early patent to be granted is US patent 4,361,549 whch describes an

OKT3 hybridoma which produces a complement fixing monoclonal antibody

to an antigen found on normal human T cells. The claims are restricted to

mouse monoclonals but the broadest is not restricted to any one T cell

antigen. Diagnostic and therapeutic applications are indicated. This product

is now on the market for use in controlling transplant rejection.

The use of mouse-derived antibodes in humans can induce a human antimouse antibody (HAMA) response which might be serious if repeated use is

necessary. The full therapeutic potential of monoclonal antibodes may

therefore depend on techniques for reducing or eliminating the anti-globulin

response to mouse and other non-human antibodies. The development of

chmeric and ‘humanised’ antibodies formed by recombinant DNA methods

as hybrid immunoglobulins now offers the promise of reducing the immune

response to such antibody products. For reasons touched on earlier,

(e.g. for the t-PA and Epo patent situations), protein engineering technology

gwes rise to the opportunity for new final product patents i.e. those

containing product-per-se claims for the new polypeptides as well as for

DNA sequences that result from these techques. Patents now being granted

in t h s field include some for new principles of immunoglobulin reshaping but

most are for specific products with partially or fully defined amino-acid

sequences. A selection of these is gven below.

The basic principle of antibody reshaping is covered by US patent

5,225,539 and its European equivalent EP 239,400. The claims granted on

t h ~ sinvention cover any ‘altered’ antibody in which the variable domain

framework regons and the complementarity-determining r w o n s (CDRs) are

derived from dlfferent immunoglobulins. The US claims specify this

difference as one of antigen binding specificity or affinity, species, class or

subclass. Inventions whch are the first to open a new field are often

described as “pioneering”, especially if they are followed by a stream of later

developments in the same field. The first patent usually issues with claims of

very broad scope because the patent examiner has not been able to cite

seriously damaging prior art relevant to either novelty or inventiveness.

Such patents are often called “master patents” because they dominate later

inventions. In these situations the requirement for adequate supporting

disclosure has often been met by providing a relatively small number of

‘proof of principle’ model examples. Thls is the case with the patent

numbered above in which one of the specific worked examples describes the

humanisation of one chain of a mouse antibody to a small chemical hapten.

The first example of an antibody humanised to a complex antigen in both

the light and heavy chains is the subject of European patent 328,404.

T h ~ santibody (known as Campath 1-H) binds to the CD52 antigen.

Patent Law for Biopharmaceuticals


The essential feature of t h ~ spatent is the choice of CDRs of specified

amino-acid sequence derived from a particular rat antibody. This patent

seems also to have been the first to include an amino-acid change in

the origmally fully human framework region of one of the immunoglobulin

chains. This favoured the paclung of the CDRs and improved the bindmg

power of the humanised antibody.

Framework changes designed to acheve the above effect are covered

in US patent 5,585,089. Thls is a more than usually complex document

and one of its European counterparts, EP451,216, has itself provoked a

response from others worlung in this field of research and in industry.

This patent covers a number of principles involved in selecting pairings of

CDRs from a donor Ig and frameworks from a human acceptor Ig showing a

hgh degree of homology to the framework of the donor Ig. These principles

include certain defined criteria for the replacement (if necessary) of aminoacids in the heavy or light chain human frameworks by the correspondmg

amino-acids in the donor Ig sequence.

Some other patents on products undergoing clinical evaluation are

US 5,585,097 which covers an aglycosyl anti-CD3 antibody claimed in

terms of fully sequence-defined light and heavy chains and aglycosylated

constant r w o n . Aglycosylation reduces the first-dose (cytolune) response

whch may be encountered with the parent antibody. As with many similar

US patents, there is also a claim in 5,585,097 to a method of treating a patient

with t h ~ santibody to prevent renal allograft rejection. Method claims of this

type are not allowed under European patent law. The reason for this is not

primarily an ethtcal one, as is sometimes thought, but because the procedural

act of treating humans is not an industrial process and therefore does not meet

the ‘susceptibility of industrial application’ requirement for patentability.

Another example of method claims is US patent 5,656,272 whch

describes the preparation of an anti-tumour necrosis factor-a chimeric

antibody for treating Crohn’s disease. This product has received US FDA

approval. The patent claims are all directed to the method of treatment.

A parallel patent application for the antibody itself may also exist.



The writing of patents for nucleic acids and proteins presents an

acute dilemma. One knows that the composition of these molecules may

be modified in various ways, leading to mutants, variants and derivative

forms which may either retain, enhance or reduce, or totally lose the original


R Stephen Crespi

biological activity. The patent draftsman attempts to guard against thud party

avoidance of claims tied too closely to the limited range of specific products

made by the inventors and presented as the patent examples. But in the

absence of data on the effect of compositional variation on activity there is

nothmg to guide h m . The patent examiners will normally stress the uncertain

effect of variation and will insist that the claims are limited to what has been


The patent draftsman will usually prepare the ground for a broad

interpretation of the claims by the use of a skilfully drawn "Definitions"

section. A comprehensive model of this tactic is to be found in the human

tissue plasminogen activator patents, especially US patent 4,766,075 whch is

the equivalent of UK patent 2,119,804 discussed above. These definitions of

t-PA embrace natural allelic variations and derivatives modified by single or

multiple amino-acid substitutions, deletions, additions or replacements in the

t-PA molecule so long as the essential biologcal function of t-PA is retained.

An infringement suit on the US t-PA patents provides an instructive

example of how these matters are treated by the courts.


Genentech v Wellcome Foundation and Genetics

Institute (1990)

Genentech sued these defendants for infringement of the following three

US patents relevant to t-PA (9) :4,752,603 (the '603 patent) is directed to Human plasminogen activator derived

from the Bowes melanoma cell line and it covers the original work carried out

by Leuven Research and Development. The claims are limited to material of

specific activity of 500,000 IU/mg against a specified reference standard. This

limitation was necessary because of an earlier publication by one of the

inventors describing material purified to an activity of 266,000 units.

4,766,075 (the '075 patent) covers "A DNA isolate consisting essentially of a

DNA sequence encoding human tissue plasminogen activator" and the

corresponding recombinant expression vectors.

4,853,330 covers the process of expressing the DNA of the '075 patent to

produce t-PA.

Wellcome's product, made in the UK and exported to the US, differs by


Wellcome product (met-t-PA) contained m&onine in place of valine at

position 245.

only one amino-acid from human t-PA,"the product of the patent".

Patent Law f o r Biopharmaceuticals


The GI product (FElX) was a product having 81 amino acid deletions

from t-PA. It lacked the finger r w o n and most of the epidermal growth

region and had other differences in the knngle region of the native protein.

The District Court of Delaware (in March 1990) held that, on their literal

interpretation, the claims in both the '603 and '075 patents were limited to the

full-length amino-acid sequences of naturally occurring human t-PA and its

naturally occurring allelic variants. The court also decided that the specific

activity limitation in the '603 patent should also apply to the definition of t-PA

in the context of the '075 patent. l h s was particularly surprising because the

claims of the '075 patent were to the DNA coding and not to the protein,

either per se or at any level of purity.

It being admitted that neither met-t-PA nor FElX naturally occur in

humans and that their specific activities were lower than that specified (or

assumed) in the claims, these products were held not to infringe the patent on

the literal interpretation. Wellcome also argued successfully that importation

of met-t-PA into the US, which involved no use of the claimed DNA or

recombinant cell lines in the US, was non-infringing for this reason also.

But US law also has a "doctrine of equivalents'' which the Delaware court

described as "an equitable doctrine permitting a more expansive interpretation

of patent claims than the literal scope thereof'. In view of the material issues

of law involved, the court declined to rule on t l x s issue and reserved it for

further trial. Genentech then applied for a jury trial on the equivalents issue.

l h commenced 7 days later and resulted withn 15 days in verdicts of

infringement by equivalents for both products. One might well marvel at the

idea that a jury could be expected competently and fairly to assess t e c h c a l

and legal issues as complex as those involved in t h s case. However, h s

victory was relatively short-lived (as legal processes go) because it was

reversed by the Court of Appeals for the Federal Circuit (CAFC) in June


W l e the Appeal to CAFC was pending, Wellcome announced their

decision to discontinue development of a t-PA product. Genentech had also

decided not to cross-appeal on the issue of the literal interpretation of the

claims. Therefore the only issue for the CAFC was whether FElX infringed

under the doctrine of equivalents.

The court identified three key issues. The first was whether the specific

activity limitation in the '603 patent applied to the '075 and '330 patents, to

which the court gave a negative answer because these were in every way

independent patents. The second was the basis of measurement of the specific

activity figure. The court decided that this was to be measured by the bovine

fibrin plate assay. The thud and much the most important question for the

court was the meaning of "human tissue plasminogen activator".

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2 Genentech's UK patent 2,119,904 on Tissue Plasminogen Activator (t-PA)

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