Reach-through claims SPC s Ir Johan Brants

& Reach-through claims SPC’s Ir. Johan Brants © 2003 De Clercq, Brants & Partners E. Gevaertdreef 10 a B-9830 Sint-Martens-Latem +32(0)9 280 23 40 +32(0)9 280 23 45 www. dcbpatent. com info@dcbpatent. com © 2006 De Clercq, Brants & Partners

& What is a research tool? • A research tool is NOT a diagnostic or therapeutic product or a commercial scale production process. • A research tool is a composition or method useful in conducting experiments. • Research tools commonly include: – cell lines, transgenic animals, monoclonal antibodies, clones, and cloning tools – nucleic acids and proteins – combinatorial chemistry libraries, genomic libraries, and © 2003 De Clercq, Brants & Partners proteomic libraries – expression and reporter systems – databases, software, equipment and reagents. © 2006 De Clercq, Brants & Partners

& • • Research Tool Controversies Reach-through claims Reach-through enforcement Damages Licensing and valuation March-in rights under Bayh-Dole Act (US) Research exceptions Royalty-stacking © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& What is a reach-through claim? • Reach-through claims seek to protect things which have not yet been discovered by an inventor, but which might be discovered in the future by making use of their invention. • Invention in a widely applicable basic research technology ("upstream" technology), – possible to envisage future technologies ("downstream" technology), developed using the basic research technology. • If the inventor of an upstream invention files a patent application for the upstream invention and attempts to © 2003 De Clercq, Brants & Partners claim downstream inventions which they have not as yet actually made, then the claims to those downstream inventions are referred to as "reach-through" claims. © 2006 De Clercq, Brants & Partners

& What is a reach-through claim? • The “reach-through” products are identified only by reference to the material or assay used to find or identify them, but they are not described specifically. © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& How a reach-through claim comes into existence • For example: Discovery of a new protein which might be suitable for use as a drug target – Protection can be obtained only for the isolated drug target and methods of screening for drugs which act as inhibitors or agonists (as appropriate) for that drug target. – Conceived to be insufficient protection. Inventor also wants to obtain explicit protection for all drugs which act as inhibitors or agonists (as appropriate) for that drug target (or all gene therapies which modulate levels of the protein in vivo). – He who discovers a drug screening process may wish to claim all drugs discovered through that process. © 2003 Devisor of a Partners – De Clercq, Brants & peptide-display library or a new combinatorial chemistry technique may wish to protect specific molecules within the library that are later found to have practical applications. © 2006 De Clercq, Brants & Partners

& Reach-through examples • Small molecule per se claim, where the molecule is only defined as binding to target • “A receptor X agonist. ” • “Functional use” claim • claim is to a method of treating a disease by a compound defined not by its structure, but by its ability to bind a target © 2003 De Clercq, Brants & Partners • “A method of treating disease Y by administering a compound which is an enzyme X agonist. ” (US style) © 2006 De Clercq, Brants & Partners

& Reach-through examples • The classic structure of the claims in a reach-through patent is the following: • “ 1. Receptor X useful to the treatment of disease Y • 2. Method for identifying an agonist of the receptor X comprising the following steps: • … • 3. Agonist of the receptor X identified with the method subject-matter of claim 2”. • © 2003 De Clercq, a receptor agonist for the manufacture of a “Use of Brants & Partners medicament for inhibiting obesity, wherein said receptor agonist is identified by the method of claim …. ” © 2006 De Clercq, Brants & Partners

& Patentability of Reach-Through Claims • Reach-through claims normally fail to meet at least one and often several of the written description, enablement, utility, novelty, or nonobviousness requirement. © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Novelty • When a reach-through claim encompasses a group of as yet unidentified biological or chemical entities, it is vulnerable to the risk that some of the group of the as yet unknown entities will turn out to already be known – Risk can be reduced if some work has already been done to characterize some specific identified entities -> claims can be directed to more defined groups of © 2003 De Clercq, Brants less likely to inadvertently include entities, & Partners that are already known. © 2006 De Clercq, Brants & Partners

& Inventive step • Problem-solution approach -> what is the objective technical problem to be solved? • Important to include credible information in a patent application about problems which might be solved by claimed products and methods. • If an inventive screening process may be used to discover new drugs – The patent application should discuss the problems to be solved by the potential drugs, not just the problems solved by the screening process. © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Industrial application • Industrial application of a reach-through claim to an unspecified drug, to be discovered later by making use of that process, may be problematic. • EPO could argue that a chemical or biological entity which has not been disclosed in the patent application, even in general terms, is incapable of industrial application. © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Enabling disclosure requirement • A European patent application must disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art. – it must be possible for the skilled worker to perform the claimed invention (over the whole area claimed) without undue burden and without needing inventive skill. • A reach-through claim to a group of biological or chemical entities may lack sufficient disclosure if insufficient examples of such entities are given or if it is not clear how to make and use such entities in an industrially applicable way. • © 2003 De also Brants & sufficient disclosure if there would be an undue May Clercq, lack Partners burden on others who would need to screen a large or potentially infinite number of biological or chemical entities to establish those which could be used in the claimed invention. © 2006 De Clercq, Brants & Partners

& Support by the description • The scope of claims must be restricted to the scope justified by the invention which has been made. – Applicants are allowed to cover all modifications, equivalents to and uses of the invention which they have described – But claims cannot generally be extended beyond the invention which has actually been made to cover further inventions which might be made in the future, © 2003 De Clercq, Brants & Partners by using the technology described in the patent application, but which have not yet been made. © 2006 De Clercq, Brants & Partners

& Clarity • Reach-through claims would be unclear if a person reading the claims cannot easily work out what is or is not covered by the claim. – Problem of a lack of clarity can be reduced once downstream research starts to make it possible to frame more specific claims to more © 2003 De Clercq, Brants & Partners clearly defined groups of entities. © 2006 De Clercq, Brants & Partners

& Risks with early patent filing • Non-fulfilment of patentability criteria, but may contain enough information to deprive later patent application for downstream developments of novelty and inventive step. • It can be appropriate to delay the filing of a patent application for an upstream research invention while research progresses and provides new information which can be usefully included in the patent application. – De Clercq, Brants & Partners © 2003 This has its own risks ->new prior art entering the public domain, or third parties filing conflicting patent applications during the period of delay. © 2006 De Clercq, Brants & Partners

& Risk for FTO’s Licensing • How to evaluate reach-through claims in FTO’s? – Most of the pending claims before the EPO might never be granted • Licensing: – Would a license be required for such claims, and hoz to deal with such cases? © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Investors • Do investors lead potential applicants to such claims, as theoretical possibility of the profitable prospect of such claims trigger more willingness to invest? • Investors should take advice on the patentability of reach-through claims when they are conducting pre-investment due diligence. – They should maintain a realistic understanding of the extent to which owners of upstream research © 2003 De Clercq, Brants & Partners technology might be able to profit from downstream developments. © 2006 De Clercq, Brants & Partners

Eli Lilly v & (US Distr. Ct Ariad Pharmaceuticals Massachusetts, May 2006) • US patent 6, 410, 516 • The '516 patent, awarded after 16 years of prosecution in the USPTO, presents 203 separate claims covering methods of treating disease by regulating a family of molecules known as NF-k. B, a biological trigger believed to play a role in a wide range of illnesses from cancer to osteoporosis to bacterial infections. © 2003 De Clercq, Brants & Partners • The '516 patent claims methods based on the discovery of a naturally-occurring biological pathway, the NF-kappa. B pathway. © 2006 De Clercq, Brants & Partners

& The invention • NF-kappa. B is a protein that: – a) resides in the cytoplasm as an inactive precursor bound to an Ikappa. B inhibitor protein; – b) when released from the inhibitor, travels to the nucleus of the cell; – c) once in the nucleus, functions to turn on transcription of certain genes by binding to specific DNA recognition sequences in those genes • Reducing NF-kappa. B activity: decreasing the function of NF-kappa. B to act as an intracellular © 2003 De Clercq, Brants & Partners messenger that regulates transcription of particular genes, in response to certain stimuli © 2006 De Clercq, Brants & Partners

& The invention • The invention relates to a method of regulating (enhancing or diminishing) the activity of NF. kappa. B in cells in which it is present and capable of acting as an intracellular messenger, as well as to substances or composition useful in such a method. • Such methods and compositions are designed to make use of the role of NF-. kappa. B as a © 2003 De Clercq, Brants & Partners mediator in the expression of genes in a variety of cell types. © 2006 De Clercq, Brants & Partners

& US 6, 410, 516 • Granted US claims at issue: • 1. A method for inhibiting expression, in a eukaryotic cell, of a gene whose transcription is regulated by NF-. kappa. KB, the method comprising reducing NF-. kappa. KB activity in the cell such that expression of said gene is inhibited. • 7. A method for modifying effects of external influences on a eukaryotic cell, which external influences induce NF-. kappa. Bmediated intracellular signaling, the method comprising altering NF-. kappa. B activity in the cells such that NF-. kappa. B-mediated effects of external influences are modified • 8. The method of claim 7, wherein NF-. kappa. B activity in the cell is reduced. • © 2003 De Clercq, Brants & Partners reducing, in eukaryotic cells, the level of 9. A method for expression of genes which are activated by extracellular influences which induce NF-. kappa. B-mediated intracellular signaling, the method comprising reducing NF-. kappa. B activity in the cells such that expression of said genes is reduced. © 2006 De Clercq, Brants & Partners

& US 6, 410, 516 • 80. The method of claim 8 wherein reducing NF-. kappa. B activity comprises reducing binding of NF-. kappa. B to NFkappa. B recognition sites on genes which are transcriptionally regulated by NF. kappa. B. • 95. The method of claim 9, carried out on human cells © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& US 6, 410, 516 • 14. A method for reducing bacterial lipopolysaccharideinduced expression of cytokines in mammalian cells, which method comprises reducing NF-. kappa. B activity in the cells so as to reduce bacterial lipopolysaccharideinduced expression of said cytokines in the cells. • 144. The method of claim 14 wherein reducing NF. kappa. B activity comprises reducing binding of NF. kappa. B to NF-. kappa. B recognition sites on genes © 2003 De Clercq, Brants & Partners which are transcriptionally regulated by NF-. kappa. B. • 145. The method of claim 14, carried out on human cells. © 2006 De Clercq, Brants & Partners

& The different views • Ariad contends that the patent covers all means for modulating the NF-kappa. B pathway, • Lilly contends that it discovered the drugs in question, Evista and Xigris (held to infringe the Ariad patent) and disclosed their medicinal properties years before the patentees' scientists made their discovery. © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Scientific literature has shown that not less than 140 compounds are known to inhibit NF-kappa. B, amongst which aspirin and lipitor © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Jury findings © 2003 De Clercq, Brants & Partners © 2006 De Clercq,

& What does the patent cover? • Patent thus covers also compounds which have inhibiting effect, already on the market • Patent covers any future compound which has said inhibiting effect © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Is there a problem here? • Questions relating to patentability: – Does it cover prior art? – Is the invention enabled? • Does not identify or disclose any specific compound which indeed has the inhibiting effect – Written description requirement? © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Univ. of Rochester v Searle • In the light of Univ. of Rochester v Searle (CAFC, 13/02/2004), the invention should not be patentable • The invention: Traditional non-steroidal antiinflammatory drugs (“NSAIDs”) such as aspirin, ibuprofen, ketoprofen, and naproxen are believed to function by inhibiting the activity of enzymes called cyclooxygenases. Cyclooxygenases catalyze the production of a molecule called prostaglandin H 2, which is a © 2003 De Clercq, Brants & Partners precursor for other prostaglandins that perform various functions in the human body. © 2006 De Clercq, Brants & Partners

& The invention • Scientists at the University of Rochester hypothesised that if PGHS-2 could be inhibited selectively, without inhibiting PGHS-1, – this would provide a method of reducing pain and inflammation – without reducing levels of beneficial PGHS-1 mediated prostaglandins. • They proposed an assay method to screen drug candidates to discover candidates which have the necessary selectivity. However, they did not © 2003 De Clercq, Brants & Partners include any description of drugs resulting from this assay in their US patent application. © 2006 De Clercq, Brants & Partners

& Univ. of Rochester v Searle • Granted US Claims 6, 048, 850 : • 1. A method for selectively inhibiting PGHS-2 activity in a human host, comprising administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product to a human host in need of such treatment. • 5. A method for selectively inhibiting PGHS-2 activity in a human host, comprising administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product in a human host in need of such treatment, wherein the activity of the non-steroidal compound does not result in significant toxic side effects © 2003 De Clercq, Brants & Partners in the human host. © 2006 De Clercq, Brants & Partners

& Univ. of Rochester v Searle • CAFC: All eight claims are directed to methods “for selectively inhibiting PGHS-2 activity in a human host” by “administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product to [or in] a human host in need of such treatment. ” © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Univ. of Rochester v Searle • The CAFC ruled that the patent was invalid for not fulfilling written description and enablement requirement • “Thus, generalized language may not suffice if it does not convey the detailed identity of an invention. In this case, there is no language here, generalized or otherwise, that describes compounds that achieve the claimed effect. ” © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Univ. of Rochester v Searle • “It is undisputed that the ’ 850 patent does not disclose any compounds that can be used in its claimed methods. The claimed methods thus cannot be practiced based on the patent’s specification, even considering the knowledge of one skilled in the art. No compounds that will perform the claimed method are disclosed, nor has any evidence been shown that such a compound was known. ” © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& European counterpart Ariad patent: EP 0407411 B 1, priority 01. 03. 1988 Granted

& • • • Look for the problem Which agent? Novel? Enabled? Medical treatment

& EPO case law • T 609/02, relating to granted EP 0552 202 • Claim 6 of main request in Opposition, corresponding to granted claim 10, found to fail on Art. 83 EPC by OD: – “The use of a compound as identified by the method of claims 1 to 5 for the preparation of a pharmaceutical against over-expression of © 2003 De Clercq, Brants & Partners steroid hormone-responsive or steroid hormone-like compoundresponsive gene(s). " © 2006 De Clercq, Brants & Partners

& T 609/02 • Claim 6 claim as suggested by new request during oral proceedings before TBA: – “The use of a steroid hormone or steroid hormone analogue as identified by the method of claims 1 to 5, which fails to promote transcriptional activation of glucocorticoid receptor or retinoic acid receptor genes, for the preparation of a pharmaceutical for the treatment of AP-1 © 2003 De Clercq, Brants & Partners stimulated tumor formation, arthritis, asthma, allergies and rashes. ” © 2006 De Clercq, Brants & Partners

& T 609/02 • TBA: “The patent specification provides no evidence at all relating to the invention in claim 6: no steroid hormone is identified as binding to the hormone receptor in such a way that the soformed complex will disrupt AP-1 stimulated transcription and at the same time fail to promote steroid hormone regulated transcription; no data of any kind are presented indicating that such an hormone (if it were © 2003 De Clercq, Brants & Partners identified) could have an impact on any of the listed specific diseases. ” © 2006 De Clercq, Brants & Partners

& T 609/02 • TBA: “The appellant provided postpublished evidence showing that steroid hormones such as needed to carry out the use according to claim 6 were later structurally identified and that they, indeed, have an effect on AP-1 stimulated transcription. ” • TBA held the claim non-patentable for lack of enabling disclosure © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants &

& Why Supplementary Protection Certificates (SPC’s)? • Developing drugs, and putting them on the market takes considerable amount of time and investment • Gap between patent application and market authorisation reduces effective term of patent protection • SPC compensates part of the loss of effective protection © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Conditions for obtaining an SPC • Art. 3 EC Reg. 1768/92: To obtain an SPC, one needs on the date of application in the territory concerned: • (a) a product covered by a basic patent in force; • (b) a valid authorization to place the product on the market as a medicinal product has been granted in accordance with Directive 2001/83/EC or Directive 2001/82/EC, as appropriate; • (c) the product has not already been the subject of a certificate; © (d) the authorization referred to in (b) is the first • 2003 De Clercq, Brants & Partners authorization to place the product on the market as a medicinal product. © 2006 De Clercq, Brants & Partners

& Medicinal product • Art. 1 Reg. 1768/92 • (a) 'medicinal product' means any substance or combination of substances presented for treating or preventing disease in human beings or animals and any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in humans or in animals; © 2003 De Clercq, Brants & Partners • (b) 'product' means the active ingredient or combination of active ingredients of a medicinal product; © 2006 De Clercq, Brants & Partners

& SPC formulation patents? • C-431/04 gives an answer to that question • The MIT is the holder of a European patent 0 260 415. That patent covers the preparation Gliadel, covering the alliance of two elements, polifeprosan, a polymeric, biodegradable excipient, and carmustine, an active ingredient already used in intravenous chemotherapy with inert excipients and drug additives for the treatment of brain tumours. Gliadel comes in the form of a device which is implanted into the cranium for the treatment of recurrent brain tumours. . • A marketing authorisation for Gliadel was granted in Germany by a decision of 3 August 1999. • MIT asked the DPMA to grant it an SPC for Gliadel. – In main application an SPC for carmustine in combination with polifeprosan. – Alternative application an SPC for carmustine only. © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& The case • The DPMA rejected the application for an SPC by a decision of 16 October 2001, on the ground that polifeprosan could not be considered to be an active ingredient within the meaning of Article 1(b) and Article 3 of Regulation No 1768/92. • It also held that no SPC could be granted for carmustine on its own as that active ingredient was already covered by a marketing © 2003 De Clercq, Brants & Partners authorisation, and had been for a long time © 2006 De Clercq, Brants & Partners

& C-431/04 – the questions • Reference by decision of the Bundesgerichtshof of 29 June 2004, Massachusetts Institute of Technology (C-431/04): • Does the term 'combination of active ingredients of a medicinal product' within the meaning of Article 1(b) of Council Regulation 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal products mean that the components of the combination must all be active ingredients with a therapeutic effect? • Is there a 'combination of active ingredients of a medicinal product' also where a combination of substances comprising two components of which one component is a known substance with a therapeutic & Partners © 2003 De Clercq, Brantseffect for a specific indication and the other component renders possible a pharmaceutical form of the medicinal product that brings about a changed efficacy of the medicinal product for this indication (in-vivo implantation with controlled release of the active ingredient to avoid toxic effects)? © 2006 De Clercq, Brants & Partners

& ECJ C-431/04 • Point 11 Explanatory Memorandum: “[t]he proposal for a Regulation therefore concerns only new medicinal products. It does not involve granting an [SPC] for all medicinal products that are authorised to be placed on the market. Only one [SPC] may be granted for any one product, a product being understood to mean an active substance in the strict sense. Minor changes to the medicinal product such as a new dose, the use of a different salt or ester or a different pharmaceutical form will not lead to the issue of a new [SPC]. ” • -> ECJ: it is apparent from that memorandum that the pharmaceutical form of the medicinal product, to which © 2003 De Clercq, Brants & Partners an excipient may contribute, does not form part of the definition of ‘product’, which is understood to mean an ‘active substance’ or ‘active ingredient’ in the strict sense. © 2006 De Clercq, Brants & Partners

& ECJ C-431/04 • Point 68 Explanatory Memorandum Reg 1610/96: – “it would not be acceptable, in view of the balance required between the interests concerned, for the total duration of protection granted by the SPC and the patent for one and the same product to be exceeded; – A strict definition of the product is necessary; – If an SPC has already been granted for the active substance itself, a new SPC may not be granted for that substance, whatever changes may have been made regarding other © 2003 De Clercq, Brants & Partners features of the plant protection product (use of a different salt, different excipients, different presentation, etc. ); ” © 2006 De Clercq, Brants & Partners

& ECJ C-431/04 • “A substance which does not have any therapeutic effect of its own and which is used to obtain a certain pharmaceutical form of the medicinal product is not covered by the concept of ‘active ingredient’, which in turn is used to define the term ‘product’. Therefore, the alliance of such a substance with a substance which does have therapeutic effects of its own cannot give © 2003 De Clercq, Brants & Partners rise to a ‘combination of active ingredients’ within the meaning of Article 1(b) of Regulation No 1768/92. ” © 2006 De Clercq, Brants & Partners

& Conclusions • It remains tempting to file patent applications for research tools in early stages • Most applicants find protection for the assay not sufficient • In order to compensate for the early stage, reach-through claims must ensure adequate and future protection • Most of these claims appear not to be patentable • Sometimes a patent can be obtained – One may face national invalidity proceedings once such patent is enforced © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Conclusions • It is recommendable to add structural language in such patent applications within the priority year – Might overcome enablement, inventive step and industrial application problems • General advice regarding reach-through claims: “Bezint eer gij begint” © 2003 De Clercq, Brants & Partners © 2006 De Clercq, Brants & Partners

& Conclusions • Applicants for SPC wish to broaden the possibilities to obtain SPC protection – Seems logical in view of growing tendency to maximize scope of protection – SPC was until relatively recently not the battlefield for high-tech protection extension strategies – Situation has changes dramatically (see also Astra Zeneca antitrust case EC) – Clever ways to optimize the possibilities offered by the SPC system will be daily menu of the future • © 2003 De Clercq, Brants & Partners ECJ seems to be in conformity Decision of the with legislative history © 2006 De Clercq, Brants & Partners