Uncertainty over pharmaceutical and biotech product ...

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Uncertainty over pharmaceutical and biotech product patents in Pakistan Saima Sadaf, Muhammad W Akhtar & Zarina Iqbal

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Saima Sadaf is at the Institute of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan. Muhammad W. Akhtar is at the School of Biological Sciences, University of the Punjab, Lahore, Pakistan. Zarina Iqbal is at United Trademark and Patent Services, Lahore, Pakistan. e-mail: [email protected]

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rom 1947 to 1997, Pakistan was among the countries that did not provide product per se patent protection for new chemical entities (NCEs) in the chemical, pharmaceutical, agricultural or biotech sectors. In 1997, when Pakistan became a signatory to the World Trade Organization agreement on traderelated aspects of intellectual property rights, it amended its patent law1 and subsequently enacted a new one2, which, among other things, provided product patent protection to inventions relating to medicine and agriculture. The statutory criteria for product patents in Pakistan are now quite stringent owing to the introduction of the ‘single chemical product’ concept3. According to this idea, for per se protection in pharmaceuticals, the product must be: (i) a compound in free form, to the exclusion of its derivatives and salts, and (ii) defined by its structural formula. In the biotech sector, for parallel protection, the statutory criteria are: (i) novelty—that is, the biological product must have had no previously recognized existence; (ii) non-obviousness; (iii) non-natural occurrence—that is, the product must be produced through recombinant DNA technology or chemical synthesis; (iv) capability of being characterized and/or identified by structure—that is, in terms of sequence and (v) utility—that is, the product must be shown to have some medicinal, antibiotic or therapeutic effect. If a structural

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Even after the enactment of a patent law in 2000, pharmaceutical and biotech-related inventions are perceived to lack strong product patent protection in Pakistan.

Figure 1 Patent applications for NCEs filed during 2004–2010 by the leading pharmaceutical and biotech companies in Pakistan. Source: The Gazette of Pakistan (Part V)

description of the biological product is not possible, protection is limited to a productby-process claim only3. The exclusion of derivatives and salts having the same activity as the free-base form of the compound from the scope of ‘single chemical product’ has greatly undermined the interests of the pharma and biotech companies that are a substantial source of intellectual property–related activities in Pakistan. Gradually increasing passivity and a mixed trend in filing patent applications by some leading pharma and biotech companies relating to NCEs has been observed over the past few years (Fig. 1). Patent protection is available through a separate or divisional filing route for derivatives and salts that show material and novel improvements over the main product. But in cases where derivatives and salts are shown or are expected to work in much the same

way, have substantially the same function and produce the same or similar results as the compound in free-base form, the pursuit and maintenance of a large number of divisional applications—for example, one for a generic claim to the salt of the active compound, another for the specific salts (such as Na+, K+ or CH3COO–), a third for the equivalent or functional derivatives of the active compound, a fourth for a process of manufacturing the active compound and even a fifth for a composition comprising the salts of the active compound—may mean throwing good money after bad and involve an unrealistic effort in answering official actions to secure multiple patents for a single invention. This exercise is not only cumbersome and a financial burden on the multinational companies, it may not even result in a defensible patent, given the likelihood that its validity will be attacked on the grounds of insufficiency, lack of fair basis,

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lack of inventive step or extension of subject matter beyond the scope of original and/or double patenting. This has created a situation in which many product patents in Pakistan are confusing and unsatisfactory, while the makers of generic drugs, whose activities may fall within the scope of such a granted patent, remain oblivious. Issues in gene and DNA-sequence patenting The challenges of securing biotech product patents would seem to be no different from those related to pharmaceutical and chemical products, yet patenting in this field presents particular problems related to eligibility—in determining the breadth of protection appropriate for materials that already exist in nature (the ‘product of nature’ issue) and the extent to which the requirements of novelty4 and inventive step5 can be met with patents to such material. Under Pakistani law, “substances that exist in nature or isolated therefrom”6 are regarded as non-inventions, so they fall outside the remit of patentable subject matter (Supplementary Discussion 1). Compared to UK and European patent laws7, Pakistan’s patent law provides no distinction between things that exist in nature and can only be unearthed or discovered (unpatentable discoveries) and things that are ‘isolated’ from their natural environment through human intervention (patentable inventions in the United Kingdom and European Union). For a product to be eligible for product patent protection, the law entails something beyond mere isolation. For instance, if a biological product—such as a protein or antibody—and its utility and/or function are already known to a person skilled in the art, mere isolation and/or reproduction by recombinant DNA technology or chemical synthesis is a “known desideratum,” and hence would lack inventive step8, unless the synthetic version has some property that the natural product does not. On the other hand, if a gene or DNA sequence or its fragments or expressed sequence tags are novel and can be shown to produce a technical effect (by having a use in protein synthesis, gene therapy or diagnostic testing, for example)9, it may be patentable. The legal position in Pakistan can be explained by recitals to the EU Biotechnology Directive, which explains that “a mere DNA sequence without any indication of a function does not contain any technical information, and is, therefore, not a patentable invention”10,11. Particularly with reference to gene sequencing, the Biotechnology Directive specifies that the industrial application of a sequence or a partial sequence of a gene must be disclosed in the application12. Stressing

the industrial-application requirement, the opposition division of the European Patent Office (EPO) has said that mere disclosure of speculative uses is not enough and that DNA sequences with indications of function that are not substantial, specific and credible are not patentable inventions according to Article 52(1) of the European Patent Convention13. Thus, where a full or partial gene sequence is used to produce all or part of a protein, the protein that is produced or the function it performs must be specified for the invention to have the requisite industrial applicability14. In its Howard Florey Institute/Relaxin decision15 among others, the EPO opposition division also applied this reasoning in upholding claims directed to DNA fragments encoding a specific hormone (human relaxin-2). This clarifies that if a gene or DNA sequence is novel and has an indicated function or use that is substantial, specific and credible, it may be patentable16.

Though the legal position on the patentability of products of nature in Pakistan is clear, the circumstances under which it is applied are controversial. Recently, the Court of Justice of the European Union, in Monsanto Technology v. Cefetra17, ruled that there is no protection for a DNA sequence as such. For a DNA sequence to be patented, its function must be disclosed. The real controversy thus surrounds the scope of protection rather than the question of whether gene or DNA sequences are patentable elsewhere. Protection for variants requires sufficient disclosure It is well settled that a per se claim to a product provides protection against any infringement against and use of that product. Applying this scope of protection to patents covering per se claims to novel biological materials, such as genes or DNA sequences possessing specific characteristics, means that protection may extend to variants or divergent forms of the material18 that retain those characteristics. Justifiably, the scope of this protection is no wider than that provided to the holder of a pioneering invention (an NCE per se) in the chemical industry, as long as the threshold of non-obviousness, clarity and conciseness and adequacy of disclosure is held firm as warranted by the law. The inquiry must be even stricter in relation to the bioinformatics of

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genetic investigation, where the work is usually an obvious desideratum, making it difficult to determine an inventive step that leads to the claimed invention19 (Supplementary Discussion 2). The ‘single-product patent’ notion that has prevailed under the practices of the Pakistan Patent Office may not encompass functional derivatives of patented gene or DNA sequences as it seems to in the United Kingdom and the European Union. Should this be, a protein or antibody that is identical in function to one derived from a patented DNA or gene sequence but is encoded by a modified nucleic acid sequence would not infringe that patent. Effects of foreign gene-patenting decisions on Pakistan Though the legal position on the patentability of products of nature in Pakistan is clear, the circumstances under which it is applied are controversial. Most of the Pakistan Patent Office’s decisions regarding the patentability of products of nature are influenced by the decisions of the US Patent and Trademark Office, the UK Intellectual Property Office and the EPO. Following precedents upholding the patentability of previously unrecognized substances found in nature that have been isolated and purified, characterized and functionally expressed—such as adrenaline20, vitamin B12 (ref. 21), human relaxin-2 (ref. 22), a polypeptide comprising an amino acid sequence encoded by DNA from hepatitis C (ref. 23) and DNA encoding hepatitis B antigens24—the Pakistan Patent Office has allowed patents on ‘isolated’ and ‘treated’ DNA sequences, novel genes encoding therapeutic or insecticidal proteins and antibodies and antigen-binding fragments thereof. Conversely, a claim may not be allowed for a DNA sequence encoding a known, naturally occurring material that has already been isolated, characterized and functionally expressed and has an established utility, as was held in the Genentech25 and Biogen26 patent decisions. The decision of the US Court of Appeals for the Federal Circuit (CAFC) regarding the BRCA1 and BRCA2 gene patents27 likewise has not affected the practices of the Pakistan Patent Office. However, the US Supreme Court’s reversal of the CAFC’s findings in this case suggests that reassessment of the Pakistan Patent Office’s current practices may be in order if Pakistan is to succeed in its efforts toward global harmonization. Conclusions Beyond any doubt, pharmaceutical and biotech products are per se patentable in Pakistan. But with a dearth of judicial decisions relating to the application and/or interpretation of the 1199

pat en t s various and conflicting provisions of the patent law in Pakistan, misreading of these provisions has made the actual scope of protection controversial. To appease the interests of multinational companies, Pakistan needs to revise its ‘one compound, one invention’ policy, which is shrinking the boundaries of protection as defined by the law. In parallel, it must allow new uses of known compounds to be covered by the patent protection net instead of allowing them to enter in the patent circle through channels the patent law does not allow. Note: Supplementary information is available at the online version of the article.

COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. 2. 3. 4. 5. 6. 7.

PK Patents and Designs Act of 1911. PK Patents Ordinance (2000). PK Patents Ordinance, Section 15(8). PK Patents Ordinance, Section 8(1)–8(3) PK Patents Ordinance, Section 9. PK Patents Ordinance, Section 7(2)(e). Section 1(2)(a) of the UK Act 1977 and Art. 52(2) of EPC. 8. See, for example, Genentech’s (tPA) patent [(1989) RPC 147 203] and Genentech’s (HGH) patent [(1989) RPC 613]. 9. EPO Guidelines part C, Chapter IV, 2.3. 10. Biotechnology Directive, Recital 23. 11. OJ EPO 293, 304, para 9 (2002). 12. Biotechnology Directive, Recital 22.

13. OJ EPO, 307, para 11(ii) (2002). 14. Biotechnology Directive, Recital 24. See Chiron v. Murex FSR 153, 177 (1996). 15. OJ EPO, 388 (1995). 16. Genentech patent (1987) RPC 553, (1989) RPC 147 and 203. 17. Monsanto Technology LLC v. Cefetra BV, Case C-428/08, (ECJ) July 06, 2010. 18. Dir. 98/44/ EC, Art 8. 19. Genentech v. Wellcome Foundation (1989) RPC 147, CA; DSM patent (2001) RPC 675 (under appeal); Biogen v. Medeva [1997] RPC 1, HL. 20. Parke-Davis & Co. V.H.K Mulford & Co., 189 F. 95 (SDNY 1911), Aff’d, 196 F. 496 (2d Cir. 1912). 21. Merck & Co. v. Olin Mathiesen Chemical Corp. 253 F. 2d 156 (4th Cir. 1958) 22. OJ EPO, 388 (1995). 23. Chiron Corp. v. Organon Teknika (1994) FSR 202 (Pat. Ct). 24. Biogen v. Medeva (1995) RPC 25. 25. (1987) RPC 553, (1989) RPC 147, CA. 26. (1997) RPC 1, HL. 27. Association for Molecular Pathology v. USPTO (Fed. Cir. 2011), 29 July 2011.

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AUTHOR CONTRIBUTIONS All authors made substantial contributions to the work presented in this paper. S.S. and Z.I. jointly

conceived this study, searched the data and prepared the manuscript. M.W.A. read and critically edited the manuscript. All authors discussed the material and commented on the manuscript at all stages.

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