INTELLECTUAL RIGHTS AND REGULATION FOR BIOTECHNOLOGY AND PHARMACEUTICALS

Transcription

1 INTELLECTUAL RIGHTS AND REGULATION FOR BIOTECHNOLOGY AND PHARMACEUTICALS John M. Naber, M. S., J.D. Registered U.S. Patent Attorney G. Viviana Andrade, J.D. Intellectual Property Attorney

2 Basic Intellectual Property in the United States

3 Types of Intellectual Property Copyrights Trademarks Trade Secrets Patents

4 Copyrights Allow authors to exclude others from publishing or copying literary dramatic, musical, artistic or software works Applies only to literary and artistic content Needs originality (more than a telephone book)

5 Copyright Protection Prior to 1978: 75 years from date of publication After 1978: Life of author plus 50 years

6 Copyright fair use 17 U.S.C. 107 Allows some copying of copyrighted material for opinion, news reporting, teaching, or research

7 Fair Use factors Purpose of use (commercial or non-profit) Nature of the work Amount of the work used Effect of use on the market or effect on the value in the market

8 Trademarks Any word or symbol that is consistently attached to or a part of a product to distinguish it from others in the marketplace Unlike copyrights or patents, trademark rights can last indefinitely

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10 Trademarks Can t be generic Aspirin was a trademark but became generic because it was used as a noun and not an adjective Buy aspirin v. Buy Aspirin brand analgesic

11 Trade Secrets Valuable Information that provides a competitive advantage from not being generally known or readily ascertainable Must be novel and useful Company must take reasonable precautions to maintain secrecy

12 Trade Secrets... Reverse engineering or independent creation will not be protected by trade secret law. Protection is indefinite in duration and lasts as long as the owner can keep it secret.

13 United States Patents

14 US Constitution: Art.1, Sec. VIII, clause 8

15 Congress shall have the power: To promote the progress of science and useful Arts, By securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries

16 USPTO Established 1790 by President George Washington and Secretary of State Thomas Jefferson

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18 United States Patent and Trademark Office Today

19 Current Head of the USPTO President George W Bush

20 New USPTO Director, Jon Dudas

21 Types of Patents Utility new and useful inventions Design unique ornamental shape Plant not found in nature

22 US Patents Utility Patents -169,028 Design - 16,574 Plant Other Total 187,053 (highest ever)

23 Patents to Foreign Inventors Foreign-resident inventors claimed a 47.3 percent share of all U.S. patents issued in 2003

24 2003 US Patents with Foreign Japanese inventors 19.9 % (37,250) German inventors 6.5% (12,140) Taiwanese inventors 3.6% (6,676) Inventors

25 Utility Patents Lasts 20 years from date of filing (but at least 17 years of enforcement) Novel, useful and not obvious Allows exclusion of others from making, using, or selling the invention

26 Novelty Requirement Not known, used, or patented by others Not on sale more than 1 year prior to filing Development not abandoned Invention not stolen

27 Useful Requirement Specific and substantial utility for the invention Beneficial use for the invention Must work

28 Non-obvious requirement Subject matter of the invention, as a whole, must not be obvious at the time of invention to one of ordinary skill in the art (area of the invention). As a legal term, obviousness is fairly narrow

29 Non-obvious requirement Biotechnology is considered highly unpredictable. Therefore, many biotech inventions that may seem obvious in the lay sense are not legally obvious, because one skilled in the art had no reasonable expectation of success. * A specific protein or nucleic acid sequence is, almost without exception, never legally obvious.

30 Non-obvious requirement Defenses against a finding of obviousness: Unexpected results (i.e., surprising properties) Commercial success (i.e., a license agreement) Long-felt unsatisfied need Failure of others who attempted a similar invention

31 U.S. Pat. No. 5,443,036

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34 Patent Disclosure Inventor Includes all inventors working towards developing the inventive concept and reducing it to practice

35 Idea of Disclosure Describe your invention, stating the problem solved (if appropriate), and indicating the advantages of using the invention.

36 Idea of Disclosure How does the invention solve the problem or achieve an advantage (a description of the invention, including figures inline as appropriate)?

37 Idea of Disclosure If the same advantage or problem has been identified by others (inside/outside company), how have those others solved it and does your solution differ and why is it better?

38 Idea of Disclosure If the invention is implemented in a product or prototype, include technical details, purpose, disclosure details to others and the date of that implementation.

39 Idea of Disclosure If the invention is implemented in a product or prototype, include technical details, purpose, disclosure details to others and the date of that implementation.

40 Critical questions On what date was the invention workable? (Workable means, i.e., when you know that your invention will solve the problem.)

41 Critical questions Is there any planned or actual publication or disclosure of your invention to anyone outside company?

42 Critical questions Are you aware of any publication or patent that relate to this invention?

43 Critical questions Has the subject matter of the invention or a product incorporating the invention been sold, used internally in manufacturing, announced for sale, or included in a proposal?

44 Critical questions Was the subject matter of your invention or a product incorporating your invention used in public, e.g., outside company or in the presence of non-company personnel?

45 Critical questions Have you ever discussed your invention with others not employed at company?

46 Critical questions Was the invention, in any way, started or developed under a government contract or project?

47 Critical questions Was the invention made in the course of any alliance, joint development or other contract activities?

48 Critical questions Have you submitted, or are you aware of, any related disclosure submission?

49 Critical questions What type of companies do you expect to compete with inventions of this type?

50 Other patentability questions Patent value anticipated market size how new is the technical field How easily can it be detected and copied Assignment of invention

51 Patent Search USPTO Website: use Boolean logic search patents and patent applications trademark searches also available

52 Intellectual Property and Biotechnology

53 BioTechnology Introduction Early BioTechnology Research centered mostly in agricultural applications. Use of genetically modified crops is now spreading around the world.

54 Nevertheless, opposition to biotech crops, particularly in Europe, has slowed their adoption. Demonstrations disrupted the Bio 2004 Conference in San Francisco protesting the spread of genetically altered food

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57 In the last 10 years biotech pharmaceuticals have gained tremendous importance in the United States to satisfy the demand for drugs in its aging Baby Boom populations. Other contributing factors include drugs to combat the threat of bio-terrorism, and a large variety of other diseases in the growing world populations

58 BioTech Patents A BioTech Group (180) was started at the USPTO in 1988 to accommodate the backlog of growing biotech patent applications. Still it takes several years to secure a US biotech patent given the complexity of the applications and thousand of BioTech companies currently in existence worldwide.

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60 BioTech Patents In general raw products of nature are not patentable. DNA may be patented only after it has been placed in a unique form not found in nature by purification, isolation, or modification

61 BioTech Patents Many biotech patents are filed provisionally Over three million genome related patents have been filed worldwide. Use of such a sequence is risky due to potential for infringement

62 BioTech patents that involved altered products of nature need to deposit a specimen in 1 of 26 worldwide depositories BioTech Patents

63 Genetic Patent Requirements Identify a novel gene sequence Specify the sequence s product Specify how the product functions in nature (i.e., its use) Enable one skilled in the art to use the sequence for this purpose

64 Genetic Patents Hard to patent gene fragments since their function is rarely known Usually the applications are forced to list vague definitions of their utility Many scientists complain about gene sequence patents being issued given this vagueness and that this technology is still in its infancy

65 Why Patent? Scientists peer review journals, once the best and most open forum to advance information, often complain about the initial secrecy of the patenting process. Nevertheless, the whole basis of patenting is to provide incentive to companies to fund research and development.

66 General BioTech Patent Prosecution Issues Restriction Requirements Just a snapshot of the invention often before utility is enabled or even known Leads to many continuation and divisional applications Expensive Often written like scientific papers or rewrites of scientific papers

67 Specific BioTech Topics: Patent maps for protein drug development including therapeutic monoclonal antibodies and recombinant protein drugs. Patent validity study in technology transfer Pharmaceutical Patents and ANDA litigations

68 Specific BioTech Topics (cont.): Generic Drugs and the Hatch-Waxman Act Federal Regulation of Biopharmaceuticals Patenting Life Forms using European Standards

69 Patent Maps

70 Patent Maps At what stage of development is it advisable to disclose your invention in a patent application? Risky to file an application without sufficient data to show: - A substantial utility for the invention - Information sufficient to enable one skilled in the art to make and use the invention - A written description in sufficient detail to conclude that the inventor had possession of the invention.

71 Patent proofs Utility proofs Enablement proofs Written description proofs Non-obviousness

72 Utility proofs Often difficult to show enablement of the actual intended utility early in development. Nevertheless, SOME utility can often be shown.

73 Utility Proofs (cont.) * For example, a recombinant protein actually intended to be used as a drug could be shown to induce production of antibodies useful, say, in clinical diagnostics. An application could then be filed for the protein, without any research supporting its use as a drug. * For another example, a monoclonal antibody actually intended to be used as a therapeutic agent could be shown to have other useful properties, such as use in immunoaffinity purification of some protein, or in immunofluorescence staining of biopsies.

74 Utility Proofs (cont.) Usually it is safe to file an application as soon as any substantial utility can be shown, which may be well before research is completed that shows enablement of the actual intended use. The actual intended use can be described in detail, effectively barring any junior claims to use of the protein or antibody for the actual intended purpose.

75 Utility Proofs (cont.) Less is needed to show enablement for patent purposes than for Food and Drug Administration (FDA) approval purposes. For therapeutic agents, once a compound or biologic can be shown to have some significant biological effect which would constitute a substantial utility in a human or other animal. Significant biological effects can be shown either directly in an acceptable animal model, or indirectly from sequence homology or other analogy to known therapeutic agents.

76 Enablement proofs (cont.) MPEP (available on-line) at: Enablement based on evidence as a whole Must not require undue experimentation Do not need to demonstrate a working example May be a predicted result

77 Enablement proofs (cont.) *Many claims are rejected under 35 USC 112 for want of enablement. *The standard of enablement is that the disclosure, when filed, must contain sufficient information to enable one skilled in the art to make and use the claimed invention without undue experimentation. * Some experimentation may be required. Whether this level of experimentation is undue depends upon several factors, including - The state of the art - The level of ordinary skill - The level of predictability - The amount of direction provided - The existence of working examples. * As a general rule of thumb, biotechnology art is considered highly unpredictable. * Consequently, a significant amount of direction and at least one working example are almost always required. * As a general rule of thumb, biotech application should provide at least one working example of an embodiment that has substantial utility. * In theory, applications may be filed based on predicted results. The finding of enablement is based on the evidence as a whole, including affidavits which may be submitted later that show the results of experiments disclosed in the application but not yet actually conducted. * For example, a working example of a recombinant protein with substantial utility in inducing production of useful antibodies could be disclosed, along with specific details of experiments to be conducted in the future concerning therapeutic uses of the protein. Claims to the protein itself would be enabled. Claims to therapeutic uses and compositions comprising the protein might also still be enabled, where subsequent affidavits present successful results of those experiments. * An application can also be filed which establishes priority of invention by disclosing important preliminary work, such as, for example, some N-terminal sequence from a recently isolated, but not yet cloned protein with demonstrated useful properties. * Subsequent research results, including the full length clone sequence, can then be filed as a continuation-in-part.

78 Enablement proofs (cont.) Many claims are rejected under 35 USC 112 for lack of enablement. Enablement Standard: the disclosure, when filed, must contain sufficient information to enable one skilled in the art to make and use the claimed invention without undue experimentation.

79 Enablement proofs (cont.) Undue experimentation depends upon several factors, including: The state of the art The level of ordinary skill The level of predictability The amount of direction provided The existence of working examples.

80 Enablement proofs (cont.) Biotechnology art is considered highly unpredictable. Consequently, a significant amount of direction and at least one working example are almost always required. Therefore, biotech applications should provide at least one working example of an embodiment that has substantial utility.

81 Enablement proofs (cont.) Applications should be filed based on predicted results. The finding of enablement is based on: the evidence as a whole, including affidavits which may be submitted later that show the results of experiments disclosed in the application but not yet actually conducted.

82 Enablement proofs (cont.) For example, a working example of a recombinant immunogenic protein with substantial utility could be disclosed, with details of future experiments for therapeutic uses of the protein. Claims to the protein itself might be enabled. Claims to therapeutic uses might still be enabled, where subsequent affidavits present successful results of those experiments. Subsequent research results, including the full length clone sequence, can then be filed as a continuation-inpart.

83 Enablement proofs (cont.) An application can also be filed that establishes priority of invention by disclosing important preliminary work, such as, for example, some N-terminal sequence from a recently isolated, but not yet cloned protein with demonstrated useful properties. Subsequent research results, including the full length clone sequence, can then be filed as a continuation-in-part (C-I-P).

84 Written description proofs For monoclonal antibodies, a biological deposit satisfies the written description requirement. For proteins, written description is often a problem in biotech.

85 Written description proofs For example, a novel sequence may be disclosed from one strain of an organism. Yet claims to homologs, such as allelic variants, immunogenic fragments, genetically engineered fusion constructs and conservatively substituted recombinant mutants are typically rejected because the inventor has not provided an adequate written description of these variants (i.e., specific sequences and examples).

86 Written description proofs Many PTOS are becoming more conservative in allowance of claims to homologs of specific proteins and isolated nucleic acids. Chances are improved by providing either: at least one working example of a protein or nucleic acid homolog a reasoned argument based on prior art as to specific homologs that would be useful or as to the range of sequence variability that is tolerated by the functional protein

87 Written description proofs Thus, it is always advisable at the very least to disclose some measure of allelic variability of the sequence, to support claims to homologs with at least X % sequence identity.

88 Patent Validity -Technology Transfer

89 Patent Validity -Technology Transfer Patent validity information may be needed: Due diligence in an merger and acquisition (M and A) Freedom to operate (infringement opinion) Licensing and Assignment

90 Patent Validity Due Diligence Broadly defined as intellectual property due diligence Due diligence can focus on: an entity (M&A), technology (freedom to practice/ infringement opinion) an investment (license, assignment)

91 Due diligence Assesses the strengths and weakness of the IP in question Usually expensive but critical especially if a large amount of investment is at stake

92 Due diligence Factors in determining the extent of due diligence: Type and value of the transaction Timeframe to complete Type of IP to review Reason for review Type of business involved Proportion of assets that are IP

93 Due diligence Issues Ownership of IP -Need to determine chain-of-title of the IP to be assured that IP is owned as advertised -Need to review licenses for proper IP transfer -Review employment agreements (e.g., duty to assign) and that they have in fact assigned

94 Due Diligence Issues As for licenses: Review scope of licenses (both in and out licenses) Look for rights of third parties to assign

95 Due Diligence Other contracts Review all material transfer agreements Review all confidentiality agreeements Review all UCC filings for security interests in any of the IP

96 Due Diligence Patents Procedural due diligence (minimal) look to see that procedural requirements for filing and maintaining a patent have been followed Identify all patents and applications Review assignments and information disclosure statements Check all maintenance fees have been paid

97 Due Diligence Patents Substantive due diligence (expensive) Review validity of patents Review patentability of pending applications (including a prior art search) Clearance studies on products and services

98 Due Diligence Copyrights Looks for all works of original authorship, including software programs Look for registrations Review contracts or licenses to software programs to determine scope of license or rights

99 Due Diligence Trade Secret Includes invention disclosures, secret processes that cannot be reversed engineered, etc. Identify trade secret materials Assure confidentiality agreements are in place Look for out licenses and review terms

100 Due Diligence Trademark Typically procedural review is all that is required Inventory all issued and pending applications Review for common law trademarks Confirm use is consistent with registration

101 Litigation Issues Pharmaceutical patents Abbreviated New Drug Applications (ANDA)

102 ANDA Litigation ANDA litigation is very common and hotly contested by parties with large amounts of money at stake. This is an expansive and rapidly evolving subject.

103 ANDA Litigation Hatch-Waxman defines what the Supreme Court has termed a highly artificial act of patent infringement - submission of an ANDA (generic drug application) to obtain approval for commercial manufacture, use or sale of a drug claimed in a patent.

104 ANDA Litigation Original pioneer drug applicants must list in their NDA applications every product or use patent pertaining to the drug sought to be approved.

105 ANDA Litigation FDA publishes an Orange Book that lists, for each approved drug product (active ingredient composition) but NOT for biologics, all such patents identified in NDAs. This provides notice to future generic producers of patents that may block introduction of generic products.

106 ANDA Litigation When a generic ANDA application is submitted, the applicant is required to certify for each relevant patent listed in the Orange Book one of the following: The patent has expired. The date on which the patent will expire. The patent is invalid, or will not be infringed by the manufacture, sale or use of the generic drug for which the application is submitted.

107 ANDA Litigation NDA holders have 45 days after filing of an ANDA to initiate infringement proceedings, after which they are entitled to a 30-month stay of FDA approval of the corresponding ANDA. NDA holders have evolved new techniques for gaming the Orange Book securing additional patents for new formulations, etc., as a means of extending the effective life of their monopoly through ANDA litigation.

108 ANDA Litigation In 2003, Congress amended the law to provide potential generic ANDA applicants with a right to sue for declaratory judgment of invalidity of any Orange Book patent. Congress, the FDA, and the Federal Circuit each have acted to balance each other s influence over this evolving area of law.

109 The Hatch-Waxman Act The Hatch-Waxman Act (HWA), formally known as the Drug Price Competition and Patent Term Restoration Act of Sought to make more lower-priced generic drugs available Allows generic companies to bypass the approval process required for new drugs seeking FDA approval and instead file an "Abbreviated New Drug Application" ("ANDA").

110 Patent Issues related to Hatch - Waxman Burden of proof is much higher for FDA approval of effectiveness than a for a patent. Allows Patent Term Extensions

111 Patent Term Extensions Because the FDA approval process takes many years, Hatch-Waxman provides a patent term extension for patents that claim the active ingredient of a new drug or human biological product. The patent term extension can be up to five years. However, the total time remaining on patent after FDA approval cannot exceed fourteen years.

112 Patent Term Extension (continued) The patent term extension is computed by adding one-half of the time during which the product was in clinical trials and the entire time the product was subject to FDA review. Patent term extensions are typically granted for the maximum five years.

113 There are 3 main routes for generic drug approval under the HWA:

114 Route 1- Used for approval and marketing of pioneer or new drugs: Before a new drug can be marketed it must obtain FDA approval The approval process for a new drug requires the submission of a New Drug Application (NDA)

115 The NDA must include full reports of investigations which have been made to show whether or not such a drug is safe for use, and specimens of the labeling proposed to be used for such a drug. Applicant must file the patent number and the expiration date of any patent that the owner could reasonably be assert protects a new drug.

116 After the NDA is approved, the holder must submit the same information for patents that issue subsequently. These pre-nda and post-nda patents are listed in the Orange Book

117 Route 2- a 505 (b)(2) application or paper NDA An applicant submits reports of investigations of safety and effectiveness. Also, relies on information required for approval that comes from studies not conducted by or for the applicant and for which the applicant has not received a right of reference.

118 An applicant can submit 2 different kinds of applications under 505 (b)(2) 1) Application for a New Chemical Entity (NCE)- To be used only when some of the information necessary for approval is derived from studies not performed by the applicant and to which the applicant has no right of reference.

119 2) Application for changes to previously approved drugs- Applicant can rely on the studies for the previously approved drug and add additional studies to support and demonstrate the changes.

120 Changes include the following: 1) changes in dosage form, strength, or route of administration 2) substitution of an active ingredient in a combination product 3) changes in formulation dosing regimen, active ingredient, indication, Rx/OTC classification, or active ingredient source or to demonstrate bioinequivalence

121 Route 3- Approvals under 21 U.S.C. 355 (j) uses the abbreviated new drug application (ANDA): ANDA s are generally filed when a generic manufacturer wishes to duplicate a NDA holder s drug product.

122 The ANDA applicant is required to show that the drug product is the same ingredient, route of administration, dosage form and strength as the product in the original NDA. The ANDA applicant must show that the drug product is the bioequivalent to the NDA product.

123 An applicant may file a petition if it wishes to change the route of administration, dosage form, strength or active ingredient. The FDA must approve such an application.

124 Limitations: A Section 505 (b)(2) applications cannot be filed where: a) The product is a duplicate of a listed drug and is eligible for approval under 505 (j) b) The only difference from the reference listed drug is the extent to which the active ingredient is less absorbed or otherwise made available at the site of action.

125 Marketing Exclusivity under 21 U.S.C. 355 Biotechnology products that are regulated as drugs or as combination drug/biologic products are eligible for market exclusivity under 21 U.S.C. 355(b) Marketing exclusivity is available only for approved drug products.

126 3-Year Exclusivity: For drug products that do not feature a new active ingredient but that require new clinical studies to support new therapeutic claims.

127 It is given for the following: a change in dosage form, for a new indication, and for switching from prescription to over-the counter (OTC) status. No other applications for the same indications can be approved. Generic applications for the same therapeutic claims may be submitted to the FDA for approval as soon as the exclusivity period ends.

128 5-Year Exclusivivity: NDAs with new active ingredients get a five-year marketing exclusivity period. This means that no other new drug applications for the same active ingredient may be submitted to the FDA.

129 Active ingredient means active moiety and is defined as: The molecule or ion excluding those appended ions that cause the drug to be an ester, salt (including a salt with hydrogen or coordinating bonds or other noncovalent derivative, such as a complex chelate or clathrate of the molecule) responsible for the physiological or pharmacological action of the drug substance.

130 Exception: Where there is a patent listed for the innovator drug, a competitor s application can be submitted after four years, provided the applicant also certifies as to noninfringement or invalidity

131 180-Day Generic Exclusivity For first-to-file generic applicant who submits a paragraph IV certification.

132 Guidelines provided by the FDA to clarify abbreviated new drug application (ANDA) exclusivity rights: Only the applicant submitting the first complete ANDA (and paragraph IV certification) will be eligible for the 180-day exclusivity. The agency will consider the 1st applicant to be eligible for exclusivity even if it is not sued by the patent owner or NDA holder--this means the ANDA applicant that designs around a patent to avoid an infringement suit.

133 If a number of applicants file their ANDAs on the same day, all are eligible for the 180-day exclusivity for the strength of the drug that is the subject of the ANDA Each strength of a drug will separately be eligible for exclusivity

134 The first ANDA applicant will not be eligible for 180-day exclusivity if it is sued and loses; and The FDA proposes a triggering period during which there must be a court decision regarding the patent that is favorable to the ANDA applicant or the applicant must begin commercial marketing. If neither occurs, then the 1st ANDA applicant loses its exclusivity and the next in-line ANDAs will be eligible for immediate approval.

135 Orphan Drug Exclusivity The Orphan Drug Act An orphan disease is a rare disease. Intended to provide incentives for drug companies to develop treatments for orphan diseases.

136 Under the act, the sponsor of an orphan drug can obtain seven years of marketing exclusivity following FDA approval of the drug. It is available for drugs (active moiety) and biologics (macromolecules, vaccines, blood products, tissues, gene therapy agents) for treatment of diseases or conditions that have a U.S. patient population of less than 200,000.

137 It is also provides protection for drugs for a disease or condition that affects more than 200,000 people in the U.S., but has no reasonable expectation that the cost of developing and production will be recovered from the sales in the U.S.

138 The Hatch-Waxman Act contemplated that only drug products (small molecules) would be eligible for generic (ANDA and 505 (b) (2)) approvals. This was due to the requirement that each formulation be separately approved, even where the active ingredient is identical to that used in a previously approved formulation.

139 Most biologics are approved under the Food and Drug Administration Modernization Act that unified the Public Health Service Act (PHS Act) and the Federal Food, Drug, and Cosmetic Act (FD&C Act)

140 Biologics and The Public Health Service Act

141 Biological products are approved for marketing under provisions of the Public Health Service Act (PHS Act). However, because most biological products also meet the definition of "drugs" under the Federal Food, Drug, and Cosmetic Act (FD&C Act), they are also subject to regulation under FD&C Act provisions.

142 Section 351 (i) of the Public Health Service Act, 42 U.S.C. 262(i), defines a biological product as follows: Biological product means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

143 Biological products include a wide range of products such as: vaccines, blood and blood components allergenics somatic cells gene therapy tissues recombinant therapeutic proteins Biologics can be composed of : sugars, proteins or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues.

144 Inherent Differences Between Drugs and Biologics: There are significant differences between biological products and other drugs - in size, complexity, and heterogeneity, among other considerations.

145 Biologics are isolated from a variety of natural sources: Human, animal, or microorganism and may be produced by biotechnology methods and other cutting-edge technologies. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available

146 Biologically-derived products: Are of highly complex and generally large molecules derived from living organisms, while chemical drugs are typically smaller and synthesized. Often manufacturers of biological products do not know precisely which of the identified components constitute the "active ingredient" and often it is the sum rather than the parts that is effective.

147 The manufacturing processes involve numerous complicated steps based upon the production and secretion of the biologically active molecule by living cells or organisms, the responses of which are inherently variable. Product heterogeneity and contamination can result during any manufacturing step.

148 In contrast to most drugs that are chemically synthesized and their structure is known, most biologics are complex mixtures that are not easily identified or characterized. Biological products, including those manufactured by biotechnology, tend to be heat sensitive and susceptible to microbial contamination. Therefore, it is necessary to use aseptic principles from initial manufacturing steps, which is also in contrast to most drugs that are chemically synthesized, known structures.

149 Section 351 (a) of the Public Health Service Act, 42 U.S.C. 262(a), provides the general regulatory framework for biological products: No person shall introduce or deliver for introduction into interstate commerce any biological product unless: a biologics license is in effect for the biological product; and

150 Each package of the biological product is plainly marked with: the proper name of the biological product contained in the package; the name, address, and applicable license number of the manufacturer of the biological product; and the expiration date of the biological product

151 Under the Public Health Service Act, a biological product manufacturer must obtain FDA's premarket approval of a license. The statute requires that FDA may only approve a license upon a demonstration that : (I) the biological product that is the subject of the application is safe, pure, and potent; and (II) the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the product continues to be safe, pure and potent.

152 The FDA has interpreted the Public Health Service Act to the effect that each biological product manufacturer must "submit data derived from non-clinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed standards of safety, purity, and potency."

153 After both the 1984 Hatch-Waxman Amendments and the 1997 Food and Drug Administration Modernization Act, FDA affirmed that nothing in these laws changed its views on how biological products would be approved under the Public Health Service Act.

154 Shortly after the 1984 Amendments, FDA advised Congress that biological products are not subject to approval under Title I of the Amendments and in its 1992 regulations implementing Hatch- Waxman, the FDA reiterated its position that the new Abbreviated New Drug Application (ANDA) procedures for duplicate versions of drugs are "inapplicable to... biological drug products licensed under 42 USC 262."

155 FDA reorganized the responsibilities of the Food and Drug Administration s (FDA) Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER), and assigned to CDER the responsibility for proteins intended for therapeutic use that are extracted from animals or microorganisms.

156 The Center for Biologics Evaluation and Research (CBER) regulates biological products. Current authority for this responsibility resides in Section 351 of the Public Health Service Act and in specific sections of the Food Drug and Cosmetic Act.

157 Biologics Product Approval The PHS Act requires individuals or companies who manufacture biologics for introduction into interstate commerce to hold a license for the products. These licenses are issued by CBER. Biological products intended for veterinary use are regulated under a separate law, the Virus, Serum, and Toxin Act, which is administered by the U.S. Department of Agriculture.

158 Following initial laboratory and animal testing, a biological product is studied in clinical trials in humans under an investigational new drug application (IND). If the data generated by the studies demonstrate that the product is safe and effective for its intended use, the data are submitted to CBER as part of a biologics license application for review and approval for marketing.

159 After a license application is approved for a biological product, the product may also be subject to official lot release. As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution.

160 If the product is subject to official release by CBER, the manufacturer submits samples of each lot of product to CBER together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer's tests performed on the lot. CBER may also perform certain confirmatory tests on lots of some products, such as viral vaccines, before releasing the lots for distribution by the manufacturer.

161 In addition, CBER conducts laboratory research related to the regulatory standards on the safety, purity, potency, and effectiveness of biological products. The CBER continues to monitor the safety and stability of biological products that have been approved. Manufacturers must report certain problems to FDA s Biological Product Deviation Reporting System.

162 Manufacturers must also report and correct product problems within established timeframes. If a significant problem is detected, a manufacturer may need to recall a product or even stop manufacturing it.

163 CBER inspects manufacturing plants before it approves products, and thereafter, on a regular basis. The purpose of these inspections is to assess whether biological products are made in compliance with appropriate laws and regulations, and to assist in identifying any changes needed to help ensure product quality.

164 CBER also may inspect clinical study sites to determine whether the studies are being carried out properly, and to ensure that accurate information is being submitted to the agency. CBER has a number of enforcement tools that may be used when a manufacturer or clinical researcher is in violation of FDA laws and regulations.

165 Vaccine Product Approval Process FDA s Center for Biologics Evaluation and Research (CBER) is responsible for regulating vaccines in the United States. Burden of proof is much higher FDA approval of effectiveness than a patent.

166 A sponsor who wishes to begin clinical trials with a vaccine must submit an Investigational New Drug application (IND) to FDA. The IND describes the vaccine, its method of manufacture, and quality control tests for release along with information about the vaccine s safety and ability to elicit a protective immune response (immunogenicity) in animal testing, as well as the proposed clinical protocol for studies in humans.

167 Pre-marketing (pre-licensure) vaccine clinical trials are typically done in three phases: Phase 1 Safety and immunogenicity studies performed in a small number of closely monitored subjects Phase 2 Dose-ranging studies and may enroll hundreds of subjects. Phase 3 Typically involves enrolling thousands of individuals and provide the critical documentation of effectiveness and important additional safety data required for licensing.

168 At any stage of the clinical or animal studies, if data raise significant concerns about either safety or effectiveness, FDA may request additional information or studies, or may halt ongoing clinical studies

169 The completion of all three phases of clinical development can be followed by the submission of a Biologics License Application (BLA). The license application must provide the multidisciplinary FDA reviewer team (medical officers, microbiologists, chemists, biostatisticians, etc.) with the efficacy and safety information necessary to make a risk/benefit assessment and to recommend or oppose the approval of a vaccine.

170 During this stage, the proposed manufacturing facility undergoes a pre-approval inspection during which production of the vaccine as it is in progress is examined in detail. Following FDA s review of a license application for a new indication, the sponsor and the FDA may present their findings to FDA s Vaccines and Related Biological Products Advisory Committee (VRBPAC).

171 This non-fda expert committee (scientists, physicians, biostatisticians, and a consumer representative) provides advice to the Agency regarding the safety and efficacy of the vaccine for the proposed indication. Vaccine approval also requires the provision of adequate product labeling to allow health care providers to understand the vaccine s proper use, including its potential benefits and risks, to communicate with patients and parents, and to safely deliver the vaccine to the public.

172 The FDA continues to oversee the production of vaccines after the vaccine and the manufacturing processes are approved, in order to ensure continuing safety. After licensure, monitoring of the product and of production activities, including periodic facility inspections, must continue as long as the manufacturer holds a license for the product.

173 Until a vaccine is given to the general population, all potential adverse events cannot be anticipated. Many vaccines undergo Phase 4 studiesformal studies on a vaccine once it is on the market.

174 Patenting Life Forms in Europe

175 Treaties and Legislation

176 TRIPS-Trade Related Aspects of Intellectual Property Rights European Patent Convention ("EPC") (1973) National laws (e.g. UK Patents Act 1977) EU Directive on Legal Protection of Biotechnological Inventions 98/44/EEC

177 TRIPS Article 27(1)...patents shall be available for any inventions in all fields of technology, provided they are new, involve an inventive step and are capable of industrial application. TRIPS Article 27(2) & (3) Members may exclude from patentability: 1) where necessary to protect... order public or morality 2) plants and animals other than micro-organisms 3) essentially biological processes for the production of plants and animals other than non-biological and microbiological

178 Position in Europe Pre 1998

179 No general exclusion in the EPC of inventions of "animate nature" (T49/83) Specific exclusions in EPC Art 53 for plant and animal varieties "essentially biological" processes for production of plants and animals (c.f. microbiological processes and products) inventions the publication or exploitation of which would be contrary to ordre public or morality

180 Directive 98/44/EEC Adopted in 1998 Aims is to harmonize and govern the position across the EU Process started in 1985 After vigorous lobbying, first proposal rejected in 1995 by European Parliament

181 Implementation of Directive 98/44/EEC EPC - no major changes of substance - Implementing Regs amended to conform UK - no major changes of substance - schedules added to 1977 Act Netherlands - case to annul directive rejected by European Court of Justice (Oct. 2001)

182 EPC: CELLS Product of microbiological process may be patentable such as: micro-organisms plasmids vectors algae and protozoa human, animal and plant cells

183 Standard patentability requirements, e.g. novelty, inventive steps must be satisfied. (EPO Guidelines for Examination Chap IV paragraph 3.5)

184 Genetically Enhanced Host Cells These can be patentable e.g. "A cell transformed by [a DNA transfer vector, characterised in that it contains cdna deoxynucleotide sequences... as defined in... claim 1]" (EP B; Howard Florey/relaxin)

185 Patentability of Plants T49/83 (CIBA-GEIGY) EPO Technical Board of Appeal allowed claims to seeds treated with chemical agents to increase herbicide resistance not within plant varieties exclusion

186 T356/93 (PGS) EPO Technical Board of Appeal considered a claim to any plant with a particular transgene (resistance to herbicide) should be refused

187 Animals - EPC Art 53(b) There is no general exclusion as to patentability of animals. But "animal varieties" and "essentially biological processes" are not patentable

188 What are "animal varieties"? Animals (Human Body) - Directive 98/44/EEC An element isolated from the human body or otherwise produced by means of a technical process, including sequence or partial sequence of a gene, may constitute a patentable invention even if the structure of that element is identical to that of a natural element.

189 the industrial application of sequence.. must be disclosed in the patent application Technical process includes "processes used to identify, purify and classify it and to reproduce it outside the human body, techniques which human beings alone are capable of putting into practice and which nature is incapable of accomplishing by itself"

190 Morality Objections to Patentability - EPC Art 53(a) and Directive 98/44/EEC Art 53(a) has provided a platform for several vigorous oppositions to biotech patents Directive 98/44/EEC mirrors EPC Art 53(a)

191 Examples of processes that are morally objectionable: process for human cloning processes for modifying germ line genetic identity of human beings uses of human embryos for industrial or commercial purposes

192 processes for modifying genetic identity of animals... likely to cause suffering without any substantial medical benefit to man or animal, and also animals resulting from such processes

193 The End!