Aconvenient starting point for addressing the interface

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1 19 Biotechnology Law Report 293 Number 3 (June 2000) Mary Ann Liebert, Inc. {BLR 3097} Obtaining Patent Protection for the Treatment of Disease with Genetic Materials RICHARD C. KOMSON and PAULA K. WITTMAYER ABSTRACT Individual scientists, the biotechnology industry, the Patent & Trademark Office, patent practitioners, and the courts do not necessarily agree on what developm ents involving genetic materials should be protected by patents and how they should be described and claimed in a patent application. The evolution in the law and the current ways in which various inventions are described and claimed in patents are addressed with the focus on the written description, enablement and utility requirements for patentability. Richard C. Komson is a partner with the law firm of Morgan & Finnegan, LLP in New York. Paula K. Wittmayer will join Morgan & Finnegan as an associate this fall. INTRODUCTION Aconvenient starting point for addressing the interface between biotechnology and patent law is the early 1980s. In 1980, the Supreme Court decided Diamond v. Chakrabarty, 447 U.S. 303, 206 U.S.P.Q. 193 (1980). There, the court held that an oil-slick-swilling, man-made microorganism is patentable. That decision can be viewed as increasing the awareness of the value of obtaining patent protection for inventions in the field of biotechnology. Shortly thereafter, in 1982, the Court of Appeals for the Federal Circuit was established with the goal of unifying decisional patent law. During the past 20 years, patent law has struggled to keep pace with the rapid research and development growth in the area of biotechnology. Not surprisingly, science has outpaced the law, which is playing catch-up when it comes to providing patent protection for biotechnology inventions involving the use of genetic materials to treat diseases. Individual scientists, the biotechnology industry, the Patent & Trademark Office, patent practitioners, and the courts do not necessarily agree on what developments should be protected and how they should described and claimed in the patent application. Indeed, at the November 4, 1998, public hearing on the written description requirement, Commissioner of Patents & Trademarks Dickinson acknowledged: Once again, technology has outpaced the application of our patent laws. The surge of research and discovery in new industries such as biotechnology and computers has frankly created some growing pains in patent law. This volatile mix of technology and law has prompted the PTO to reevaluate examination standards regarding patentablility in these new technologies. It remains to be seen whether complete cures for cancer, hepatitis, herpes, immunodeficiency viruses, and Alzheimer s disease will be found in our lifetimes. Similarly, there are open questions as to how well new treatments and partial cures will be protected by the patent laws. Because a patent is both a technical and a legal document, care must be taken in preparing the patent application with both the 293

2 294 Biotechnology Law Report Volume 19, Number 3 technical and legal aspects in mind. For example, is the best available form of protection a method claim, a product claim, or a composition claim? Should composition or product claims be drafted for cdna, genes, vectors, or transformed cells? What kind of method claim will be accepted by the U.S. Patent & Trademark Office a method of treating, a method of inhibiting, a method of preventing, or a method of curing? What data and how much testing are required to support such claims in the patent application? The first paragraph of 35 U.S.C. 112, entitled Specification, reads: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to, enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. The paragraph contains three requirements for patentability: (1) written description; (2) enablement or how to make and use the invention; and (3) best mode. The inventor must describe the invention, teach one how to make and how to use it, and provide the best known way of practicing the invention. Only the first two requirements will be addressed here, namely written description and enablement along with its related utility requirement. Best mode will not be discussed further. In the past, 112 objections were readily overcome in the PTO and were rarely successful to invalidate patents in litigation. More recently, 112 has taken on greater significance in the area of biotechnolog y than for other scientific areas, such as mechanical devices, electrical circuitry, and conventional chemical compounds and pharmaceuticals. Today, biotechnolog y patent claims involving genetic materials are more likely to be rejected or held invalid under 112 than are inventions in the other scientific disciplines. With 112 as the statutory framework, this paper covers current case law as well as proposed PTO examination guidelines. In addition, claims from recently issued patents directed to inventions for treating medical conditions using genetic materials are provided for illustrative purposes. WRITTEN DESCRIPTION REQUIREMENT Applicable law and proposed PTO guidelines The specification must provide an adequate written description of the invention under 35 U.S.C The written description requirement serves to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed (In re Wertheim, 541 F.2d 257, 262, 191 U.S.P.Q. 90, 96 (C.C.P.A. 1976)). To provide an adequate written description, a patent specification must describe an invention in sufficient detail so that one skilled in the art can clearly conclude that the inventor has invented what is claimed (Lockwood v. American Airlines, Inc. 107 F.3d 1565, 1572, 41 U.S.P.Q. 2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 U.S.P.Q. 2d 1614, 1618 (Fed. Cir. 1989)). Thus, an applicant complies with the written description requirement by using such descriptive means as words, structures, figures, diagrams, formulas, etc. that set forth the claimed invention. Lockwood, at In the 1990s, several Federal Circuit cases focused on the particularity or specificity of the description of inventions involving genetic materials. These cases concerned primarily product or composition claims; for example, claims for cdna, vectors or transformed cells. However, they are also relevant for patents containing method claims for treating diseases that involve genetic materials. Claims regarding genetic material will generally comply with the written description requirement when the specification describes the nucleic acid in some way related to its structure or physical properties. However, a description of genetic material by its biologic function alone will generally not be adequate. First, in 1991, in Amgen Inc. v. Chugai Pharmaceutical Co. (927 F.2d 1200, 18 U.S.P.Q.2d 1016 (Fed. Cir. 1991)), the Court considered what constituted conception of an invention regarding genetic material. Amgen s claims were directed to a purified and isolated DNA sequence consisting essentially of a DNA sequence encoding human erythropoietin (Epo). Erythropoietin is a protein that stimulates the production of red blood cells and is used to treat blood disorders, such as anemia. The Court held the claims valid against an attack of prior invention. The defendants asserted that another scientist was the first to conceive of the methodology

3 Biotechnology Law Report Volume 19, Number for identifying and isolating the gene encoding Epo and therefore had prior conception of the invention, which he later reduced to practice. The Court disagreed, however, finding that a generalized approach for screening a DNA library is not conception of a purified and isolated DNA sequence because it is not a definite and permanent idea of the complete and operative invention. Amgen s researcher was the first person to actually isolate the gene, namely, the DNA sequence encoding Epo. At that point, the structure of the gene became known. At 927 F.2d 1206, the Court stated: Conception does not occur unless one has a mental picture of the structure of the chemical, or is able to define it by its method of preparation, its physical or chemical properties, or whatever characteristics sufficiently distinguish it. It is not sufficient to define it solely by its principal biological property, e.g., encoding human erythropoietin, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. We hold that when an inventor is unable to envision the detailed constitution of a gene so as to distinguish it from other materials, as well as a method for obtaining it, conception has not been achieved until reduction to practice has occurred, i.e., until after the gene has been isolated. Therefore, defining an invention regarding genetic material requires more than a statement of a goal or an idea of a possible method for making a product. In 1993, the Court extended this reasoning regarding the conception of an invention involving genetic material to the requirements for the written description. The Court decided a three-way interference captioned Fiers v. Revel (984 F.2d 1164, 25 U.S.P.Q. 2d1601 (Fed. Cir. 1993)). The patent claim or interference count was: A DNA which consists essentially of a DNA which codes for a human fibroblast interferonbeta polypeptide. Thus, the invention concerned a protein that promotes resistance to a virus in humans. The prevailing party was the first one who set forth the complete and correct nucleotide sequence of the DNA in its foreign patent application. In pertinent part, the Court of Appeals stated at 984 F.2d : An adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself. * * *... if a conception of a DNA requires a precise definition, such as by structure, formula, chemical name, or physical properties,..., then a description also requires that degree of specificity. Again, the Court noted that more is needed than a specification that represents a wish or even a plan for obtaining DNA. The latest pronouncem ent on the written description requirement is the 1997 decision Regents of the University of California v. Eli Lilly & Co. (119 F.3d 1559, 43 U.S.P.Q. 2d 1398 (Fed. Cir. 1997)). In Lilly, the Court of Appeals affirmed the District Court s holding that the University s patent claims were invalid under 112 for failing to provide an adequate written description. The patent s description of the isolated cdna sequence for rat insulin did not provide the necessary written description for broad claims directed to vertebrate, mammalian, and human insulin cdna. The court found that a written description of the method for preparing cdna does not necessarily describe the cdna itself. Quoting Fiers, the court repeated: Accordingly, an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself. 119 F.3d at The decision has an extended discussion of the patentability of claim 5, which was directed to a microorganism containing a human insulin cdna: The name cdna is not itself a written description of that DNA; it conveys no distinguishing information concerning its identify.

4 296 Biotechnology Law Report Volume 19, Number 3 While the example provides a process for obtaining human insulin-encoding cdna, there is no further information in the patent pertaining to that cdna s relevant structural or physical characteristics; in other words, it thus does not describe human insulin cdna. Describing a method of preparing a cdna or even describing the protein that the cdna encodes, as the example does, does not necessarily describe the cdna itself. No sequence information indicating which nucleotides constitute human cdna appears in the patent, as appears for rat cdna in Example 5 of the patent. Accordingly, the specification does not provide a written description of the invention of claim F.3d at The patentee s isolation of the cdna sequence for rat insulin did not provide the necessary written description to claim the genus of vertebrate or mammalian insulin. A general statement that does not distinguish the claimed genus from others, except by function, does not provide an adequate written description of the genus. Therefore, a general statement, such as mammalian insulin cdna, fails to specifically define any of the genes within the definition and any structural or physical features common to members of the genus. The Court further elaborated that the written description requirement for a genus of cdnas may be satisfied:... by means of a recitation of a representative number of cdnas, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. 119 F.2d at On December 21, 1999, the PTO published a revised set of guidelines for the written description requirement (Revised Interim Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1 Written Description Requirement, 64 Fed. Reg (Dec. 21, 1999); for text of Revised Guidelines and correction thereto, see below in this issue at k BLR 3114l ). These Revised Interim Guidelines supersede the previous Interim Guidelines on Written Description, published in June 1998 (63 Fed. Reg (June 15, 1998)). In response to comments on the earlier guidelines, the Revised Interim Guidelines have been substantially modified. They are rewritten in a technology- neutral manner, directed to all areas of technology rather than specifically addressing biotechnology. Many of the biotechnolog ical examples in the earlier version have been removed, and these examples will be incorporated into examiner training materials. Furthermore, the Revised Interim Guidelines cover all types of claims: original, new, or amended and product, process, or product-by process claims. Additional comments have been invited, and the PTO will accept such comments until March 22, Under the Revised Guidelines, the patent examiners are instructed to review the entire application to determine what each claim covers as a whole. Each claim is to be separately analyzed including the preamble, transitional phrase, and body. Claims directed to nucleic acids that use the term gene in the preamble could face difficulties complying with the written description requirement. In the previous guidelines, the PTO indicated that the term gene would be construed to include regulatory elements, giving gene its broadest possible interpretation. This interpretation met with much criticism. Commentators argued that the art often uses gene to refer only to the coding portion of the molecule and does not necessarily imply the presence of regulatory elements. In the Revised Interim Guidelines, the PTO does not define gene but maintains the view that the term gene in the preamble could lead to an interpretation that includes regulatory elements. If so, a claim could be vulnerable to a written description rejection if regulatory elements are not sufficiently described in the specification. Footnote 12 of the Revised Interim Guidelines states:... consider the claim A gene comprising SEQ ID NO: 1. A determination of what the claim as a whole covers may result in a conclusion that specific structures such as a promoter, a coding region, or other elements are included. Although all genes encompassed by this claim share the characteristic of comprising SEQ ID NO: 1, there may be insufficient description of those specific structures (e.g., promoters, enhancers, coding regions and other regulatory elements) which are also included. After determining what each claim covers as a whole, the examiner is instructed to review the en-

5 Biotechnology Law Report Volume 19, Number tire application to understand what the applicant described as the essential features of the invention. From this, the examiner will determine whether there is a written description that is sufficient to inform a skilled artisan that the applicant was in possession of the claimed invention as a whole at the time the application was filed. Generally, there is an inverse correlation between the level of skill and knowledge in the art and the specificity of disclosure necessary to satisfy the written description requirement. The previous guidelines discussed the level of predictability in the art; however, the Revised Interim Guidelines reduce the emphasis on predictability and instead emphasize the knowledge in the art and the skill of the practitioner. A mature field has a higher level of skill and knowledge in the art than an emerging area of technology. Thus, in cases of emerging technologies, more description is necessary. Again, the test remains whether one of skill in the art, provided with the disclosure, would recognize that the applicant was in possession of the claimed subject matter when the application was filed. The Revised Interim Guidelines more fully explain the concept of possession by incorporating the Supreme Court s statements in Pfaff into the analysis (Pfaff v. Wells Electronic, Inc., 525 U.S. 55, 48 U.S.P.Q. 2d 1641 (1998)) (the word invention must refer to a concept that is complete: one can prove that an invention is complete and ready for patenting before it has been reduced to practice). Possession may be shown by actual reduction to practice (for example, a biologic deposit is evidence of actual reduction to practice), by a clear depiction of the invention in detailed drawings (for example, an outline of a specific nucleic acid or amino acid sequence), or by a description of a sufficient number of relevant identifying characteristics. Such relevant identifying characteristics for biotechnolog ical inventions include a complete or partial structure of the invention, other physical or chemical characteristics, or functional characteristics when coupled with a known or disclosed correlation between function and structure. The disclosed identifying characteristics need to reasonably convey that the applicant was in possession of the claimed invention at the time of filing. Disclosure of only a method of making the invention and its biologic function, when there is no well-established correlation between structure and function, will be unlikely satisfy the written description requirement for a product claim. Footnote 13 of the Revised Interim Guidelines states: A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence. For example, even though a genetic code table would correlate a known amino acid sequence with a genus of coding nucleic acids, the same table cannot predict the native, naturally occurring nucleic acid sequence of a naturally occurring mrna or its corresponding cdna. Cf. In re Duel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). A disclosure of a method for making the invention and the biologic function would support a product-by-process claim. Examples of possible relevant identifying characteristics for nucleic acids or proteins to disclose in a specification include a sequence, structure, binding affinity, binding specificity, molecular weight and length, unique cleavage by particular enzymes, isoelectric points of fragments, detailed restriction maps, a comparison of enzymatic activities, or antibody cross-reactivity. When no specific sequence is provided, some combination of the identifying characteristics must be disclosed to describe the claimed invention adequately (see Lockwood, 107 F.3d at 1572 (Fed. Cir. 1997)). The relevant identifying characteristics must sufficiently distinguish the claimed invention. For example, footnote 39 of the Revised Interim Guidelines states:... the presence of a restriction enzyme map of a gene may be relevant to a statement that the gene has been isolated. One skilled in the art may be able to determine when the gene disclosed is the same as or different from a gene isolated by another by comparing the restriction enzyme map. In contrast, evidence that the gene could be digested with a [general nonspecific] nuclease would not normally represent a relevant characteristic since any gene would be digested with a nuclease. Similarly, isolation of an mrna and its expression to produce the protein of interest is strong evi-

6 298 Biotechnology Law Report Volume 19, Number 3 dence of possession of an mrna for the protein. Similarly, disclosure of a partial structure without additional characterization of the product may not be sufficient to evidence possession. The best way to describe a species of genetic material, therefore, is to give a complete sequence disclosure. For example, an acceptable description in the previous Interim Guidelines is a probe for use in detecting nucleic acid sequences coding for enzyme Q from the genus Bacillus consisting of SEQ ID NO: 16. Today, such a standard should be much easier to comply with than it was 10 or 20 years ago. However, if a complete sequence cannot be disclosed, one should make an adequate biologic deposit or include as many relevant identifying characteristics as possible in the specification or deposit and include the characteristics as well. For DNA, include the size of the DNA, the source, and a restriction cleavage map for doublestranded DNA. For example, the previous Interim Guidelines included an isolated double-stranded DNA consisting of (1) a single-stranded DNA which has a molecular size of 2.57 kb and is derived from golden mosaic virus; and (2) a DNA complementary to said single-stranded DNA, giving the restriction endonuclease cleavage map shown in a figure and having no MboI restriction endonuclease site. For a protein, include the molecular weight, origin and activity; e.g., specific chemical function, optimum ph, and temperature stability range. For example, the previous Interim Guidelines included an isolated alginate lyase enzyme wherein the enzyme lyses alginate in the mucous substance produced in a patient with cystic fibrosis and wherein the enzyme has the N-terminal amino acid sequence SEQ ID NO. 1, obtained from Flavobacterium pepermentium and has the following physicochemical properties: (1) activity: lyses alginate to saccharides having a nonreducing end 4-5 double bond and ultimately to 4-deoxy-5-ketouronic acid; (2) molecular weight 60,000 daltons; (3) optimal ph 8.0; (4) stable ph ; (5) optimal temperature 70 C.; and (6) substrate specificity alginate. For a genus claim, the written description requirement may be satisfied by a specification that discloses a sufficient description of a representative number of species within the genus. Clearly, a good way to describe a genus claim, therefore, is to disclose a complete structure for as many species as possible. If complete structures of the various species are not known, the description should include relevant identifying characteristics. The more readily those characteristics relate to structure, the better. For example, the previous Interim Guidelines endorsed the following description: a DNA probe for detecting HIV-X, wherein said DNA probe hybridizes to the nucleotide sequence set forth in SEQ ID NO:1 under the following conditions: hybridization in 7% sodium dodecylsulfa te, 0.5 M NaPO 4 ph 7.0, 1 mm EDTA at 50 C; and washing with 1% sodium dodecylsulfate at 42 C. The Revised Interim Guidelines explain that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, a sufficient variety of species must be described to reflect the variation with in the genus. In addition, the number of species required varies inversely with the level of skill and knowledge in the art. Hence, in an unpredictable art, a genus that embraces widely variant species cannot be described adequately with a single species. Instead, a sufficient number of species must be disclosed so that a person of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. However, a description of such specificity that it would provide individual support for each species in the genus is not necessary (see In re Vaeck, 947 F.2d 488, 496, 20 U.S.P.Q.2d 1438, 1445 (Fed. Cir. 1991)) ( it is well settled that patent applicants are not required to disclose every species encompassed by their claims, even in an unpredictable art. citing In re Angstadt, 537 F.2d 498, , 190 U.S.P.Q 214, 218 (C.C.P.A. 1976)). The previous guidelines had included examples disclosing more than one species for DNA and antibodies, describing DNA in terms of its hybridization to a disclosed nucleic acid sequence and describing antibodies in terms of binding specificity and binding affinity. For example, an antibody could be described as a monoclonal antibody that binds specifically to the novel cancer-associated TAG-31 antigen but which does not substantially bind normal adult human tissues, wherein said monoclonal antibody has a binding affinity of greater than 3 times 10 9 M 2 1 for TAG-31. Also, enzymes can be described with a list of particular physicochem ical

7 Biotechnology Law Report Volume 19, Number properties where multiple species are disclosed. For example, an enzyme could be described as an isolated mutanase enzyme produced by Bacillus having the following physicochemical properties: (1) action; (2) substrate specificity; (3) optimum ph; (4) ph range for stability; (5) optimum temperature; (6) thermal stability; (7) effect of metal ions; (8) effect of inhibitors; and (9) molecular weight. As biotechnolog y has advanced, it has become increasingly routine to probe a cdna library and clone a gene. As a result, there may be fewer decisions invalidating biotechnolog y patents under 112 in the future. It may be possible to distinguish Lilly by arguing that the written description requirement will be easier to satisfy in the future as the technology becomes better understood and hence the level of skill and knowledge of one skilled in the art at the time of filing was quite high. Nevertheless, Lilly is the current state of the law, and the proposed guidelines reflect the current thinking of the PTO for examining applications. However, the law is evolving. The guidelines have not been adopted, and they are not entirely consistent with current law, nor are they universally endorsed. To summarize, one should not rely too heavily on the Revised Interim Guidelines and should be on the lookout for new case law. Recent examples Typical claims directed to a genetic material composition for medical purposes recite nucleic acids, nucleotides, genes, vectors, and transduced cells with reference to a specific sequence. U.S. Patent No. 5,744,460 entitled Combination for treatment of proliferative diseases, assigned to Novartis Corporation, contains claim 7, which reads: A pharmaceutical preparation for the treatment of cancer in a mammal comprising: (a) an antisense oligonucleotide targeted to PKC consisting of nucleotides comprising the following nucleic acid sequence: 59 -GTT CTC GCT GGT GAG TTT CA-39 SEQ ID NO:1, or a sequence that differs from said sequence by up to 3 nucleotides, or a derivative of said oligonucleotide, and (b) a chemotherapeutic agent or combination thereof selected from the following: (i) vinblastine, (ii) cisplatin, (iii) 5-fluorouracil, (iv) mitomycin, (v) adriamycine, (vi) vinblastine and adriamycine, or (vii) 5-fluorauracil and adriamycine; and one or more pharmaceutically acceptable carrier materials, wherein component (a) and/or (b) can be present in the form of a pharmaceutically acceptable salt, if at least one saltforming group is present, and wherein the combination of (a) and (b) has a synergistic anti-tumor effect. Another example is U.S. Patent No. 5,869,040 entitled Gene therapy methods and composition, assigned to Biogen, Inc. Claim 1 reads: A composition comprising an isolated, mutant proto-oncoge ne that encodes a dominant interfering mutant of a transcription factor, wherein the mutant proto-oncogene comprises a polynucleotide selected form from the group consisting of: (a) SEQ ID NOS.: 4-5 (SEQ ID NO.: 4 contains 591 base pairs and SEQ ID NO.: 5 contains 1100 base pairs); (b) a polynucleotide that hybridizes to any of the foregoing sequences under standard hybridization conditions and that encodes a protein having the cell growth inhibition activity of a dominant interfering mutant of an E2F transcription factor; (c) a polynucleotide that encodes a protein encoded by any of the foregoing polynucleotide sequences. These two examples recite specific sequences in the claims and have taken steps to include variation on the specific sequence. The 460 patent describes a 20-nucleotide sequence and includes any sequences differing by three nucleotides. The 040 patent describes significantly longer sequences and has included sequences that hybridize to and encode a similar protein. Hybridization claims have yet to be tested in the courts. They may have difficulty meeting the enablement requirement. U. S. Patent 5,902,576, entitled Antitumor phar-

8 300 Biotechnology Law Report Volume 19, Number 3 maceutical composition comprising IL-6 transfected cells, assigned to YEDA Research and Development Co. Ltd. at the Weizmann Institute of Science, claims a transfected cell as a pharmaceutical composition: 1. An anti-tumor pharmaceutical composition comprising tumor cells from a patient wherein a nucleic acid construct comprising a DNA sequence encoding human IL-6 operably linked to a promoter has been inserted into said cells, and wherein in said cells further have been inactivated to inhibit cell decision, and a pharmaceutically acceptable carrier. Here, the sequence encoding human IL-6 is presumably well known in the art and hence need not be specifically disclosed in detail (see Hybritech Inc. v. Monoclonal Antibodies, Inc. 802 F.2d 1367, 1384, 231 U.S.P.Q. 81,. 94 (Fed. Cir. 1986)). The sequence could also be incorporated by reference to another patent in the specification. THE UTILITY AND ENABLEM ENT REQUIREMENTS Utility under 101 Under 35 U.S.C. 101, an invention must be useful to be patentable: what is commonly referred to as the utility requirement in patent law. In addition, 35 U.S.C. 112 states that the specification should contain enough information to enable one to make and use the invention. Thus, an invention must be useful, and the patent specification must enable one to make and use the invention. There is a close relation between the utility requirement of 101 and the how-to-use enabling disclosure requirement of 112. In 1966, the Supreme Court defined the standard for utility as a specific benefit in currently available form (Brenner v. Manson, 383 U.S. 519, , 148 U.S.P.Q. 689, 695 (1966)). The Court of Appeals for the Federal Circuit and its predecessor court, the Court of Customs and Patent Appeals, have interpreted this as a minimal requirement of practical utility. All that is needed is some form of real-world value or practical utility (see Nelson v. Bowler, 626 F.2d 853, 856, 206 U.S.P.Q. 881, 883 (C.C.P.A. 1980)). Thus, nearly any use for an invention should satisfy 101 as long as it is credible and does not violate a law of nature, such as the laws of thermodynamics (see, e.g., Newman v. Quigg, 877 F.2d 1575, 1581, 11 U.S.P.Q.2d 1340, 1345 (Fed. Cir. 1989); see also Juicy Whip, Inc. v. Orange Bang Inc. et al, 185 F.3d 1364 (Fed. Cir. 1999), where an invention designed to deceive customers by imitating another product in order to increase sales satisfied the utility requirement). Inventions relating to the treatment of human or animal disorders should be supported by in vitro or in vivo evidence of usefulness. For compound claims, such as claims to genes, primers, probes, proteins, or polypeptides, in vitro data alone can be sufficient where the in vitro data are reasonably correlated with the in vivo activity (see Cross v. Iizuka, 753 F.2d 1040, 1046, 224 U.S.P.Q. 739, 744 (Fed. Cir 1985) (finding where a compound is claimed, adequate proof of any pharmacological activity constitutes a showing of practical utility )). In Cross, the Federal Circuit stated that for the claimed imidazole derivatives, which were said to inhibit thromboxans syntheses in human or bovine platelet microsomes:... there is a reasonable correlation between the disclosed in vitro utility and an in vivo activity, and therefore a rigorous correlation is not necessary where the disclosure of pharmacological activity is reasonable based upon the probative evidence. 753 F.2d at For therapeutic inventions that recite a particular utility, evidence should be provided that supports that particular use. In Fujikawa v. Wattanasin (93 F.3d 1559, 1564, 39 U.S.P.Q.2d 1895, 1899 (Fed. Cir. 1996)), the CAFC commented that when a method count recites a particular utility, there must be an adequate showing for that particular utility rather than any pharmaceutical activity such as for a compound claim. For biotechnolog ical inventions, overcoming the minimal threshold standard for utility is not automatic. For therapeutic inventions, and in particular those using genetic materials, the utility requirement appears to have a higher threshold than for other types of inventions. For example, a strict view of utility was taken in Ex parte Aggarwal (23 U.S.P.Q.2d 1334 (Bd. Pat. App. & Int f. 1992)). Aggarwal involved broad claims to a method of treatment for tumors in animals by administering lym-

9 Biotechnology Law Report Volume 19, Number photoxin, a cytotoxic protein, as a product of expression in a recombinant host cell. The application set out the preparation of the claimed pharmaceutical, a demonstration of in vivo activity in mice, and evidence of in vitro activity. The examiner rejected the application because of the unpredictability of the treatment of tumors with lymphotoxin at the time of filing and the doubts expressed in the literature, indicating that the limited results did not support the breadth of the claims. The Board affirmed the rejection, requiring evidence showing substantial activity in screening tests customarily used and accepted as predictive of human activity for the type of chemical tested (23 U.S.P.Q.2d at 1339). Thus, the PTO applied a high standard, and seemed to apply the standards of efficacy and safety of the Food and Drug Administration. In 1995, the CAFC clarified that clinical testing is not required to satisfy the utility requirement (In re Brana, 51 F.3d 1560, 34 U.S.P.Q.2d 1436 (Fed. Cir. 1995)). Therapeutic utility sufficient under the patent laws is not to be confused with the requirements of the FDA with regard to safety and efficacy of drugs to obtain market approval in the United States. In re Brana involved a claim for new antitumor pharmaceutical compounds. The claim was rejected by the PTO on the grounds that the specification failed to describe any specific disease against which the claimed compounds were active. In fact, the application disclosed tumor models involving injection of a cancerous cell line in mice. Although there were animal data, there were no human data. The Board affirmed the rejection, but the Federal Circuit reversed, holding that the FDA s requirements of testing for safety and effectiveness are not required by the patent laws. The Court stated: The Commissioner, as did the Board, confuses the requirements under the law for obtaining a patent with the requirements for obtaining government approval to market a particular drug for human consumption. 51 F.3d at * * * FDA approval, however, is not a prerequisite for finding a compound useful within the meaning of the patent laws. Scott, 34 F.3d 1058, 1063, 32 U.S.P.Q.2d 1115, Usefulness in patent law, and in particular in the context of pharmaceutical inventions, necessarily includes the expectation of further research and developm ent. The stage at which an invention in this field becomes useful is well before it is ready to be administered to humans. Were we to require Phase II testing in order to prove utility, the associated costs would prevent many companies from obtaining patent protection on promising new inventions, thereby eliminating an incentive to pursue, through research and development, potential cures in many crucial areas such as the treatment of cancer. 51 F.3d at In December 1999, the PTO proposed a revised set of guidelines regarding the utility requirement under 35 U.S. C. 101 and 112 (Revised Interim Utility Examination Guidelines, 64 Fed. Reg (Dec. 21, 1999); correction filed 65 Fed. Reg (Jan. 21, 2000)). The Revised Interim Guidelines supersede the 1995 Utility Guidelines (60 Fed. Reg (1995)). Under the Revised Interim Guidelines, the emphasis is on whether the utility of an invention is credible, specific, and substantial. The previous guidelines focused on the credibility of the claimed invention s utility. In addition, throwaway utilities, such as the use of a complex invention as landfill, have been distinguished as nonspecific and insubstantial utilities and therefore do not satisfy the utility requirement. Specificity and substantiality of an asserted utility has been incorporated into the utility analysis to address concerns regarding the patentability of expressed sequence tags (ESTs). The PTO relies on the language of Brenner to support the incorporation (383 U.S. at ; requiring disclosure of specific utility and of substantial utility, where specific benefit exists in currently available form ). These modifications in the Revised Utility Interim Guidelines should not further restrict the PTO s practice regarding the use of genetic materials in treating diseases. However, patent claims to methods of diagnosing diseases with genetic material should include directions to specific diseases or conditions. The progress made by the 1995 Utility Guidelines with regard to the patentability of biotechnolog ical inventions should not be minimized with the Revised Interim Guidelines. Updated training materials will be developed to address technology specific issues. To satisfy the utility requirement, the invention

10 302 Biotechnology Law Report Volume 19, Number 3 must have a specific and substantial utility that is credible. An applicant can comply with the utility requirement if the invention has any well-established utility, regardless of any assertion by the applicant. An invention has a well-established utility if a person of ordinary skill in the art would immediately appreciate why the invention is useful based on the characteristics of the invention. An applicant could also comply with the utility requirement if he or she has asserted that the claimed invention is useful for any particular purpose; i.e., it has a specific and substantial utility, and that assertion would be considered credible by a person of ordinary skill in the art. Credibility is assessed in view of the disclosure and any other evidence of record such as test data, affidavits, or declarations from experts in the art, patents, or printed publication. An applicant need provide only one credible assertion of specific and substantial utility for each claimed invention to satisfy the utility requirement. A throw-away, insubstantial, or nonspecific utility, such as the use of a complex invention as landfill, does not satisfy the utility requirement. Other possible examples of throw-away utilities in the biotechnological arts might be the use of a specific protein as a source of general amino-acid nutrition or the use of an organic compound as a potential source of carbon. If a utility rejection is made, the examiner has the burden of providing a well-reasoned explanation as to why the claimed invention has no specific and substantial credible utility. The explanation should include evidentiary support. The examiner must treat as true a statement of fact made by an applicant in relation to an asserted utility unless countervailing evidence can be provided that shows that one of ordinary skill in the art would have a legitimate basis to doubt the objective truth of such a statement. Similarly, the examiner must accept an opinion from a qualified expert that is based on relevant facts whose accuracy is not being question; it is improper for the examiner to disregard the opinion solely because of a disagreement over the significance or meaning of the facts offered. The previous 1995 Utility Guidelines were designed to reign in the trend of utility and non-enablement rejections in therapeutic or pharmacological inventions. Alhough these Guidelines have been superseded, the basic principles they set out for therapeutic and pharmaceutical inventions should still be helpful when considering what type of support to include in an application. These principles include: A reasonable correlation between the evidence and the asserted utility is sufficient. The reasonable correlation may be established by relying on statistically relevant data or documentary evidence, such as articles in scientific journals. Structural similarity may be enough. Data from in vitro or animal testing is generally sufficient to support therapeutic utility. Variables considered include test parameters, choice of animal, relationship of the activity to the particular disorder to be treated, characteristics of the compound or composition, relative significance of the data provided. Evidence does not have to be in the form of data from a recognized animal model for the particular disease. Thus, if one skilled in the art would accept the animal tests as being reasonably predictive of utility in humans, evidence from those tests should be considered sufficient to support the credibility of the asserted utility. There is no requirement for human clinical data to establish the utility of any invention related to treatment of human diseases, even where there are no recognized animal models for the human disease. It is improper for the PTO to request evidence of safety or effectiveness in the treatment of humans or regarding the degree of effectiveness. On the other hand, claims directed to treating or curing a disease known to be incurable at present warrant careful review. Whereas claims directed to a method of treatment or treating a symptom may pass muster with suitable test data, method of curing or preventing claims can expect rejections for lack of utility. Despite the minimal utility standard, many inventors have continued to encounter challenges from the PTO regarding patent applications for treatments involving genetic materials. For example, a typical patent application relating to gene therapy may still face a rejection in the first office action for lack of utility under 101 and for failure to teach how to use under 112. Such a rejection is commonly accompanied by a 1995 report from the National Institutes of Health panel appointed by the Director, Dr. Harold Varmus, to assess the NIH investment in research on gene therapy, which states

11 Biotechnology Law Report Volume 19, Number that significant problems remain in all basic aspects of gene therapy. Such rejections are often difficult to overcome. Therefore, although theoretically, in vitro data alone can be sufficient in particular circumstances, more data may be required for inventions to therapeutics using genetic materials. Animal tests that are reasonably predictive of utility in humans should be included. Animals used in the field to study particular conditions are helpful. For example, R388 and L1210 murine tumor models were cited with approval in Brana (51 F.3d at , 1567). Mice and rat data represent good evidence and can be sufficient, but primate data are better. Of course, human clinical data, if feasible, are best. Challenges to lack of utility can often be overcome by asserting a utility that is not directly for a therapeutic but for some biological mechanism. The level of disclosure is less stringent for DNA delivery or tumor reduction than for the treatment or cure of cancer. Recent patents with sufficient evidence of utility Claims to specific biologic mechanisms are fairly easy to support. Typically, minimal data are required. One such example is U.S. Patent 5,869,037 entitled Adenoviral-mediated gene transfer to adipocytes and assigned to Cornell Research Foundation, Inc. Claim 1 reads: 1. A method of increasing the vascularity of adipose tissue which comprises contacting said adipose tissue with an adenoviral vector comprising a promoter and, operably linked thereto, a DNA encoding an angiogenic protein such that said adenoviral vector enters said adipose tissue, said angiogenic protein is produced, and said adipose tissue has an increased vascularity. The 037 patent contains in vivo data in rats showing gene transfer to adipose tissue for multiple proteins and also in vivo data showing increased vascularity in rats. Other examples include patents for a method of inhibiting growth of tumor cells (U.S. 5,869,040) and a method to reduce the growth of an epithelial ovarian tumor in mammals (U.S. 5,891,857). Similarly, claims for methods of DNA or protein delivery to cells are relatively easy to support. For example, U.S. Patent 5,843,742 claims a method of integrating a selected nucleotide sequence into the genome of a mammalian cell and provides support with in vitro transduction into a human cell line. A more involved method for protein delivery may require more data. In U.S. Patent 5,885,971, entitled Gene therapy by secretory gland expression assigned to the University of California, claim 1 provides: A method of delivering a protein to the bloodstream of mammal, the method comprising the step of: introducing a DNA construct into a salivary gland cell in vivo, wherein the DNA construct comprises a DNA sequence of interest which encodes a protein and a eukaryotic promoting sequence operably linked to the DNA sequence of interest; wherein the introduced DNA construct is expressed and the protein encoded by the introduced DNA construct is delivered into the blood stream of the mammal. In vivo expression data in rats and in vivo insulin response data in rats support the patent claims. Furthermore, the specification lists exemplary proteins and exemplary diseases amenable to therapy. Claims directed to methods of treating a general condition or disease are more difficult to obtain. One successful example is U.S. Patent 5,705,151 entitled Gene therapy for T cell regulation assigned to the National Jewish Center for Immunology & Respiratory Medicine. Claim 1 reads: 1. A method to treat a mammal that has cancer, said method comprising administering to said mammal a therapeutic composition comprising (a) a liposom e delivery vehicle; and (b) a recombinant construct comprising a first isolated nucleic acid sequence encoding a superantigen, and a second isolated nucleic acid sequence encoding a cytokine, said first and second nucleic acid sequences being operatively linked to one or more transcription control sequences; wherein said first and said second nucleic

12 304 Biotechnology Law Report Volume 19, Number 3 acid sequences encoding said superantigen and said cytokine, respectively, are coexpressed at or adjacent to said cancer; and wherein coexpression of said superantigen and said cytokine produces a result selected from the group consisting of alleviation of said cancer, reduction of a tumor associated with said cancer, elimination of a tumor associated with said cancer, prevention of meta static (sic) cancer, and stimulation of effector cell immunity against said cancer. This patent contains in vitro expression data in canine cells, in vivo expression studies in mice, and in vivo studies in dogs showing tumor reduction. Claims to treating specific diseases are typically easier to support and can be stronger claims. For example, U.S. Patent 5,849, 719, entitled Method for treating allergic lung disease and assigned to the University of California, claims: 1. A method for immunotherapy of allergic asthma in a host comprising: immunizing the host against an asthma-initiating antigen by introducing a naked polynucleotide composition comprised of a recombinant expression vector which encodes an asthma-initiating antigen into antigen presenting cells in the host s mucosa, wherein the polynucleotide is naked in that it is not complexed to any colloidal material which interferes with uptake of the polynucleotide by the antigen presenting cells; wherein the asthma-initiating antigen is expressed in the antigen presenting cells to stimulate Th1 lymphocytes in the host and inhibit antigen-stimulated IgE antibody production as well as cytokine mediated eosinophil infiltration of lung tissue. The claims are supported by in vivo studies showing suppression of IgE antibody response in mice that were models for airway hyperactivity of allergic asthma. Patents for Methods of Treating Incurable Conditions A previous lack of success in treating a disease or condition, or the absence of a proven animal model for testing the effectiveness of drugs for treating a disorder in humans, should not, standing alone, serve as a basis for challenging the asserted utility under 35 U.S.C However, the PTO may challenge an invention s utility when it is inherently unbelievable or involves implausible scientific principles (In re Brana, 51 F.3d at 1566). On the other hand, a treatment for a condition that at one time was suspect may not be so at a later date. In In re Cortright (165 F.3d 1353, 1357, 49 U.S.P.Q.2d 1464, (Fed. Cir. 1999)), the CAFC reversed the Board s decision that a claim for using a balm to restore hair growth failed for lack of utility. The Board held that the utility was incredible in light of Cortright s failure to prove utility with clinical evidence. The Court of Appeals reversed the rejection, finding that treating baldness was no longer considered an inherently unbelievable undertaking, noting that the claim for restoring hair growth should not be construed to mean that hair growth would return to its original state. Nonetheless, obtaining patents for the treatment of particular diseases such as AIDS, cancer, Alzheimer s disease, or multiple sclerosis has traditionally been difficult. A recent patent, U.S. No. 5,861,290 entitled Methods and polynucleotide constructs for treating host cells for infection or hyperproliferative disorders, may be directed to the treatment of AIDS. The claims were drafted so that they are specifically directed to the treatment of a host cell. For example, claim 28 states: 28. A method for treating a host cell ex vivo to render the host cell protected from infection by an infectious agent, or to destroy the host cell when infected by said agent, wherein said infection by said infectious agent is associated with the expression in said host cell of a trans-acting regulatory factor, and wherein said trans-acting regulatory factor is capable of regulating expression of genes under the control of a cis-acting regulatory sequence, which method comprises: inserting into said host cell a polynucleotide construct comprising said cis-acting regulatory sequence and an effector gene under the control of said cis-acting regulatory sequence, wherein said effector gene is expressed in the presence of the trans-acting regulatory factor