—— — —..— —-— . .—.—. . ————-

Chapter 4

The Interested Parties

“Biomedical research is in considerable measure so esoteric an activity that a great dealof the social control that guides it must be in the hands of the biomedical research commu-nity itself. Yet, like all other specialized and esoteric social activities, biomedical researchis too important to the larger society to be left entirely to its experts. In part it needs tobe effectively and continuously scrutinized and controlled by outsiders. An effective systemof control, including both insiders and outsiders would better protect all the parties of in-terest . . .“

—Leon R. KassScience, 174:779-788, 1971

1

CONTENTS

PageWhy Commercial Interest in Human Biological Research and Inventions? . . . . . . 49

Patentability of Recombinant and Nonrecombinant Cell Lines . . . . . . . . . . . . . . 49Patenting and Licensing of Government-Sponsored Inventions . . . . . . . . . . . . . . 50Effect of 1980 Patent Law Changes on Biocommerce . . . . . . . . . . . . . . . . . . . . . 50

Sources of Human Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51The Research Community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Obtaining Human Biological Materials for Research . . . . . . . . . . . . . . . . . . . . . . . 52Uses of Tissues and Cells in Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54The Research Process and Rarity of Human Tissue . . . . . . . . . . . . . . . . . . . . . . . 55

Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56The Companies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Industrial Product Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60University-Industry Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Fee-for-Service Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62Summary and Conclusions . . . . . ..+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Chapter preferences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

TablesTable No. Page6. Repositories for Human Tissues and Cells, Cell Cultures, and Cloned Genes . . 537. Financial Statistics for Selected Biotechnology Companies ..., . . . . . . . . . . . . . 588. Estimated U.S. Marketing Date for Some Human Therapeutic Products. . . . . . 589. Some Human Therapeutic Products Being Developed by the Biotechnology

Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

FiguresFigure No. Page11. Rarity of Human Tissues and Cells Used in Biotechnology . . . . . . . . . . . . . . . . 5612. Number of Human Therapeutic Biotechnology projects by Company . . . . . . . 5713. The Development of Angiogenin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

BoxBox No. PageC. Angiogenin: A Case History From Research to Product Development. . . . . . . 60

Chapter 4

The Interested Parties

Why has controversy arisen over the use of hu-man biological materials, and who are the stake-holders in this controversy? How has it even cometo pass that naturally occurring substances, suchas genes, plasmids, and even organisms, can bepatented? While the technological advances de-scribed in chapter 3 have increased the availabil-ity and promise of new inventions and productsof great importance to human health, the chang-

ing legal climate in the United States also has beena factor responsible for increasing interest in hu-man biological materials. These events have ledto an increased commercial interest in humanspecimens and have affected three major groupsof stakeholders: the sources of human tissues andcells, the research community, and the biotech-nology industry.

WHY COMMERCIAL INTEREST IN HUMAN BIOLOGICAL RESEARCHAND INVENTIONS?

The controversy that has arisen over the useof human tissues and cells can be attributed inpart to two landmark events that occurred in 1980to accelerate industry-sponsored research and in-terest in human biological materials. First, the U.S.Supreme Court held for the first time that Fed-eral patent law applies to new life forms createdby DNA recombination, thus opening the possi-bility that products containing human cells andgenes might also be patentable. Second, Congressamended the patent statute to encourage patent-ing and licensing of inventions resulting from gov-ernment-sponsored research.

Patentability of Recombinant andNonrecombinant Cell Lines

In the early 1970s, General Electric microbiolo-gist Ananda Chakrabarty used both classicalgenetic selection and recombinant DNA tech-niques to find and develop a novel bacterial straincapable of digesting oil slicks. Chakrabarty andhis employer sought patent protection under theFederal patent statute (35 U.S.C. 101). While judg-ing the process for producing and maintaining thenew bacterium to be patentable, the Patent andTrademark Office examiner rejected patent claimsto the bacterium itself. The Patent and TrademarkOffice’s Board of Appeals upheld the examiner’srejection on the ground that living organisms wereper se unpatentable.

Later, the U.S. Court of Customs and Patent Ap-peals (CCPA) reversed this ruling (29), relying ona prior decision in In re Bergy that held “the factthat microorganisms are alive is a distinction with-out legal significance” (27). Bergy concerned thecreation of a biologically pure culture of a natu-rally occurring but previously undiscoveredmicro-organism capable of efficiently producingan antibiotic similar to penicillin. A patent had notbeen sought for the naturally occurring micro-organism, but one was sought for the purified sam-ple and the processes used to create the pureculture.

A chain of related Supreme Court and CCPAdecisions ultimately led to a five-to-four SupremeCourt ruling upholding the CCPA’s decision thatgenetically engineered microorganisms are withinthe scope of patentable subject matter defined bysection 101. The high court Diamond v. Chakra-barty decision (14) makes it clear that the ques-tion of whether or not an invention embracesliving matter is irrelevant to the issue of pat-entability, as long as the invention is the re-sult of human intervention.

The court did not directly address the questionof whether purified nonrecombinant cell samplesare patentable since Chakrabarty dealt with a ge-netically recombined organism and the Bergy casewas not directly considered, However, the CCPA’ssecond Bergy decision (28) suggests that a puri-

49

50 . Ownership of Human Tissues and Cells

fied strain of naturally occurring organisms is stat-utory subject matter unless precluded under the“product of nature” doctrine (6).

Under the product of nature doctrine, a cell orother substance occurring in nature is not patent-able unless it is given a substantially new form,quality, or property not present in the original(6,46). Purification of a naturally occurring sub-stance or organism must result in a substantialchange in its characteristics, functions, or activ-ity for the purified material or cell line to be patent-able (6). If a patent examiner decides to rejectpatentability for an invention on grounds that itis a product of nature, he must show that theclaimed product, such as a biologically pure cul-ture, is likely to exist in nature as a result of nat-ural processes and not merely that it possiblyexists in nature (6,56).

The Patent and Trademark Office has histori-cally taken the position that, in the absence of aSupreme Court ruling addressing the issue, higherlife forms such as mammals, fish, and insects willnot be considered to be patentable subject mat-ter under section 101 (56). This position finds somesupport in a statement in Bergy that biologicallypure cultures created and used for their chemi-cal reactions are more similar to inanimate chem-ical compositions than they are to animals or plants(27). However, the rationale for this position issomewhat weakened by the Court’s statement inChakrabarty that “Congress intended statutorysubject matter to include anything under the sunthat is made by man” (14).

Patenting and Licensing ofGovernment-Sponsored Inventions

The Federal Government is the primary sourceof funding for basic biomedical research. Yet un-til 1980, no single patent policy existed with re-spect to government-supported research. Eachagency developed its own rules, resulting in 25different patent policies, and under this system,only about 4 percent of some 30,000 government-owned patents were licensed (40). Furthermore,the government policy of granting nonexclusivelicenses discouraged investment, since a companylacking an exclusive license was reluctant to paythe cost of developing a product and building a

production facility. Potentially valuable researchthus remained unexploited.

Congressional concern about this so-called “in-novation lag” prompted efforts to develop a uni-form patent policy that would encourage coop-erative relationships between universities andindustry, with the goal of taking government-sponsored inventions off the shelf and into themarketplace. In 1980, Congress passed the Pat-ent and Trademark Amendment Act (Public Law96-517) and added additional amendments in 1984(Public Law 98-620).’ The law allows nonprofitinstitutions (including universities) to apply forpatents on federally funded inventions, with theFederal agency retaining a nonexclusive world-wide license. Universities are required to shareroyalties with the inventor and to use their ownshare for research, development, and education.The patent policy of the National Institutes ofHealth (NIH) served as a model for the uniformpatent policy established by the law.

Effect of 1980 Patent Law Changeson Biocommerce

The impacts of technological breakthroughs andthe changing legal climate on human biologicalproduct development is demonstrated by a 1985survey of American medical institutions conductedby the House Science and Technology Commit-tee’s Investigations and Oversight Subcommittee.During the 5 years from 1980 to 1984, patent ap-plications by universities and hospitals for inven-tions containing human biological increased morethan 300 percent as compared with the preced-ing 5-year period and constituted 22 percent ofall patent applications filed by these institutions.Forty-nine percent of all medical institutions haveapplied for such patents (50).

Whether these and forthcoming patents will beof commercial value is difficult to assess. The phar-maceutical industry has usually experienced ahigher rate of commercial value for its patentsthan industry in general (10). There is reason tobelieve that biopharmaceuticals will have a stillhigher rate since they often have the potential

IThe U.S. Department of Commerce recently requested commenton revised regulations under this statute (51 FR 22508).

Ch. 4—The Interested Parties ● 5 1

to supplant an entire, well-established market oc-cupied by a conventional drug (41). At this point,however, it is still too early to determine what

pattern will be established inindustry for the commercial

the biotechnologyvalue of patents.

SOURCES OF HUMAN TISSUE

Individuals who are sources of human tissuesand cells are one major group of people affectedby the U.S. Supreme Court and congressional ac-tions contributing to increased development andcommercialization of human biological materials.Tissues and cells can be removed from sourcesfor medical purposes, research purposes, or both.The primary medical reasons for withdrawing hu-man biological materials are diagnosis (removalof specimens to determine the nature and extentof a disease) and therapy (removal of diseased tis-sue, either permanently or for treatment and rein-troduction, as in renal dialysis or homologous bonemarrow transplants). Removing human specimenscan

●

●

●

●

involve a variety of procedures, including:

aspiration of bodily fluids (e.g., blood, am-niotic fluid) through a needle;examination of cells from a surface (e.g., skinor cervix cells from a Pap smear);surgical removal of nonsurface tissue (e.g.,lymph node biopsy, tumor material); andnoninvasive procedures to collect excretions(e.g., urine and feces) and certain secretions(e.g., semen, saliva, milk, and perspiration).

There are three major categories of sources ofhuman tissues and cells: patients, healthy researchsubjects, and cadavers.

● Patients area source of both normal and atyp-ical specimens and these individuals may ormay not be research subjects. Patient-derivedspecimens may be ‘(leftovers” from diagnos-tic or therapeutic procedures and most hu-man tissues or cells that find their way intoresearch protocols are of this type. Patient-derived samples can also be provided as partof a research protocol.

● Healthy volunteer research subjects maydonate replenishing biological if specimenremoval involves little or no risk of harm,according to generally accepted principles ofhuman subject research.

● Cadavers are the only permissible source ofnormal and atypical vital organs (includingthe brain, heart, and liver, but excluding kid-neys and corneas). They are also the only per-missible source of healthy organs (e.g., cor-neas) destined for research rather thantransplantation.

While the different classifications of humansources—patient, volunteer research subject, orcadaver—may seem to be fairly straightforward,the human relationships involved between sourcesand physician/researchers (or another interestedparty) are more dynamic than these categoriessuggest.

For example, the distinction between an indi-vidual as a patient versus a research subject cansometimes change over the course of time. Therelationship between physician and patient canalso evolve from physician-patient to researcher-subject. Thus, if a patient’s specimen is removedfor diagnostic or therapeutic purposes and thephysician subsequently uses the specimen in re-search, should the patient still be considered apatient, or has he become a research subject andhas the relationship become one between researchsubject and researcher? Or, if a patient hospi-talized with a broken leg is asked to donate a bloodsample, should he be considered a research sub-ject because any risk he undergoes is for altruis-tic rather than selfish reasons, or is he still a pa-tient because of the possibility that he may feelcoerced to cooperate with the hospital staff onwhom he is physically and psychologically de-pendent?

Determining whether a person is a patient ora research subject is relevant in determining theapplicability of Federal regulations governing fed-erally funded research using human biological ma-terials. These issues are addressed further in chap-ter 6.

. — — .

52 ● ownership of Human Tissues and Cells

THE RESEARCH COMMUNITY

Investigators who use human tissues and cellsin their research are a second stakeholder in thecontroversy about access, use, and profit fromspecimens. A recent survey conducted by theHouse Committee on Science and Technologyfound that 49 percent of the researchers at medi-cal institutions surveyed used human tissues orcells in their research (50). According to one re-cent estimate, at least 500 principal investigatorsnationwide use human cell lines (42). NIH providesgrants to about 200 individuals whose primaryresearch focuses on human cell lines and to anundetermined number of scientists whose second-ary interest is human-related (34). The use of hu-man specimens is principally due to three factors:

● the newly emerging abilities to isolate increas-ingly smaller amounts of important naturallyoccurring human biological factors (alsoknown as biopharmaceuticals, bioresponsemodulators, or biological mediators);

• the ability to produce virtually unlimitedquantities of these factors, usually found inminute amounts in the body, through recom-binant DNA methods; and

● the invention of hybridomas, making possi-ble the generation of large, pure supplies ofspecific antibodies (47).

Obtaining Human BiologicalMaterials for Research

Although tens of thousands of samples of hu-man tissue are probably used in research, detailedinformation on the amount and type of humanbiological materials used is difficult to obtain. Nocentral records are kept on this data, and infor-mation on the source or use of human biologicalby biotechnology companies is often consideredconfidential business information. Moreover, theways in which researchers obtain human samplesvary with the type of scientist and the nature ofthe research.

Physicians working at a university hospital willoften obtain tissue as a result of biopsies or surgerydone on their patients. The physician/researchermay obtain samples directly from the operatingroom in cases when fresh, live tissue is needed,

or receive the material after pathologists have ex-amined it (48).

Nonphysician researchers or clinicians needinghuman tissues or cells that are not obtainable fromtheir own patients or patients within the hospitalobtain specimens by other avenues. Informaltransfers are common among researchers at hos-pitals and universities around the country. Re-searchers and companies are becoming more cau-tious, however, and are moving toward a muchtighter, more formal system of transferring re-search materials. This caution is a result of con-cerns over patent and ownership rights and it ap-plies to newly isolated tissue, as well asinvestigator-developed cell lines and gene clones(41,43).

Researchers at some large universities and re-search institutes also can obtain needed materialfrom volunteers who are asked to donate tissuesamples. For example, at NIH, blood is collectedby the NIH Blood Bank specifically for researchpurposes. Most volunteer donors are membersof the NIH staff, although some outside donorsare also used. Payment for blood donations forresearch purposes is usually about $25. Volun-teers providing bone marrow for research pur-poses receive around $75 for a specimen (45). Gen-erally, these types of arrangements are ad hoc,and no systematic data are available on theamounts and type of human materials collectedor on payments for such material.

Researchers at biotechnology and pharmaceu-tical companies who need human biological alsohave a variety of options at hand for obtainingmaterials. They can pay individual volunteers foroccasional specimens, usually of blood, or pur-chase outdated blood from the Red Cross or otherblood banks. Biotechnology companies often ob-tain specimens as a result of their research rela-tionships with universities and medical researchcenters. The biotechnology company may obtainspecimens either through individual affiliationswith university/hospital researchers or throughresearch arrangements with university and hos-pital departments (12,25,38)41,43),

Organized repositories provide an additionalavenue for both noncommercial and commercial

Ch. 4—The Interested Parties 5 3

investigators to obtain research material. Most ofthe material available from these “warehouses”are not human biological as defined in this re-port–i.e., primary tissues or cells–but are celllines or gene clones (containing human DNApieces) developed and discovered by investigatorsand deposited at the repositories. Organizationsin this field are usually funded by NIH and oper-ated on a nonprofit basis, providing samples oftissue and genetic material to qualified research-ers for a nominal processing fee. Many universi-ties and cancer research centers maintain theirown collections as well. Table 6 lists some of thesefacilities and indicates some of the types of mate-rial each stores.

Although no systematic survey was undertakenfor this analysis, anecdotal information suggeststhat most university or other nonprofit research-ers usually are able to obtain the samples theyneed for research, but individuals who need cer-tain types of tissue must make their own arrange-ments. The process, however, of obtaining sam-ples is sometimes characterized as a “scramble. ”Additionally, odd samples are usually less in de-mand than some common types of cancer or tis-sue. Research popularity coupled with a higherincidence of a particular tumor can result in fiercecompetition for a continued supply of new speci-

Table 6.— Repositories for Human Tissues and Cells,Cell Cultures, and Cloned Genes

Organization Type of material collected

The American Type Culture Collection( A T C C )a Cell cultures, cloned genes

The Human Genetic Mutant Cell Repository, b

Coriell Institute (formerly the Institute forMedical Research) ., Cell cultures

The National Cancer Institute, BiologicalCarcinogenesis Branch Sera, tumor tissue

(benign and malignant)The Cell Culture Center, Massachusetts

Institute of Technology Cell culturesaThe ATCC IS one of the largest repositories of Its type mamtammg some 40000 cultures mclud-

lng about 1 325 human cell Imes (48) These materials are prowded fo nonproht researchersfor an average fee of $40 and to for-profit researchers at an average fee of $64 Many research-ers send samples of their cell cultures to the ATCC I or other repositories) once they have beendeveloped and reported 10 avoid the t[me and money required to respond to requests for samplesfrom o!her researchers Samples are requued to be placed m a repowtory If a patent apphca!!onhas been f(led relatlng 10 the sample Access to samples for which patents are pending IS strictlyrestricted once a palent IS granted [he sample IS ava(lable to anyone In 1985 ATCC distributedbetween 12000 and 19000 human cell cultures 10 researchers the majority of which went tounlversltles and hosp!tal research centers (see refs 19351

bThe Human Genetic Mutant Cell Reposlfory with 3550 human Cd 1106’S In stock respondedto 3472 requests In 1985 (see refs 52 53 I

SOURCE Off Ice ot Technology Assessment 1987

Photo credit: National Institutes of Health

Human cell lines at the American Type CultureCollection’s Human Tumor Cell Bank are put into

ampules for shipment to researchers.

mens. Colon and bladder carcinomas are two tis-sues currently in high demand (1,13,23).

To assist in this process, various organizations,networks, and interchanges, are undertakingmore comprehensive coordinating activities. In1980, a nonprofit organization, the National Dis-ease Research Interchange (NDRI), pioneered theworld’s first retrieval/preservation/distributionmechanism for organs and tissues. NDRI makesover 100 types of tissues available to researchersstudying a wide range of diseases, including dia-betes, retinitis pigmentosa, cardiovascular disease,cystic fibrosis, and glaucoma (55). In response toinquiries, the National Cancer Institute (NCI) hasissued a request for cooperative agreement ap-plications to establish a cooperative network, in-cluding computer communication, to improve col-lection and distribution of human cancer tissues(54). The network is not a tissue bank, but willrespond to requests from investigators to helpthem obtain the multiple fresh tumor samples theyneed to screen for tumor protein markers, genes,and other characteristics (1). NIH recentlyawarded a contract to the University of MinnesotaHospital in Minneapolis for a “Liver Tissue Pro-curement and Distribution System. ” This programis designed to establish regional centers to collectlivers removed from transplant patients and thendistribute them to researchers nationwide. Finally,a project at the University of Alabama is also be-

54 ● Ownership of Human Tissues and Cells

ing designed to address shortages in the availabilityof tissue for research (23).

Uses of Tissues and Cellsin Research

The research community uses undeveloped tis-sues and cells provided by sources for a widerange of purposes. Material obtained from an in-dividual is not necessarily used strictly for re-search purposes, however, but can be divided formedical, research, or commercial uses. In fact,diagnostic, therapeutic, research, and commer-cial uses of biological are usually intertwined,sometimes inextricably. The present economic dy-namics of research coupled with the proliferationof biotechnology companies have spawned a pleth-ora of university-industry relationships that havemade it increasingly difficult to separate the useof human samples in university (or otherinstitution-based) basic research from basic andapplied research in commercial settings.

Uses of human tissues and cells in basic researchare diverse and thus difficult to categorize, oncehuman biological material is provided by an indi-vidual, it is examined, manipulated, and developedby researchers. Human tissues and cells can beexamined directly from the patient with limitedhandling (e.g., screened for a particular tumormarker) or they can be manipulated extensivelyto obtain a useful research tool or potentially mar-ketable product. Generally, basic researchers usethese materials to study the characteristics andfunctions of healthy and diseased organs, tissues,and cells.

The researcher’s choice of a source of specimenis based on the type of tissue being studied andthe goals of the particular research project. Thematerial could be used for a “one-shot” experi-ment or used in the long-term development ofsomething (e.g., a cell line, cloned gene, or geneprobe) that expands the base of knowledge abouta complex problem and advances the investiga-tor’s project. Specimens can also be used by theresearcher to create cell lines that generate a con-tinual supply of products such as monoclinal an-tibodies; provide insight into a patient’s heredi-tary disease; provide the basic genetic materialfrom which recombinant products can be

produced; or serve as a medium to propagateviruses or amplify cloned DNA sequences. At themost fundamental scientific level, human mate-rial is used in experiments to examine and under-stand basic biological processes. This basic re-search can subsequently lead to other uses ofhuman tissue, such as product development bythe commercial sector.

Commercial enterprises use specimens as rawmaterials for both product-oriented purposes andnonproduct--oriented basic research. The use ofhuman biological by companies for nonproductresearch differs little from that just described fornonindustrial research. In product-oriented re-search, a specimen could be used for a one-timeprocess to produce or test something, or it couldbe used as part of a long-term investigation to pro-duce a product. Proteins might be extracted fromhuman specimens or tissue culture cell lines de-rived from specimens. Similarly, genes for theseuseful proteins might be isolated by industrial re-searchers directly from undeveloped material orfrom an established cell line. These cloned genescan then be used to mass produce large quanti-ties of therapeutic or diagnostic human-derivedproducts. Human insulin, human growth hor-mone, and human alpha-interferon are three prod-ucts produced through recombinant DNA tech-niques that are licensed for therapeutic use in theUnited States. Standardized diagnostic products(e.g., pregnancy test kits) often contain humanproteins.

Companies also sometimes use human-derivedmaterial to study the efficacy of an item prior tomarketing, to meet safety criteria, or to manu-facture a biological product such as a viral vac-cine. Specimens can be used as reagents in feder-ally required, preclinical testing of pharmaceuticalproducts (44). Use of such reagents is necessaryto develop the potential value of the product, butis not itself the marketable item. The material usedby the company for testing or manufacturing couldbe newly isolated specimens or standard cell lines.The new technologies, such as hybridoma tech-nology or recombinant DNA technology, led theFood and Drug Administration (FDA) to recentlyamend its regulations to establish general require-ments for cell lines used for manufacturing anybiological product for human use (5 I FR 44451).

Ch. 4—The Interested Parties ● 5 5

Some firms maintain that they do not use anyoriginal human tissue in research, concentratingtheir efforts on established cell lines instead. Thesecompanies obtain and manipulate generally avail-able cell lines, resulting in new, unique, or im-proved cell lines.

The Research Process andHuman Tissue

Rarity of

To what extent are human biological mate-rials, provided by any single (or very few) in-dividuals), potentially profit-yielding to the re-search community because the material isboth commercially useful and rare? Biomedi-cal research and development using human ma-terial is a dynamic process that rarely culminatesin a profit-making product. Research results aretypically a series of several joint efforts withspecimens provided by several individuals.This diversity is critical to advancing the knowl-edge about an area under study and the expecta-tion of developing a commercial product at theoutset of the research is often extraordinarilysmall. Thus, any product developed is a conse-quence of many source and researcher contri-butions. A determination of the contributionof any single individual in the marketableproduct would be speculative.

In general, the value to the researcher of cer-tain types of tissue results more from the key is-sues of access and availability to the sample thanfrom the inherent rarity or commercial potentialof the tissue. Both industry and nonindustry-supported investigators usually are interested ina specified type of tissue that occurs with a knownfrequency in the population, but cannot be termedtruly rare—such as cells from a cystic fibrosis pa-tient; a particular type of tumor (e.g., breast, lung,liver, or other); or a collection of samples fromseveral generations of a family. Certain types ofspecimens might be more easily obtained (e.g.,blood instead of bone marrow), or certain sam-ples might not be commonly removed during sur-gery (e.g., healthy spleens). The typical goal whenobtaining human specimens is acquiring any livertumor, for instance, not obtaining one from a spe-cific individual that is truly rare.

Although the goal of a researcher is often toobtain many random samples of human tissue orcells, once a scientist has investigated differenttissue samples it may become apparent that oneor a few specimens (or the cell line the investiga-tor has developed) “overproduces” an interestingsubstance. Some people might naturally producegreater than normal amounts of a substance, orsome might overproduce it because of an illness.This overproduction could enable the researcherto identify a novel entity that would otherwisehave gone undiscovered, or the overproductioncould be useful in further research and experi-ments (21)—particularly if the investigator hasbeen fortunate and able to establish a culture ofthe sample that continues the overproduction.Thus, once found (usually serendipitously) a noveltissue or cell can become a valuable research toolor be developed into a potential commercial prod-uct. It should be emphasized, however, that a sys-tematic method of obtaining such unique tissuesor cells does not appear to exist. Furthermore,unique human samples do not necessarilyhave any actual or potential commercial value.

It is conceivable, of course, that one person oronly a handful of people are overproducers of apotential commercial substance. More likely, how-ever, many people are overproducers but simplyhave not been identified by researchers (nor couldthey feasibly be identified). Furthermore, whilesome people are overproducers, nearly all per-sons are capable of being high, moderate, or lowproducers of the substance (unless an individualhas a deletion in the gene for the substance—which is a rare condition itself), and once the sub-stance has been identified with the aid of the over-producer, it usually can be detected in and iso-lated from anyone’s tissue. Thus, while the originalspecimen(s) may have been useful to initially iden-tify an interesting product, its value for commer-cial exploitation is diminished because the sam-ple is not truly rare.

In a few instances, however, a specific biologi-cal substance is sought in a group of individualsto produce a specific quantity of a pharmaceuti-cal product (which may or may not be producedwith the aid of biotechnology). These sources areusually paid for their specimens; the amount paiddepending on a variety of factors, including the

Figure 11 .- Rarity of Human Tissues and CellsUsed in Biotechnology

SOURCE: Office of Technology Assessment, 1987,

number of people who are potential sources. Anexample would be the bleeding of people withchronic hepatitis who have the viral antigen nec-essary to prepare hepatitis B vaccine from humanserum (9). In these isolated instances, a reason.able attempt can be made to determine the ratioof source material to final commodity.

In summary) the issue of rarity in human bi-ological used in biotechnological research

takes the form of a pyramid (see figure 11). Atthe bottom are the vast majority of materials, rela-tively common and easy to obtain (though by nomeans does this irnply an infinite supply). Muchfarther up the pyramid is an intermediate level,where particular samples may exhibit uncommon

characteristics (e.g., the overproducers of certainsubstances mentioned above) or occur in the pop-ulation at a low frequency (e.g., a genetic disorder

like Tay-Sachs). At the top of the pyramid are thefew cases of true uniqueness, which are by defi-nition difficult, if not impossible, to identify in ad-vance of chance discovery. Assigning, a priori}

a value to any one level is not possible sincea commercial product can be developed fromtissues and ceils obtained from any level. Fi-nally, to an increasing degree, both the “uncom-monness” of cell tissue at the intermediate leveland the “rarity” of some specimens at the top levelcan be overtaken by technology. That is, rarityof the original sample is not the only importantfactor because as newer techniques develop, re-searchers are better able to detect novel sub-stances or purify smaller amounts of known com-pounds. Once the peculiarities of the tissue or ceilline have been identified and studied, biotech-niques (e.g., gene cloning) provide a means to re-produce the peculiarity without further need ofthe material itself,

INDUS T Ry

The biotechnology industry is a third major Thestakeholder in the controversy surrounding theuse of human tissues and cells for financial gain. There are nearlyIt is comprised of a variety of different types of ogy firms in the UI ely engagedorganizations including the established pharma- in—biotechnology research and commercial prod-

Companies

350 commercialited States activ.

biotechnol.

ceutical companies, oil and chemical companies,agricultural product manufacturers, and the newbiotechnology companies, A detailed treatmentof commercial biotechnology activities was pub-lished in 1984 by OTA (51); thus this section pro-vides only a brief description of pharmaceutical.related biotechnology companies to give a senseof the current and projected levels of activity inthe industry. This section also discusses the prod-uct development process.

uct development and approximately 25 to 30 per-cent appear to be engaged in research to developa human therapeutic or diagnostic reagent (37),Many companies are developing several humantherapeutic products (see figure 12). Most, but notall, of the human therapeutic products are derivedfrom human tissues and cells, or human cell linesor cloned genes. (Most human diagnostic reagentsare rodent-derived.)

Ch. 4—The Interested Parties ● 5 7

Figure 12.—Number

1

41)

(19)

2 3

of Human

(11)

Therapeutic Biotechnology

(lo)

1(5)

(4)v (2) (2)

(3)

(1)

4 5 6 7 8 9 10 11 12 13 14 15 >15

Projects

(1) (1)

by

Number of products

SOURCE: L 1. Miller, E?iotec/mo/ogy Industry 1986 Fact Book (New York: Paine Webber, 19S6).

58 Ownership of Human Tissues and Cells

In addition to the commercial firms operatingin the United States, there is a strong internationalcomponent to the biotechnology industry, withnumerous research and development arrange-ments and partnerships between American firmsand firms in Japan and Europe. Recent financialstatistics on the top 10 U.S. firms in the industryare provided in table 7.

Through 1985, no new biotechnology firm hadreported annual sales over $100 million or netprofits over $6 million. Revenues in the industryhave come largely from contract research and re-search and development (R&.D) partnerships,rather than product sales (7). Since 1980, the bio-technology industry has raised about $1 billionin corporate and public investments, excludingabout $400 million in R&D limited partnerships(5). Nevertheless, many business analysts considerthat the human biological market has come ofage in the last 2 years, as witnessed by govern-ment approval for marketing of the industry’s firstcommercial therapeutic products.

Table 8 is a business analysis of the human ther-apeutic products (many using human-derived ma-terial) most likely to be marketed in this countryover the next 10 years. The industry as a wholeis actively researching and developing over 100different therapeutic products with commercialpotential, as demonstrated in table 9. Again, many,but not all, of these products use human-derivedmaterial.

The established pharmaceutical industry’s in-volvement in biotechnology indicates that biotech-nology is viewed as commercially valuable. These

Table 7.-Financial Statistics for SelectedBiotechnology Companies (as of Dec. 31, 1985)

Annual sales Net profitsCompany ($ millions) ($ millions)Genentech (CA) . . . . . . . . . . . . . . 89.6 5.6Cetus (CA) . . . . . . . . . . . . . . . . . . 45.9 1.4Biogen (MA) . . . . . . . . . . . . . . . . . 31.4 – 19.1Centocor (PA). . . . . . . . . . . . . . . . 22.4 3.5Amgen (CA) . . . . . . . . . . . . . . . . . 19.8 –1.5Genex (MD). . . . . . . . . . . . . . . . . . 16.2 – 15.9California Biotech (CA). . . . . . . . 9.6 –0.5Collaborative Research (MA) . . . 8.8 4.3Molecular Genetics (MN) . . . . . . 8.3 –2.5Integrated Genetics (MA) . . . . . 7.3 –3.7SOURCE: Shearson Lehman Brothers, Inc. (reprinted in The Economist, Apr. 19,

1966)

established firms provide two significant advan-tages to fledgling, startup companies. First, theexperience and long-term funding capacities ofpharmaceutical firms are believed to be neededfor the extensive product testing phases that mustprecede any commercial marketing of a humantherapeutic product (57). Second, the professionalsales forces of the pharmaceutical companies areseen as necessary for immediate, successful mar-keting of biotechnology products. Major multina-tional pharmaceutical firms based in the United

Table 8.—Estimated U.S. Marketing Date forSome Human Therapeutic Productsa

1982Insulin

198319841985

Human growth hormone1986

Interferon (alpha)Orthoclone OKT-3Hepatitis B vaccine

1987ImmunoagentsImmunocytotoxic agentsImmunotoxinsIMREG-1Interferon (beta)Interferon (gamma)Pro insulinProtein ATissue plasminogen

activator1988

Acylated plasminogenstreptokinase complex

Alpha-1 antitrypsinCalcitoninEpidermal growth factorErythropoietinImmunoradiotherapeutic-Slnterleukin-2Superoxide dismutaseVitamin E microemulsion

1989Atrial natriuretic factorHerpes vaccineHyaluronic acid (anti-

infIammatory)IMREG-2Lipid emulsionProtein CPro-urokinaseTumor necrosis factor

1990Bone morphogenic proteinColony stimulating factor

(alpha)Colony stimulating factor

(GM)Colony stimulating factor

(megakaryocyte)Colony stimulating factor

(granulocyte)Colony stimulating factor

(microphage)Human osteogenic proteinInterferon (gamma

analogue)Interferon (gamma

fragment)Interleukin-1 (alpha)Interleukin-1 betablockerLipocortinLung surfactant protein

1991Factor VIIIC

1992AngiogeninAnti-inflammatorypeptideB-cell factorsBurst promoting activityColony stimulating factor

(G-pluripoietin)Factor IXFertility hormones

(FSH, LH, and HCG)Fibroblast growth factorTissue inhibitor of

metalloproteinasesUrokinase-antibody

conjugate199319941995

Renin inhibitorsaMany, but not ail, Of these therapeutic products contain humanderived material

SOURCE L.1 Miller, EJiotectmo/ogy /ndustry 1986 Fact Book (New York: PaineWebber, 1966).

Ch. 4—The Interested Parties 59

Table 9.—Some Human Therapeutic Products Being Developed by the Biotechnology Industrya

Immune modifiers:Allogeneic effect factorB cell growth factorsBurst promoting activityColony stimulating factor (GM)Colony stimulating factor (alpha)Colony stimulating factor (granulocyte)Colony stimulating factor (microphage)Colony stimulating factor (megakaryoctye)Colony stimulating factor (G-pluripoietin)Colony stimulating factor (other)D-glutamic acid, d-lysine conjugatesDesacetylthymosin alpha-1lgE peptidesIMREG-1IMREG-2Interferon (alpha)Interferon (alpha) receptorInterferon (beta)Interferon (gamma)Interferon (gamma analogue)Interferon (gamma fragment)Interferon (gamma) receptorInterferon analogueInterferon inducerInterferon-interleukin hybridInterleukin-1 (alpha)Interleukin-1 (beta)Interleukin-1 antagonistInterleukin-1 receptorlnterleukin-2lnterleukin-2 analoguelnterleukin-2 in Iiposomeslnterleukin-2 receptorlnterleukin-3lnterleukin-4LipocortinMicrophage activating factorMicrophage migration inhibiting factorMicrophage peptidesMonoclinal antibodies to T cellsMonoclinal antibodies to HLA antigensMonoclinal antibodies to lnterleukin-2

receptorOrthoclone OKT-3Protein AProtein A analogueSuppressive factor of allergySuppressor factor LSuppressor factor SSuppressor factors, otherT cell suppressor inducer factorTissue inhibitor of metalloproteinasesXL factorXN factor

Anticancer therapy agents:AmpligenAngiogeninAnaiaoaenesis inhibitor

. . . .AntlCellular factorsCytotoxic glycoproteinDetoxHuman endogenous regulatory factorsImmunoagentsImmunocytotoxic agentsImmunoradiotherapeuticsImmunotoxinsLectinLymphotoxinMinactivinOH-1OncostatinOvamidTumor growth inhibitor factorsTumor necrosis factorTumor necrosis factor KBS

Blood proteins/enzymes:Acylated plasminogen streptokinase

complexPEG-Adenosine deaminaseAlpha-1 antitrypsinAntithrombin IllApolipoprotein-EPEG-AsparaginasePEG-CatalaseCoagulation agentsElastaseElastase inhibitorEnzyme 1Enzyme 2ErythropoietinFactor VIIICFactor IXFactor XaFibrinolytic agentsHementinHemopoietin-lHirudinHuman serum albuminLipoproteinsLung surfactant proteinLysozymeProtein CPro-urokinaseRenin inhibitorsRenin monoclinal antibodyStreptokinaseStreptokinase complexSuperoxide dismutaseSuperoxide dismutase analoguePEG-Superoxide dismutaseExtracellular superoxide dismutaseTissue plasminogen activatorTrypsin inhibitorUrokinaseUrokinase antibody conjugatePEG-U rokinasevon Willebrand factor

aMany~ ~ut-not all, of these therapeutic products COfMi3in humanderived material.

Hormones:AngiogeninAngiogenic factorAngiogenesis factorAtrial natriuretic factorAtrial natriuretic factor analogueBone morphogenic proteinBone growth factorsCalcitoninCalcitonin analogueCalcitonin gene related peptideCalcitonin precursorCartilage inducing factor (a)Cartilage inducing factor (b)Connective tissue activator proteinCNS growth factorEnkephalinesEpidermal growth factorFertility hormonesGonadotrophin releasing hormoneGrowth associated proteinGrowth hormone releasing factorHuman growth hormoneHyaluronic acidInhibinInsulinInsulin receptorLuteinizing hormone releasing hormoneNerve growth factor (beta)Neuropeptide YNeurotransmitter agentsNeurotrophic factorsOxytocinParathyroid hormone inhibitorsPlatelet derived growth factorProinsulinProlactin-release inhibiting factorRelaxinSecretinSomatomedin CSomatostatinSomatostatin analogueSomatostatin peptidesTetragastrinThyrotropin releasing hormoneTransforming growth factor (alpha)Transforming growth factor (beta)Vasopressin

Other products:Chimeric antibodiesEncapsulated islet cellsMonoclinal antibodies against human

proteinsVaccines for contraceptionVaccine for Epstein-Barr virus-induced

malignant IymphomaVaccine for lung cancerVaccine for melanoma

SOURCE: L.1. Miller, E7iotechrro/ogy /rrdushy 19S6 Factbook (New York: Paine Webb@r, 19S6).

60 ● Ownership of Human Tissues and Cc//s

States budget between $300 million and $400 mil- a detailed process of research, development, andlion annually for research and development (5). testing before the product can be marketed.

Studies of the conventional pharmaceutical de-

Industrial Product Development velopment process have shown that only about12 percent of the drugs that enter the human test-

The Food and Drug Administration (FDA) re- ing - process reach the marketplace, and that thequires a biopharmaceutical product to undergo testing process itself is lengthy and costly (24). The

Ch. 4—The Interested Parties • 61

Figure 13.—The Development of Angiogenin

1930

1960

1991

1992

PrOCeSS of angiogenesis first

described

Additional report on process

Additional report on process

Additonal report on process

Monsanto. Harvard agreement signedHT 29 cell Iine isolated

Partial purification using HT 29cell conditioned mediumMolecule purified. cloned, separated

Expected U S marketing ofangiogenin

SOURCE” Off Ice of Technology Assessment, 1987

cost associated with bringing a single new prod-uct to the marketplace is on the order of $65 mil-lion to $100 million (spread over several years ortwo to three decades) (4). In general, the biophar-maceutical product development process includesthe

●

●

●

●

●

following steps:

Research: Identification and purification ofthe natural protein; characterization of themolecule, often including genetic engineer-ing technology to produce the product.Research and Development: Improvementof product yield, initial formulation, and lab-oratory testing.Development: Formulation of the productinto a pharmaceutical; preparation and scale-up of product manufacture.Preclinical Testing: Animal testing for acuteor long-term toxicity and activity of the product.Clinical Testing—Physician IND: Humanpatient testing at one or more clinical centerswhere the actual application for testing has

●

●

●

●

been filed by a physician, rather than the cor-poration.Clinical Trials-Phase I: Patient trials to de-termine drug safety and appropriate dosingschedules with only modest information re-garding efficacy generated.Clinical Trials-Phase II: Broadened clini-cal patient trials to determine drug efficacyin one or more indications.Clinical Trials-Phase III: Advanced clini-cal patient trials to determine drug efficacyin one or more indications.Product License Approval Filing: Materi-als filed with the FDA to apply for marketingapproval (36).

While it is difficult to predict whether all phar-maceuticals produced by biotechnology will emu-late traditional pharmaceuticals, it is likely thatstandard government requirements for testing ofpharmaceutical products will apply to all biotech-nology products (51 FR 23309).

University-Industry Relationships

A critical aspect of the controversy surround-ing the use of undeveloped human tissues and cellsis the increasing overlap between the spheres oftwo of the interested parties: the research commu-nity and the biotechnology industry. University-industry research relationships in biotechnologyassume a variety of forms, and these relationshipsare of relatively recent vintage. One estimate in-dicates that the total amount of money industrysupplied to universities for biotechnology researchin 1984 was about $120 million, accounting for16 to 24 percent of all funds for biotechnologyR&D available to institutions of higher educationthat year (11).

Faculty consulting and research relationshipsbetween individual professors and corporationscan

●

●

●

include:

single or occasional visits and interchanges,informal collaboration;formal collaboration with or without consult-ing arrangements;consulting arrangements with or without for-mal collaboration (exclusive or nonexclusive);and

62 . Ownership of Human Tissues and Cells

● formal exclusive relationships with under-stood financial commitments and patentrights.

Faculty may also be involved with scientific advi-sory boards for biotechnology companies and maybe offered some type of restricted stock or stockoptions not generally awarded to external con-sultants.

Relationships between universities and cor-porations can include:

●

●

●

In

corporate contributions, directed or un-directed or in the form of fellowships;industrial procurement of particular services,for example, education and training or con-tract research;industrial affiliates;

●

●

●

●

●

cooperative research;privately funded research centers, with ei-ther a single funder or multicorporatesponsors;long-term contracts, such as those betweenMonsanto and Harvard or Exxon and Massa-chusetts Institute of Technology;university-controlled companies set up to de-velop commercial potential from universityresearch; andprivate companies that secure patent rightsfor resale (30).

The implications for a market in human speci-mens involving researchers, universities, uni-versity-industry partnerships, and industry arediscussed in detail in chapter 7.

FEE-FOR-SERVICE RESEARCH

addition to the commercial biotechnologyfirms and basic research members of the researchcommunity, a novel party that uses human tis-sues and cells has emerged. In 1984, the first for-profit company offering personalized cancer treat-ments was established in Franklin, TN. Biother-apeutics, Inc., was founded by R.K. Oldham,former director and founder of NCI's BiologicalModifiers Program, and W.H. West, his colleague.A second branch in La Jolla, CA, is scheduled toopen soon. It is a pioneer in what has been termed‘(fee-for-service” research: the company offersservices to individuals who can afford to bear thecosts of the research protocol involved in the can-cer treatment (32).

As one part of its program, Biotherapeuticsmakes hybridomas producing monoclinal anti-bodies unique to an individual’s tumor. These mon-oclinal antibodies are used with a mixture of othermonoclinal antibodies (produced in response totumors from other individuals) to treat the pa-tient’s tumor. The current cost of participatingin the full service, not covered by conventionalinsurance policies, is $35,000. A $2)750 fee is

charged for processingtient’s tumor for future

and preserving the pa-use in therapy. Patient-

funded research accounted for approximately 65percent of Biotherapeutics’ total revenues.

Biotherapeutics also uses interleukin-2, a lym-phokine, to activate certain cells of the patient tobecome “lymphokine-activated killer cells.” Thesecells can attack tumor cells in some individuals.The therapy regimens offered at Biotherapeuticsare in use as experimental treatments elsewhere,particularly at NCI (32). Unlike other programs,however, patients at Biotherapeutics bear the costof their individualized research/treatments. Per-sons contracting with Biotherapeutics waive allrights to “any cell line, reagent, product, approach,or properties that may be derived from tumortissue, blood, or other specimens . . ,“ (8).

At present, Biotherapeutics is a unique combi-nation of business, therapeutic institution, and re-search venture that uses human biological mate-rials. About 200 patients have been treated at theTennessee facility, and it is difficult to evaluatewhether fee-for-service research companies willbe an important interested party in the future.

Ch. 4—The Interested Parties ● 63

SUMMARY AND CONCLUSIONS

In addition to scientific advances in biotechnol-ogy, the legal and economic considerations sur-rounding research on human biological havechanged in the past decade. Many parties nowhave an interest in developing human tissues andcells: the source, the physician (or physician/researcher), the researcher, the university, andthe biotechnology company. And, importantly, thespheres in which these parties operate are fre-quently intertwined—making resolution of con-flicts difficult.

The ability to patent novel life forms createdthrough biotechnology has spurred interest in de-veloping human tissue and cells into marketableinventions. The crucial element of patentabil-ity for most biological inventions in the UnitedStates, as shown in the Chakrabarty case, wasthe fact that the substance was in some waychanged from the naturally occurring sub-stance by human intervention. This decision,coupled with technical advances in biotechnology,has resulted in increased interest in developingprimary human biological material into market-able products.

Patients, healthy research subjects, and cadaversare all sources of undeveloped human tissues andcells, providing both normal and diseased speci-mens. As a general principle, sources of specimensare not paid for the types of samples most com-monly used in biotechnology research. Volunteerresearch subjects, however, may be reimbursedfor time or out-of-pocket expenses.

The research community, including both univer-sity and industry scientists, obtains human speci-mens for a broad spectrum of uses. These tissuesand cells may be sought for single experimentsas well as for the long-term development of celllines or cloned genes. A sample might also be useddirectly to extract a commercial product. Re-searchers obtain human biological materials viamany avenues, ranging from ad hoc agreementswith local hospitals to federally supported col-lections.

In most cases, it is difficult to ascertain thecontribution of anyone individual’s sample toa final commercial product. Moreover, becausethe process of research is a continuum, the ex-pectation of developing a commercial product atthe outset of research is extraordinarily small.Atypical human tissues and cells are sometimesdiscovered, however, and can be valuable to theR&D process of a marketable human commodity.

Recently, researchers and universities havesought innovative methods to fund research. Theemerging presence of the biotechnology indus-try has become a logical partner in such researchfunding, and consequently a number of university-industry or investigator-industry arrangementshave developed. These arrangements range frominformal colfunding.

—laboration to formal contracting or

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64 ● Ownership of Human Tissues and Cells

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35

36

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Ch. 4—The Interested Parties ● 6 5

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