Legal

1
Legal Ethical Perspectives on
the Role of Intellectual Property in Human Tissue
Research

• Amy R. Schofield, JD, MPH
• San Francisco, CA
• aschofield_at_kirkland.com

2
Overview

• Context
• Patents generally
• Commercializing patented inventions
• Patenting and commercializing human tissue
  inventions
• Legal precedent re human tissue ownership
• Ethical perspectives on human tissue ownership

3
How Did We Get Here?

• Biotechnology innovations of the 1970s (e.g.,
  PCR)
• Legislation intended to spur commercialization of
  American innovation
• Bayh-Dole Act (1980)
• Changing role of U.S. universities in the
  marketplace
• Dramatic increase in human tissue patent
  applications
• Court decisions allowed patents for broad range
  of biotechnology innovations
• Diamond v. Chakrabarty (1980)

4
Patents Generally
5
What is a Patent?

• A bundle of property rights
• Permits the patent owner to exclude others from
• Making
• Using
• Selling
• Offering for sale
• Importing
• the claimed invention
• But does not necessarily permit the patent owner
  to lawfully practice the claimed invention

6
Patent Policy

• A patent is, essentially, a government-sanctioned
  monopoly
• Term of monopoly 20 years from filing
• Justifications
• Spur scientific innovation and progress
• Increase general knowledge
• The statutory criteria for patentability are
  intended to ensure these policy goals are
  realized
• Novelty and nonobviousness
• Written description and enablement

7
Anatomy of a Patent

• Specification (including drawings)
• Claims
• Prosecution history
• Cited references
• The scope of an invention is defined by the
  claims
• That is, patentability is assessed with reference
  to the claim language and not the specification
  as a whole
• The specification informs the meaning of the
  claims

8
Criteria for Patentability

• Patentable subject matter (35 U.S.C. 101)
• Process
• Machine
• Manufacture
• Composition of matter
• Improvement thereof
• Utility (35 U.S.C. 101)
• Novelty (35 U.S.C. 102)
• Nonobviousness (35 U.S.C. 103)
• Enablement (35 U.S.C. 112)
• Adequate written description (35 U.S.C. 112)

9
Limits on Patentability

• The following are not patentable
• Laws of nature
• Physical phenomena
• Abstract ideas
• No morality requirement
• Contra European Patent Office

10
Patentable Subject Matter

• Anything under the sun that is made by man
• Modification of naturally-occurring organism
  yields patentable composition of matter
• Diamond v. Chakrabarty (1980) (Genetically-modifie
  d bacterium patentable because the patentee has
  produced a new bacterium with markedly different
  characteristics from any found in nature)
• Isolated nucleic acid sequences
• In vitro human tissue preparations having
  specified properties

11
Patentable Subject Matter

• What types of inventions result from human tissue
  research?
• Compositions of matter
• Isolated human tissue cells and preparations
  thereof
• Cell lines
• Therapeutics
• Processes
• Methods of isolating human cell preparations
• Methods of culturing cell lines
• Methods of treatment
• Research tools v. end-user applications
• Diagnostic kits and methods?

12
Commercializing Patented Inventions
13
Commercializing Patented Inventions

• How does a patent holder realize a profit on
  his/her invention?
• Sale
• License
• Exclusive v. nonexclusive
• Geographic regions
• Field of use
• Challenge of moving inventions from bench to
  bedside

14
The Bayh-Dole Act (35 U.S.C. 200-212 (1980))

• Perception in the late 1970s that America was
  falling behind in technological innovation
• Indications that government-funded inventions
  were languishing on the shelves (i.e.,
  bench-to-bedside transition not happening)

15
The Bayh-Dole Scheme

• Grantees own inventions made with government
  funds and the patents on those inventions
• Grantees are permitted (indeed, encouraged) to
  license those inventions to promote
  commercialization
• Licenses to nonprofit or for-profit entities
• Exclusive or nonexclusive licenses
• Terms as grantee sees fit
• Grantee does not owe the government royalties or
  other payments
• Government retains a right to practice the
  claimed inventions
• March-in rights never exercised

16
Bayh-Doles Success

• Has Bayh-Dole achieved its stated goal of
  increasing commercialization?
• 5000 new products from 1998-2007 (686 in 2007)
• Most visible results
• Changing nature of academic research institutions
• Technology transfer offices
• Dramatic increases in RD funding from
  corporations
• Start-ups/spin-offs (gt6200 from 1980-2007 555 in
  2007)
• Increasing number of patent applications filed by
  universities and non-profit organizations
• 250 in 1980, gt11,700 in 2007
• See, e.g., Association of University Technology
  Managers (AUTM) Licensing Activity Surveys,
  available at www.autm.net.

17
Patenting and Commercializing Human Tissue
Inventions
18
Why is Commercialization of Human Tissue Patents
So Controversial?

• Human body parts/tissues should not be
  commodified (See, e.g., D. Nelkin L.
  Andrews, homo Economicus Commercialization of
  Body Tissue in the Age of Biotechnology, 28
  HASTINGS CTR. REP. 30 (1998))
• Gut reaction
• Religious influences
• Larger societal debate about health care
• Misunderstandings about patent scope?

19
Why is Commercialization of Human Tissue Patents
So Controversial?

• Human tissue patents hinder data sharing among
  scientists
• Recall a patentee is granted a 20-year monopoly
  in exchange for full disclosure of invention to
  the public
• However, at least some studies suggest that
  researchers are withholding data to preserve
  patent rights (See Campbell et al., Data
  Withholding in Academic Genetics Evidence from a
  National Survey, J.A.M.A. (2002) 287(4) 473-80)
• Inventions previously known by, disclosed to, or
  used by the public are not novel under the patent
  laws (35 U.S.C. 102)
• Suppression of adverse findings
• Washington University v. Catalona, 437 F. Supp.
  2d 985 (E.D. Mo. 2006), affirmed by 490 F.3d 667
  (8th Cir. 2007)

20
Why is Commercialization of Human Tissue Patents
So Controversial?

• Human tissue patents impede scientific research
• Patents granted on research tools most
  controversial
• Isolated gene sequences needed to carry out
  genetic tests
• Cell lines
• Diagnostics
• Research-tool patents expose tensions underlying
  the patent system
• Knowledge sharing v. monopoly

21
Do Patents Really Impede Research?

• Studies suggest that scientists engaged in
  research routinely use patented research tools
  without obtaining a license from the patent owner
  (See John P. Walsh et al.,
  Research Tool Patenting and Licensing and
  Biomedical Innovation, in PATENTS IN THE
  KNOWLEDGE-BASED ECONOMY 285-340 (S. Merrill et
  al. eds., 2003)
• Research exemption
• Patent invalidity
• Widely-held belief that corporations will not sue
  university researchers due to lack of monetary
  damages and bad publicity

22
Do Patents Really Impede Research?

• However, Federal Circuit precedent clearly
  indicates that the research exemption is very
  narrow and strictly limited in application.
• Madey v. Duke, 307 F.3d 1351 (Fed. Cir. 2003)
• The exemption applies only to research undertaken
  solely for amusement, to satisfy idle curiosity,
  or for strictly philosophical inquiry. (Id. at
  1362)
• Contra Merck KGaA v. Integra Lifesciences I,
  Ltd., 545 U.S. 193 (2005)
• Statutorily-specified research exemptions
  (Hatch-Waxman)
• Research reasonably related to exemption

23
Do Patents Really Impede Research?

• Our precedent clearly does not immunize use that
  is in any way commercial in nature. Similarly,
  our precedent does not immunize any conduct that
  is in keeping with the alleged infringers
  legitimate business, regardless of commercial
  implications. For example, major research
  universities, such as Duke, often sanction and
  fund research projects with arguably no
  commercial application whatsoever. However,
  these projects unmistakably further the
  institutions legitimate business objectives,
  including educating and enlightening students and
  faculty participating in these projects. These
  projects also serve, for example, to increase the
  status of the institution and lure lucrative
  research grants, students and faculty. Madey at
  1362 (emphasis added).

24
Why is Commercialization of Human Tissue Patents
So Controversial?

• The prospect of commercialization undermines the
  mission of academic research institutions
• Changing role knowledge generation and
  dissemination to profits?
• Recall Madey opinion
• Potential for conflicts of interest
• Start-ups and spin-offs
• Corporate funding of scientific laboratories

25
Why is Commercialization of Human Tissue Patents
So Controversial?

• Negative impacts on health care delivery
• The prospect of commercialization jeopardizes the
  integrity of the doctor-patient relationship
• Human tissue patents increase the costs of
  patient care and, in some cases, prevent access
  to necessary diagnostics and/or treatments

26
Human Tissue Research Subjects and
Commercialization

• What happens when a patented invention derived
  using body fluids or tissue samples from human
  research subjects is commercialized?
• Do those individuals own the patent?
• Are those individuals entitled to share in the
  financial benefits the patent yields?
• Can those individuals control the extent to which
  the patent is asserted against potential
  infringers?
• Do individuals have a right to prevent the use of
  their body fluids or tissues in the development
  of patented inventions and/or commercialized
  products?

27
Human Tissue OwnershipLegal Precedent
28
Moore v. Regents of the University of California,
793 P.2d 479 (Cal. 1990)

• The (disputed) facts
• John Moore underwent treatment for hairy-cell
  leukemia at UCLA Medical Center in 1976.
• This treatment included the withdrawal and
  testing of numerous bodily fluids, as well as the
  removal of Moores spleen upon his doctors
  recommendation.
• Moores doctor instructed him to return to UCLA
  Medical Center numerous times for additional
  testing over the next 7 years.

29
Moore, cont.

• Unbeknownst to Moore, his doctor was conducting
  research using the cells obtained during his
  testing and treatment.
• In 1981, Moores doctor applied for a patent on a
  cell line established from Moores T-lymphocytes.
• U.S. Patent No. 4,438,032 issued on March 20,
  1984.
• UCLA licensed the patent to Genetics Institute
  (GI), and Moores doctor received 75,000 shares
  of GI stock and more than 400,000 in
  compensation pursuant to the license.

30
Moore, cont.

• Upon learning his cells had been patented and
  commercialized, Moore sued his doctor and UCLA
  claiming
• Violation of the doctor-patient relationship
  (breach of fiduciary duty) and lack of informed
  consent and
• Interference with his possessory and ownership
  interests in his personal property (conversion).

31
Moore, cont.

• The Court held that Moores doctor had violated
  the doctor-patient relationship and failed to
  obtain Moores informed consent.
• A doctor must disclose personal interests in
  medical procedures if those interests are
  unrelated to the patients health and may affect
  the doctors medical judgment.
  See Moore, 793 P.2d at 485.
• These personal interests may be research-related
  or economic.

32
Moore, cont.

• However, the Court concluded that Moore retained
  neither a possessory nor an ownership interest in
  his cells after they were removed. See id. at
  487-89.
• The threat of liability will chill downstream
  medical research.
• The patented cell line is distinct from the cells
  removed from Moores body.
• Commodification of the human body is immoral.
  See id. at 497-98 (Arabian, J., concurring).

33
Uncertainties After Moore

• Would the Courts decision have differed if the
  researcher and the tissue donor were not in a
  doctor-patient relationship?

34
Greenberg v. Miami Childrens Hosp. Research
Inst., Inc., 264 F. Supp. 2d 1064 (S.D. Fla. 2003)

• In 1987, families of persons suffering from
  Canavan disease formed a collaboration with Dr.
  Reuben Matalon to identify the disease gene.
• The families, in association with several
  nonprofit organizations, located other Canavan
  families throughout the world and convinced those
  families to provide tissue samples, familial
  pedigrees, and financial support.
• Using these resources, Dr. Matalon isolated the
  Canavan gene in 1993.

35
Greenberg, cont.

• In 1994, Dr. Matalon filed a patent application
  on the Canavan disease gene without informing the
  families.
• U.S. Patent No. 5,679,635 issued in October 1997.
• In 1998, Dr. Matalon and his employer, Miami
  Childrens Hospital (MCH), initiated an
  aggressive campaign to restrict use of the
  Canavan test through (lucrative) exclusive
  licensing agreements.

36
Greenberg, cont.

• Upon learning of the patent and licensing scheme,
  the families sued Dr. Matalon and MCH on numerous
  grounds, including
• Violation of a fiduciary duty and lack of
  informed consent
• Interference with their possessory and ownership
  interests in their personal property
  (conversion) and
• Unjust enrichment.

37
Greenberg, cont.

• The Court concluded that medical researchers have
  no duty to disclose their economic interests in
  research to research subjects.
  See Greenberg, 264 F.
  Supp. 2d at 1069-70.
• Imposition of such a duty would chill downstream
  medical research.
• But note The Court found that in certain
  circumstances a medical researcher does have a
  duty of informed consent with respect to
  non-economic interests. See id. at 1070.
• Citing Moore, the Court concluded that the
  families retained neither a possessory nor an
  ownership interest in their donated tissues.
  See id. at
  1074-76.

38
Greenberg, cont.

• However, the Court held that a trial was need to
  determine whether Dr. Matalon and MCH had
  unjustly obtained a financial benefit using the
  resources provided by the families.
  See id. at 1072-73.
• The Court noted that, in certain circumstances,
  the procurement and enforcement of a gene patent
  may give rise to an unjust enrichment claim. See
  id. at 1072.
• Following this decision, the case settled on
  undisclosed terms.

39
Uncertainties After Greenberg

• If the research subjects dont own their tissue
  samples, who does?

40
Washington Univ. v. Catalona, 437 F. Supp. 2d 985
(E.D. Mo. 2006), affd 490 F.3d 667 (8th Cir.
2007)

• Dr. William Catalona was a prominent urologic
  surgeon at Washington University
• Dr. Catalona also conducted prostrate cancer
  research as part of his employment
• Dr. Catalona collected blood and tissue samples
  from his surgical patients for use in research
  re the genetic bases of prostrate cancer

41
Catalona, cont.

• Dr. Catalona helped to establish the
  Genito-Urinary (GU) Repository at Washington
  University to hold the collected samples
• The GU Repository also held samples collected by
  Dr. Catalonas colleagues
• GU Repository holds approximately 109,000 total
  samples, 3,000 of which were derived from Dr.
  Catalonas patients
• Patients contributing to the GU Repository
  executed informed consent forms
• Patients contributions referred to as
  donations
• Patients waived all claims to donated materials
  and to any materials and processes developed
  from them

42
Catalona, cont.

• In 2003, Dr. Catalona transferred to Northwestern
  University and sought to take the GU Repository
  samples with him
• Dr. Catalona contacted patients and requested
  they transfer their samples to him
• Approximately 6,000 patients did so

43
Catalona, cont.

• The Court held that individuals who make an
  informed, voluntary decision to contribute their
  biological materials to a particular research
  institution for the purpose of medical research
  do not retain an ownership interest in those
  materials
• Individuals cannot direct or authorize the
  transfer of their materials to a third party.
• The contributions were inter vivos gifts to
  Washington University
• Under Missouri law, Washington University took
  absolute ownership immediately upon delivery
• Pursuant to the informed consent forms, patients
  retained only the right to withdraw from the
  study and have their samples destroyed

44
Practical Implications

• A researcher must disclose his/her financial
  interests in the research to a research subject
  only if the researcher and the subject are in a
  doctor-patient relationship.
• A research subject does not retain any ownership
  interest in his/her tissue samples.
• A research subject does not retain any right to
  the financial benefits arising from patents and
  commercialized products derived from his/her
  tissue samples.

45
Practical Implications

• This status quo is reflected in the following
  exemplary informed consent form paragraph
• Discoveries made with your DNA samples may be
  patented by us and the University. These patents
  may be sold or licensed, which could give a
  company the sole right to make and sell products
  or offer testing based on the discovery.
  Royalties may be paid to us, the University, and
  the Sponsor. It is not our intent to share any
  of these possible royalties with you.
• Jon F. Merz et al., Protecting Subjects
  Interests in Genetics Research, 70 AM. J. HUM.
  GENET. 965 (2002).

46
Human Tissue OwnershipEthical Perspectives
47
Ethical Approaches to Moore, Greenberg, and
Catalona

• The correct legal decision isnt always the most
  ethical one
• Framework for ethical analyses
• Beneficence (do no harm)
• Autonomy
• Justice

48
Defining Benefits to Research Subjects

• Direct therapeutic benefit
• Therapeutic benefit to others
• Generalizable knowledge
• Personal and/or emotional fulfillment
• Payment for participation/contribution

49
Defining Benefits to Researchers

• Prestige
• Wealth
• Professional advancement
• Intellectual and personal satisfaction
• Societal contributions

50
Defining Benefits to Society

• Information
• Treatments
• Social progress
• Interconnection

51
Autonomy and Informed Consent

• Federal regulations require informed consent for
  some but not all human tissue research
• Anonymized
• Minimal risk
• Not focused on autonomy per se but rather
  giving human subjects the opportunity to decide
  how their interests are best protected
• R. Alta Charo, Body of Research - Ownership and
  Use of Human Tissue, 355 NEJM 15 1517-19 (2006)
• Ascertaining how human subjects want their tissue
  used may be an ethical requirement, but it is not
  a legal one
• See, e.g., Havasupai litigation

52
Autonomy and Conflicts of Interest

• Human Genome Organization (HUGO)
• The human genome project is part of the common
  heritage of humanity.
• Any actual or potential conflict of interest
  should be revealed at the time information is
  communicated and before agreement is reached.
• Human Genomes Organization Council, STATEMENT ON
  THE PRINCIPLED CONDUCT OF GENETICS RESEARCH
  (1996).

53
Justice How to Distribute Financial Benefits of
Research

• No sharing of financial benefits
• Fixed or minimal financial compensation to
  research subjects
• Proportional financial compensation to research
  subjects
• Alternative, non-monetary benefits

54
Justice No/Minimal Compensation

• Human Genomes Organization Council
• The actual or future benefits discussed should
  not serve as an inducement to participation. Nor
  should there be any financial gain from
  participation in genetic research. This does not
  exclude, however, the possibility of
  reimbursement for an individuals time,
  inconvenience and expenses (if any), even if
  there is a general distribution of benefits to
  the community.
• Human Genomes Organization Council, STATEMENT ON
  BENEFIT-SHARING (2000).

55
Justice Proportional Compensation

• Some commentators have suggested that benefits
  of genetic research, including financial
  benefits, should be distributed equitably among
  all individuals who contribute to the research.
• Contribute ? invent
• Contributing individuals can then negotiate among
  themselves the terms on which benefits are
  distributed and the form in which benefits are
  taken.
• See, e.g., Jon F. Merz et al., Protecting
  Subjects Interests in Genetics Research, 70 AM.
  J. HUM. GENET. 965 (2002).

56
Justice Alternative Benefits

• Some organizations advocate sharing of
  alternative benefits
• Undue influence through compensation for
  individual participants, families, and
  populations should be prohibited.
• This prohibition, however, does not include
  agreements with individuals, families, groups,
  communities or populations that foresee
  technology transfer, local training, joint
  ventures, provision of health care or
  agreements on information infrastructures,
  reimbursement of costs, or the possible use of a
  percentage of any royalties for humanitarian
  purposes.
• Human Genomes Organization Council, STATEMENT ON
  THE PRINCIPLED CONDUCT OF GENETICS RESEARCH
  (1996).

57
Justice Alternative Benefits

• HUGO Statement on Benefit-Sharing
• Recognizes the increasing commercialization of
  government and nonprofit research.
• Prior consultation with individuals and
  communities and their involvement and
  participation in the research design is a
  preliminary basis for the future distribution of
  benefit and may be considered a benefit in
  itself. Such prior discussion should include
  consideration of affordability and accessibility
  of eventual therapy, and preventative and
  diagnostic products of research.

58
Practical Implications

• Inventions derived from human tissue samples may
  be ethically acceptable, but those covering DNA
  sequences and research tools should be subject to
  particular scrutiny.
• Ethical principles suggest that a researcher
  should disclose his/her financial interests in
  the research to a research subject even if the
  researcher and the subject are not in a
  doctor-patient relationship.
• A research subject should not receive financial
  compensation for participating in human tissue
  research, but sharing of alternative benefits may
  be appropriate.

59
Unanswered Questions

• Does this status quo fairly allocate the benefits
  of genetic research among researchers, research
  sponsors, and research subjects?
• A patient may opt-out of research with commercial
  implications or opt-in without sharing in the
  financial benefits, but a patient may not opt-in
  and share in the financial benefits.
• Static presumption that research subjects
  participate for altruistic purposes despite the
  explosive growth in commercialized research.
  See, e.g., Jon F. Merz et al., Protecting
  Subjects Interests in Genetics Research, 70 AM.
  J. HUM. GENET. 965, 969 (2002).

60
Novel Benefit-Sharing Approaches

• In recent years, patient advocacy groups have
  negotiated benefit-sharing agreements with
  researchers to control the terms on which
  patented inventions derived from their genetic
  samples are available to the public.

61
Negotiated Benefit Sharing

• PXE International
• Sharon Terry, mother of children affected by rare
  genetic disease (pseudoxanthoma elasticum),
  formed the PXE International advocacy group in
  1995.
• PXE International created a patient registry and
  tissue repository.
• PXE International granted researchers access to
  its tissue repository only after they agreed to
  jointly share any intellectual property resulting
  from their research.

62
Negotiated Benefit Sharing

• PXE International, cont.
• Ms. Terry worked with scientists at the
  University of Hawaii to discover the PXE gene and
  is named as a co-inventor on the gene patent
  (U.S. Patent No. 6,780,587).
• All rights in the patent have been assigned to
  PXE International, who licensed the diagnostic
  rights to Transgenomic. PXE International and
  Transgenomic are working together to develop an
  FDA-approved diagnostic test for PXE and bring
  the test to market.
• See Paul Smaglik, Tissue Donors Use Their
  Influence in Deal Over Gene Patent Terms, 407
  NATURE 821 (2000) PXE International, U.S. Patent
  Office Issues First Gene Patent to Patient
  Advocacy Group (Aug. 24, 2004), available at
  www.pxe.org.

63
Negotiated Benefit Sharing

• Genetic researchers should expect savvy, cohesive
  advocacy groups to condition the provision of
  their biological samples upon the execution of
  contractual agreements that ensure the subjects
  at least some control over the commercialization
  of derivative inventions.
• But, how many groups truly have this leverage?
• Size
• Disease prevalence
• Practicality

64
Other Approaches

• Mediation

See www.bioethics.upenn.edu