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Patenting Human Genes and Genetic Tests: Recent Developments

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Patenting Human Genes and Genetic Tests: Recent Developments National Advisory Council on Human Genome Research May 17, 2010 Jorge L. Contreras Washington University ... – PowerPoint PPT presentation

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Title: Patenting Human Genes and Genetic Tests: Recent Developments


1
Patenting Human Genes and Genetic Tests Recent
Developments
  • National Advisory Council on Human Genome
    Research
  • May 17, 2010
  • Jorge L. Contreras
  • Washington University in St. Louis
  • School of Law
  • Pilar N. Ossorio
  • University of Wisconsin

2
Requirements for Patentability
  • Patentable subject matter (101)
  • Utility (101, 112)
  • Novelty (102)
  • Non-obviousness (103)

3
Topics
  • Patentable subject matter
  • Association for Molecular Pathology v. USPTO
    (a/k/a ACLU v. Myriad) (S.D.N.Y. Mar. 2010)
  • Utility
  • Eli Lilly v. Human Genome Sciences (UK Ct.
    Appeal, Feb. 2010)
  • Non-obviousness
  • KSR v. Teleflex, US Supreme Ct. (2007)
  • In re Kubin, Fed. Cir. (2009)
  • SACGHS Report on Gene Patents (Feb. 2010)

4
Patent Law
  • The intellectual property right is defined by a
    claim. Claims come at the end of a narrative
    description of the invention and the problem the
    invention is intended to solve. E.g.,
  • I claim an isolated nucleic acid molecule
    comprising a polypeptide at least 80 identical
    to amino acids 22 - 221 of SEQ ID No. 2, wherein
    the polypeptide binds CD48.

5
Patent Litigation
6
Patentable Subject Matter
7
Patentable Subject Matter
  • 35 USC 101 Whoever invents or discovers any new
    and useful process, machine, manufacture, or
    composition of matter, or any new and useful
    improvement thereof, may obtain a patent
    therefor, subject to the conditions and
    requirements of this title.

8
Association for Molecular Pathology v. USPTO
(S.D.N.Y. Mar. 2010)
9
BRCA1 and Myriad Background
  • Early 1980s various groups (incl. Collins) begin
    to seek DNA sequences associated with breast
    cancer
  • 1988/89 Intl. Breast Cancer Linkage Consortium
    established
  • 1990 Mary-Claire King (Berkeley) linkage
    analysis paper locating BRCA1 on long arm of
    chromosome 17
  • 1991 Mark Skolnick (w/ W. Gilbert and P.
    Meldrum) founds Myriad to search for breast
    cancer genes
  • Funding VC, Lilly, NIH (5M to Univ. UT)
  • Aug. 1994 Myriad (w/ NIEHS, Univ. UT, McGill
    Lilly) clones BRCA1
  • Myriad files patent application on BRCA1

10
BRCA2 and Myriad
  • Sept. 1994 BRCA2 localized through linkage
    analysis to chromosome 13
  • 1995 BRCA2 race between Myriad and UK team
    (Michael Stratton at ICR and Sanger)
  • Dec. 18, 1995 Myriad files US patent on BRCA2
  • Dec. 22, 1995 Stratton announces sequencing of
    BRCA2 and files UK patent
  • Dec. 23, 1995 Stratton BRCA2 paper appears in
    Nature Myriad releases sequence to GenBank

11
Myriad Patent Timeline
  • Oct 1991 Univ. UT grants Myriad exclusive
    license to BRCA1
  • Aug. 1994 Myriad files BRCA1 application
  • Nov. 1994 Univ. UT grants Myriad exclusive
    license to BRCA2
  • Dec. 1995 Myriad files BRCA2 application
  • Dec. 1997 first BRCA1 patent issues
  • Nov. 1998 first BRCA2 patent issues

12
Competing Rights
  • NIH
  • Initial Myriad BRCA1 application omitted NIH
    inventors Wiseman, Futreal
  • 1994 NIH settles dispute with Myriad/Utah and
    grants Utah exclusive license under BRCA1 rights
  • Oncormed
  • 1997 Oncormed sues Myriad
  • infringement of 1996 consensus wild-type BRCA1
    sequence (NIH)
  • incorrect inventorship of 2 Myriad patents
  • 1998 Myriad settles with Oncormed and obtains
    Oncormed patents

13
BRCA1/2 Testing/Enforcement
  • 1996 Myriad begins to offer BRCA1/2 screening
    U. Penn screens 500 patients/year
  • 1998 Myriad sues U. Penn for patent
    infringement Penn ceases testing
  • 1999 Myriad requests Georgetown to stop testing
    for NCIs Cancer Genetics Network Project (CGNP)
  • 2000 Myriad cease and desist to Yale
  • Today Myriad is the only U.S. provider of
    commercial BRCA1/2 screening
  • Myriad permits research, but without provision of
    results to patients

14
Alleged Effects of Myriads Gene Patents
  • Pricing (3200/test) places testing beyond
    financial means of many patients
  • Inability for patients to get confirmatory
    testing from second lab
  • Myriad testing is not state-of-the-art
  • Researchers cannot tell patients results of
    testing, conflicting with ethical obligations
  • General chilling effect on research into genetic
    tests
  • Interference with ability to investigate complex
    multi-gene diseases

15
The Litigation
  • On May 12, 2009, a group of plaintiffs
    represented by the American Civil Liberties Union
    (ACLU) sued Myriad, the Univ. of Utah and the
    USPTO to invalidate 15 claims of 7 Myriad BRCA1/2
    patents

16
The Litigation Plaintiffs
  • Counsel ACLU and Public Patent Foundation at
    Cardozo School of Law
  • Plaintiffs
  • Associations Assn. for Molecular Pathology
    (AMP), Am. Coll. Of Medical Genetics (AMCG), Am.
    Soc. For Clin. Pathology (ASCP), Coll. Of Am.
    Pathologists (CAP)
  • Researchers Kazazian, Ganguly (Penn), Chung
    (Columbia), Ostrer, Reich (NYU), Ledbetter,
    Warren (Emory), Matloff (Yale)
  • Advocacy Groups Breast Cancer Action (BCA), Our
    Bodies Ourselves
  • Patients Ceriani, Limary, Girard, Fortune,
    Thomason, Raker

17
The Patents
  • 7 patents (5 BRCA1, 2 BRCA2)
  • 15 claims
  • Composition of Matter claims
  • Method/Process claims
  • Terms extend from 2015-2018
  • Myriad holds 16 other BRCA1/2 patents not in suit
    (expiring 2023)

18
Composition of Matter Claims
  • An isolated DNA coding for a BRCA1 polypeptide,
    said polypeptide having the amino acid sequence
    set forth in SEQ ID NO2 (282, cl.1)
  • Cl. 1 wherein said DNA has the nucleotide
    sequence set forth in SEQ ID NO1 (282, cl. 2)
  • An isolated DNA having at least 15 of the
    nucleotides of the DNA of claim 1/2 (282, cl.
    5/6)

19
Patentable Subject Matter Laws of Nature
  • The qualities of these bacteria, like the heat
    of the sun, electricity, or the qualities of
    metals, are part of the storehouse of knowledge
    of all men. They are manifestations of laws of
    nature, free to all men and reserved exclusively
    to none. He who discovers a hitherto unknown
    phenomenon of nature has no claim to a monopoly
    of it which the law recognizes (Funk Bros. Seed
    Co. V .Kalo Inoculant Co. (US 1948)
  • Phenomena of nature, though just discovered,
    mental processes, and abstract intellectual
    concepts are not patentable, as they are the
    basic tools of scientific and technological
    work. Gottschalk v. Benson (US 1972)

20
Do Myriads Composition Patents Cover Products
of Nature?
  • Myriads arguments
  • USPTO Utility Examination Guidelines expressly
    allow patenting of isolated genetic material
  • Patents claim isolated DNA, which does not occur
    in nature

21
What is not a Product of Nature?
  • To be patentable, a composition must have
    markedly different characteristics from any
    occurring in nature. (Diamond v. Chakrabarty (US
    1980))
  • Mere purification of a natural compound does
    not render it patentable. (Am Wood-Paper Co. v.
    Fibre Disintegrating Co. (US 1874)
  • Discredits Learned Hands 1911 holding in
    Parke-Davis v. Mulford, that isolated and
    purified adrenaline is patentable

22
Myriads Product of Nature Arguments
  • M Isolated DNA has different structural and
    chemical properties (chromatin, introns,
    methylation) than native DNA
  • Court In light of DNAs unique qualities as a
    physical embodiment of information, none of the
    structural and functional differences cited by
    Myriad render the claimed DNA markedly
    different.
  • M Isolated DNA has functional utility in probes
    and primers that native DNA does not.
  • Court usefulness of isolated DNA in
    probes/primers exists only because of the
    identity of nucleotide sequence between isolated
    and native DNA.

23
Myriads Product of Nature Arguments, cont.
  • M Invention required identification of genes
    plus isolation of sequences away from other DNA
    and cellular material
  • Court Discovery is of the handiwork of nature
    and not patentable
  • Isolation was simply the application of
    techniques well-known to those skilled in the art

24
Holding Myriads BRCA Composition of Matter
Claims Invalid
  • Because the claimed isolated DNA is not markedly
    different from native DNA as it exists in nature,
    it constitutes unpatentable subject matter
  • Claims are thus invalid.

25
Method Claims
  • A method for detecting a germline alteration
    in a BRCA1 gene, said alteration selected from a
    group consisting of the alterations set forth in
    Tables in a human which comprises analyzing a
    sequence of a BRCA1 gene or BRCA1 RNA from a
    human sample or analyzing a sequence of BRCA1
    cDNA made from mRNA from said human sample with
    the proviso that said germline alteration is not
    a deletion of 4 nucleotides corresponding to base
    numbers (999, cl. 1)

26
Method Claims Unpatentable Subject Matter
  • Phenomena of nature, though just discovered,
    mental processes, and abstract intellectual
    concepts are not patentable, as they are the
    basic tools of scientific and technological
    work. Gottschalk v. Benson (US 1972)
  • A claimed process may be patentable if it
    transforms a particular article into a different
    state or thing (In re. Bilski (Fed. Cir. en banc
    2008, cert. granted 2009)

27
Myriads Methods Not Transformative
  • Simply analyzing and comparing DNA sequences
    is an abstract mental process
  • The preparatory isolation/purification steps are
    not part of these claims
  • Any transformations associated with isolating
    and sequencing DNA are mere data gathering steps
    that are not central to patentability.
  • Holding method claims are invalid

28
Outcome
  • All 15 of Myriads claims-in-suit are invalid
  • Myriad has announced plans to appeal to the
    Federal Circuit
  • At least some justices of the Supreme Court
    (Breyer) have indicated an interested in
    patentability issues
  • 2-4 more years before a final resolution

29
Myriads European Patents
  • 1998 EPO allows patenting of genes (Council Dir.
    98/44)
  • 2001 Myriads European patents on BRCA1 granted
  • 2002 Institut Curie and other oppose Myriad
    patents
  • Feb. 2004 Cancer Res. UK gets patent on BRCA2
  • May 2004 EPO revokes first Myriad BRCA1 patent
  • Jan. 2005 EPO limits claims of 2 remaining
    Myriad BRCA1 patents
  • Jan. 2005 Myriad gets European patent covering
    BRCA2 test for Ashkenazi-Jewish women
  • Nov. 2008 EPO limits BRCA1 patent to BRCA1
    frameshift mutations only (not full BRCA1 gene)

30
Utility
31
Utility in the U.S.
  • 35 USC 101 Whoever invents or discovers any new
    and useful process, machine, manufacture, or
    composition of matter, or any new and useful
    improvement thereof, may obtain a patent
    therefor...
  • 35 USC 112 The specification shall contain a
    written description of the invention, and of the
    manner and process of making and using it

32
Eli Lilly v. Human Genome Sciences (UK Ct.
Appeal, Feb. 2010)
33
HGSs neutrokine-a Patent
  • 1996 HGS patents sequence for neutrokine-a, a
    protein identified using bioinformatics
    techniques
  • Function is unknown, so a list of potential uses
    including therapies for solid tumors,
    schistosomiasis, and other parasitic diseases is
    listed
  • Eli Lilly, also developing neotrokine-a
    antibodies, challenges patent

34
Industrial Application Test
  • Comparable to U.S. specific and substantial
    utility test
  • Patent description must disclose a practical way
    of exploiting the invention in at least one field
    of industrial activity
  • Requirement is not satisfied by claiming an
    interesting research result without specified
    application
  • Speculative indication of possible objectives not
    sufficient

35
Challenges to Patent
  • Jul 2008 UK Patent Court strikes down patent
  • 2009 EPO Technical Board of Appeals upholds
    patent
  • Feb. 2010 UK Court of Appeal strikes down
    patent
  • Possible appeal to UK Supreme Court
  • NOTE UK decisions not binding in other EU states

36
Non-obviousness
37
Non-obviousness
  • A patent may not be obtained if the differences
    between the subject matter sought to be patented
    and the prior art are such that the subject
    matter as a whole would have been obvious at the
    time the invention was made to a person having
    ordinary skill in the art to which said subject
    matter pertains. Patentability shall not be
    negatived by the manner in which the invention
    was made.

38
Biotech Non-obviousness
  • 1990s to 2007
  • Many scholars and firms believed that the court
    of national jurisdiction for patent appeals
    (CAFC) had developed the law in such a way that
    the non-obviousness requirement was too lenient.
  • Other requirements of the patent law are being
    applied so as only to uphold relatively narrow
    claims to DNA or protein sequences ( 112
    requirements).
  • The upshot many DNA patents, none of which are
    worth much. Patent thicket?

39
Biotech Non-obviousness
  • In re. Bell, 991 F. 2d 781 (CAFC 1993)
  • DNA seq and cDNA seq for Insulin-like Growth
    Factor 1 and 2 (IGF1 2) are not obvious in
    light of the complete protein sequences for each
    and a well-known method for cloning the DNA.
  • CAFC Not obvious!

40
Biotech Non-obviousness
  • In re Deuel, 51 F. 3d 1552 (Fed. Cir. 1995)
  • Claim for DNA seq and cDNA seq for heparin
    binding growth factor (HBGF) not obvious over
    method of cloning, and a partial protein seq
    (amino terminus.
  • PTO argued that when a protein sequence or part
    of it was put into the public domain, then so was
    the DNA sequence because a person of ordinary
    skill in the art would be motivated to clone the
    gene and would know how to do it. CAFC disagreed!

41
Biotech Non-obviousness
  • Protein seq plus a method of cloning the gene
    does not make DNA seq obvious because
  • The relationship between DNA seq and protein seq
    through the genetic code does not establish a
    prima facie case of obviousness.
  • Redundancy of the genetic code precludes a
    scientist from formulating an idea of the exact
    DNA sequence just by knowing a protein sequence.
  • No structural similarity between nucleotides and
    amino acids ? there is no structurally similar
    compound in the prior art for somebody to modify
    to create the specific, structurally defined DNA
    molecule.
  • It is not enough that the general idea of the
    claimed molecule exists in scientists minds.

42
Biotech Non-obviousness
  • From Deuel and Bell
  • The existence of a method of cloning is
    essentially irrelevant in the absence of
    information in the field suggesting the exact
    structure of the DNA molecule (including every
    base in each codon).
  • A general incentive does not make obvious a
    particular result and obvious to try has long
    been held not to constitute obviousness. Deuel
    at 1559.

43
Biotech non-obviousness
  • Biology as an unpredictable art
  • Analogy to small molecule chemistry in which a
    very small change in the molecule can
    substantially alter its properties.
  • Contrast to the predictable arts, e.g.
    mechanical and electrical arts
  • DNA is just another chemical, and we have a
    chemistry jurisprudence already.

44
KSR International Co. v. Teleflex Inc., 127
S.Ct. 1727 (2007)
45
Facts and Case History
  • Teleflex holds an exclusive license to pt for an
    adjustable pedal assembly.
  • Teleflex sues KSR for infringing claim 4 of its
    patent.
  • Claim for combining an electronic sensor with an
    adjustable automobile pedal so that the pedals
    position could be transmitted to a computer that
    controls the automobiles throttle.
  • Supreme Ct. held that the trial court correctly
    applied the law when it found this invention
    obvious.

46
Predictability Non-obviousness
  • After KSR, role of predictability in assessing
    obviousness
  • An invention is obvious if
  • It is a combination of familiar elements
  • According to known methods
  • That does no more than yield predictable results.
  • An invention is obvious if
  • It claims a structure already known in the field
    and does no more than
  • Substitute one material or element for another
    known in the field
  • And produces a predictable result.

47
Biotech Non-obviousness
  • Obvious to try test after KSR?
  • Obvious to try
  • Motivation to try from design need or market
    pressure (or regulatory pressure, or ???)
  • Finite number of identified, predictable
    solutions
  • Likelihood of success.
  • If all of the above apply, then the invention was
    obvious. Repudiates Deuels formulation of the
    obvious-to-try doctrine.

48
In re Kubin, 561 F. 3rd 1561 (Fed Cir 2009)
49
Kubin
  • Claim for isolated DNA encoding a protein at
    least 80 identical to 199 amino acids of the
    NAIL protein (natural killer cell activation
    inducing ligand, aka P38), wherein the
    polypeptide binds CD48.
  • Protein had previously been reported, there was
    a commercially available MAb to NAIL/p38, a
    mouse ortholog had been cloned and had bound to
    human DNA.
  • Previous patent disclosed p38 receptor/NAIL
    protein and gave explicit instructions on how to
    clone the cDNA.

50
Kubin
  • The CAFC upheld the Patent Offices finding that
    the Kubins NAIL gene sequences were obvious.
  • Here, the prior patent and lab manual taught the
    existence of the protein, provided motivation to
    clone the gene, and provided a step-by-step
    method for cloning this particular gene ?
  • The prior art provided explicit motivation for
    somebody to try cloning the NAIL gene, and a
    person of ordinary skill in the art would have
    had a reasonable expectation of success in doing
    so given what was disclosed in the prior art.
  • A person of skill in this advanced art would
    find these claimed results profoundly
    predictable. p. 1360.
  • Granting patent protection to advances that would
    have occurred in the ordinary course of
    activities in the field retards innovation rather
    than advancing it.

51
Biotech Non-obviousness
  • In the future, it will be at least somewhat more
    difficult for researchers to obtain patent
    protection for DNA sequences.
  • It remains to be seen how broadly the obvious
    to try doctrine will be applied.
  • Will it apply to a DNA sequence when nothing
    about the protein was previously known?
  • Will it apply to a DNA sequence when there was no
    explicit discussion in the literature of how to
    clone that exact protein?
  • At least some existing DNA sequence claims likely
    will be held invalid under the Kubin standard.

52
Biotech Non-obviousness
  • CAFC may be giving up its view that for a DNA seq
    to be obvious one needs to be able to predict
    exactly which nucleotides will be in the sequence!

53
SACHGS Report on Gene Patents and Licensing (Feb.
2010)
54
Scope of SACGHS Report
  • Review of clinical impact of gene patents and
    licensing practices on access to genetic testing
  • Case studies
  • Breast, ovarian and colon cancer
  • Alzheimers Disease
  • Cystic Fibrosis
  • Hearing Loss
  • Hemochromatosis
  • Long QT Syndrome
  • Spinocerebellar Ataxia
  • Tay-Sachs and Canavan Disease

55
SACGHS Recommendations
  • Exemption from infringement of gene patents for
    patient care and research
  • Require non-exclusive licensing of diagnostic
    genetic technologies
  • Ensure that clinically useful genetic tests are
    equitably available and accessible to patients
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