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Myriad, Metabolite, Bilski, andPrometheus:The Four Horsemen of the Biotech Apocalypse?

Kevin E. Noonan, Ph.D.McDonnell Boehnen Hulbert & Berghoff

LLP

Professor Christopher Holman

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Outline of the Talk Introduction

How did we get here?

AMP v. Myriad Genetics Parties and interests The claims: DNA and methods The arguments The court’s decision Constitutional issues?

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Outline of the Talk Labcorp v. Metabolite

The claims The Supreme Court argument The dissent from dismissal of cert

In re Bilski The Claims and Federal Circuit decision How does this relate to biotech?

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Outline of the Talk Prometheus v. Mayo Labs

Claims and issue The Federal Circuit decision: Diagnostic

method claims can be patent-eligible Relevance to Myriad decision

Recommendations To patent or not to patent

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Introduction

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How did we get here? Tremendous success of a technological age Biotechnology the beneficiary of strong

patent protection Biotechnology developed in university setting

– 1980 Bayh-Dole Act promotes patenting But success breeds criticism – from variety of

sources These include political criticism from those

opposed to university patenting

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Where is here? Politically-motivated groups in the arena: ACLU

and PubPat PubPat challenges variety of patents (not just

biotech); notable the WARF human ESC patents General attitude that patents have become too

powerful and retard innovation (little empirical support)

Time ripe for Myriad challenge: in addition, the “right” defendant, due to aggressive patent enforcement tactics

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AMP v. Myriad

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Myriad: The parties Suit brought in May 2009, SDNY (Judge Sweet) Plaintiffs: several breast cancer victims, variety

of physicians’ groups, certain researchers who claimed research impeded by BRCA patents

Defendants: University of Utah (patent assignee), Myriad Genetics, U.S. PTO

Supporters: ACLU, PubPat, academics Seven patents/ 15 claims at issue Invalid under patent statute and Constitution

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Patent eligibility versus patentability Patent-ineligible means that the subject

matter is not eligible for a patent for public policy reasons notwithstanding the fact that it may be patentable (i.e., useful, novel, and not obvious).

Patentable subject matter means the invention as claimed is useful, novel, and not obvious.

Myriad: The issue

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Myriad: The claims Two broad types of claims at issue: claims to

isolated DNA molecules, and diagnostic method claims

DNA claims recite “isolated” DNA encoding specific amino acid sequences (cDNA)

Also claims to oligonucleotide probes Method claims: methods of detecting mutation

or providing a diagnosis/risk assessment Method claims involve “comparing” mutant

sequence to normal sequence

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Myriad: The claims Composition of matter claims covering

“isolated DNA” covering the BRCA 1 and BRCA 2 genes. Claim 1 of US Patent 5,747,282 is representative of this class of claims:

An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2.

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Myriad: The claims Composition of matter claims covering

“isolated DNA” covering the mutations of BRCA 1 and BRCA 2 genes. Claim 1 of US Patent 5,693,473 is representative of this class of claims:

An isolated DNA comprising an altered BRCA1 DNA having at least one of the alterations set forth in Tables 12A, 14, 18 or 19 with the proviso that the alteration is not a deletion of four nucleotides corresponding to base numbers 4184-4187 in SEQ. ID. NO:1.

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Myriad: The claims Methods of detecting mutations in the BRCA

genes. Claim 1 of US Patent 5,709,999 is the only claim in this class:

A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 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 4184-4187 of SEQ ID NO:1

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Myriad: The claims Methods that “compare” and “correlate”

mutations in the BRCA genes with an increased risk of breast or ovarian cancer. Claim 2 of US Patent 6,033,857 is representative of this class of claims:

A method for diagnosing a predisposition for breast cancer in a human subject which comprises comparing the germline sequence of the BRCA2 gene or the sequence of its mRNA in a tissue sample from said subject with the germline sequence of the wild-type BRCA2 gene or the sequence of its mRNA, wherein an alteration in the germline sequence of the BRCA2 gene or the sequence of its mRNA of the subject indicates a predisposition to said cancer.

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Myriad: The arguments Regarding the DNA claims, plaintiffs argue that

they are “products of nature” and hence not “inventions”

No Supreme Court case that DNA patent-eligible

Precedent (19th century, subject to interpretation) that “supports” their view

Method claim arguments based on Bilski Constitutional argument: violation of 1st

Amendment right to biological information and 14th Amendment due process

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Myriad: The decision Judge Sweet agrees that DNA an

unpatentable “product of nature” DNA is “the physical embodiment of genetic

information” Distinguishes other types of “natural

products” (antibiotics, vitamins) on this basis

Method claim invalid on Bilski Constitutional arguments avoided, Patent

Office dismissed from the lawsuit

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Myriad: The Constitution Although the judge avoided, still important Quickest way to get the Supreme Court’s

attention Depends on a failure to appreciate that the

information isn’t what is patented in claims to isolated DNA

However, information is implicated in method claims, because that is what a diagnostic method claim produces – diagnostic information

Should it matter?

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Myriad: Remaining claims A vector comprising isolated DNA operative in a host

cell. A host cell containing isolated DNA and control

sequences Methods for producing BRCA1 polypeptide comprising

culturing cells and harvesting the BRCA1 polypeptide A kit for detecting mutations in the BRCA1 gene A nucleic acid probe specifically hybridizable to

BRCA1 DNA The method that amplifies all or part of a BRCA1

gene and sequences the amplified BRCA1 nucleic acids.

Patentability of Diagnostic Methods

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Labcorp v. Metabolite

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Claim 13. A method for detecting a deficiency of cobalamin or folate in warm-blooded animals comprising the steps of:  assaying a body fluid for an elevated level of total homocysteine; [a “detecting” step] and correlating an elevated level of total homocysteine in said body fluid with a deficiency of cobalamin or folate [an “inferring” step].

Labcorp Claim

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General problem of “determine and infer” claims (Prof. Kevin Emerson Collins):

Characterized by one or more “determining” steps that involve assays, etc. = transformative

Include “mental step” of reaching a conclusion or arriving at an inference based on outcome of determining steps

Claim preamble directs method to activity (e.g., diagnosing) based on inference

Labcorp dissent - context

Supreme Court argument Defendant argued that the claim was not

patent-eligible, because it was merely mental activity directed at making a diagnosis

Raised the issue of patents interfering with medicine (surgical techniques earlier lost patent infringement liability)

Methods that occur wholly in the mind, by “correlating” or “comparing” should not be patented

Supreme Court argument Justices heard the arguments, then

decided (for procedural reasons) that the Court should not have heard the case

Justices Breyer, Souter and Stevens dissented from this decision

Justice Breyer’s dissent based on his acceptance and agreement with defendants’ argument that the claims not eligible for patenting

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“As construed by the Federal Circuit, claim 13 provides those researchers with control over doctors' efforts to use that correlation to diagnose vitamin deficiencies in a patient.  Does the law permit such protection or does claim 13, in the circumstances, amount to an invalid effort to patent a ‘phenomenon of nature’"? 

“At most, respondents have simply described the natural law at issue in the abstract patent language of a ‘process.’  But they cannot avoid the fact that the process is no more than an instruction to read some numbers in light of medical knowledge.” 

“[H]ere, aside from the unpatented test, they embody only the correlation between homocysteine and vitamin deficiency that the researchers uncovered.  In my view, that correlation is an unpatentable ‘natural phenomenon,’ and I can find nothing in claim 13 that adds anything more of significance.

Labcorp dissent

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Justice Breyer misses a few points of well-established patent law:

Whether a claim recites patent-eligible subject matter does not depend on whether the claim is itself patentable

Applications of “phenomena of nature” are patentable; the phenomenon itself is not

Patent eligibility of a claim must be determined from the claim “as a whole”

Labcorp dissent

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In re Bilski

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In re Bilski: The claims Claims directed to a method for hedging risk

in commodities trading Rejected by the patent examiner, affirmed by

the patent board of appeals Federal Circuit (appellate court that hears

these appeals) agrees, announcing a new test A method to be patentable has to either

Be tied to a particular machine orTransform a particular article into a differentstate or thing

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Supreme Court weighs in Does not reject Federal Circuit test, but says it

is not the only test Goes back to first principles, relating to whether

what is claimed is an abstract idea that pre-empts every use thereof

Benson/Flook/Diehr precedent, wherein applications of abstract ideas are patent-eligible but not if the idea is completely pre-empted

But MOT test “should be satisfied” is most cases

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How does Bilski apply to biotech?

MOT test not limited to “business methods” Test required for any method, including

diagnostic methods Typical diagnostic method is not tied to a

particular machine Many diagnostic methods (like in Metabolite)

involve using data to make a diagnosis, so don’t “transform”

Also based on medical knowledge – is this an “abstract idea”?

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Prometheus Labs v. Mayo

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Consequences of Bilski Decision

Prometheus Labs v. Mayo (decided September 16, 2009) Claims a method for optimizing treatment of an immune-

mediated gastrointestinal disorder with 6-thioguanine Recited steps of administering the drug to a patient and

detecting 6-thioguanine or 6-methyl-mercaptopurine (metabolite) in blood

Recites inferring step of therapeutic efficacy when 6-thioguanine levels in red blood cells are between 230 pmol-400 pmol per 8 x 108 red blood cells

Levels outside these ranges “indicates a need” to adjust administration amounts accordingly – but does not recite affirmative steps of adjusting

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Prometheus Labs v. Mayo Steps for administering a drug and determining

metabolites can be transformative and satisfy Bilski Such steps can be “method of treatment” steps

that are “always transformative” Involving “natural processes” not determinative,

since “every transformation of physical matter . . . occurs as the result of natural processes”

A process for chemical or physical transformation of a physical object or substance are “virtually self-evidently” patent-eligible subject matter

Inclusion of a mental step does not negate patent-eligibility

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Prometheus Labs v. Mayo

In the wake of Bilski, the Supreme Court granted cert, vacated the Federal Circuit decision and remanded

Mayo has asked the court for en banc review

No matter what the Federal Circuit decides, expect appeal to Supreme Court

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Consequences and the Future

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Recommendations: Isolated DNA claims

If “isolated” is insufficient, many DNA claims invalid

Consequences depend on what the claims are protecting For making therapeutic proteins,

recombinant cell claims should survive Vector claims should also be patentable

(man-made) Kit claims should also be patentable, as

manufactures

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Recommendations: Diagnostic Method claims

Fate of diagnostic method claims may be language-dependent

Insofar as claim can be cast as “merely mental step” then at greater risk

“Correlating”/“comparing” language problematical

Claims containing more active steps (like “sequencing”) may be at lower risk

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Recommendations: Diagnostic Method claims

Bigger problem for these claims (even if they survive Bilski /Prometheus decisions)

Potential for a patent “thicket” Some efforts around this (patent pooling,

SNP consortium, Navigenics “ASCAP” solution)

Will get worse before it gets better, particularly regarding personalized medicine

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Recommendations: Ways forward

• Patented technology• Licensing• Litigation

• New technology• To patent or not to patent

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Recommendations: Patented technology

“Narrowing” reissue a possibility For DNA claims, can limit to

“manufactured” DNA – claim scope expressly outside chromosomal DNA by structure

Can also narrow vector claims to these embodiments

Diagnostic method claims to include “active” steps like sequencing

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Recommendations: Patented technology

In litigation, DNA claims not usefully asserted

But then, what damage (usually) from DNA claim alone?

Recombinant cells should survive Myriad even at Supreme Court

Pharmaceutical infringement should involve at least use of recombinant cells

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Recommendations: New technology

Patenting may not be an option (or at least be unattractive)

For industry, when you cannot patent, trade secret becomes attractive

Not easy, but attractive But may be worth the risk and investment Broad (and negative) implications for

academic research

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“Old” technology

BRCA1 and BRCA2 the anomalous – many common diseases (diabetes, most cancers, cardiovascular disease) multigenic

Requires detection of more than one dominant mutant gene

Not difficult to identify “disease” genes But may be difficult to obtain sufficient

correlations between several genes to be useful

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Recommendations: New technology

Academia versus industry: what industry does better

Focused investigation to determine which genes in combination are diagnostic

Wealth of genetic data (thanks, Human Genome Project) + large reservoirs of frozen tumor and other tissue

Capacity to use both for to develop assays for making diagnostic decisions

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Recommendations: Diagnostic methods/ trade secrets

With existing technology, can analyze tens of thousands of frozen normal and disease-specific tissue samples

Identify the differences between normal and disease that are common in disease

Perform prospective study on normal/ diseased cohorts to show predictive power

Assemble roster of disease-specific genes for a particular disease

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Recommendations: Diagnostic methods/ trade secrets

Diagnostic test is “gene chip” containing >10,000 sequences

Some of these are specific for the disease (multiple sequences from different genes)

Some are positive controls Some are negative controls All are assembled on the chip “randomly”

– positions encrypted for each chip

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Recommendations: Diagnostic methods/ trade secrets

Encryption informs reader which sequences are determinative for disease

Billions of permutations, (almost) impossible to decipher/reverse engineer

Showing of reliability may be required, but identity of genes should not be

FDA issues regarding extent of disclosure required, but alternative may be no test at all

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Recommendations: Diagnostic methods/ trade secrets

Consequences: Academia/industry collaborations over Research-intensive efforts preclude global

approaches Pace of genetic research on diseases slows Disclosure disappears No disclosure = no need to reduce prices

ever Fundamentally shifts progress (negatively)

and incentives to innovate

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Recommendations: Possible alternative

Industry abandons the space entirely Diagnostic genetic testing done in

university or hospital settings exclusively

Concentrated in large medical centers, with advantages and disadvantages: Test consistency and reliability concerns Relationship to university mission Best use of resources Availability/cost of genetic counseling

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Recommendations: Diagnostic methods/ trade secrets

Exchange of powerful incentives Today, early-stage, research-

intensive, high-risk research Tomorrow, focused, disease-specific

research by industry to develop diagnostic products

Provides rationale/explanation to counter “free is good” arguments

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Conclusions Situation very unsettled No clear and unambiguous path forward Myriad appeal on track, appellant briefs

due in October Prometheus will most likely be the next

opportunity for a Supreme Court decision Possible that the Court will let the Federal

Circuit flesh things out in a few cases before granting cert

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Thank you!Kevin E. Noonan, Ph.D.noonan@mbhb.com

www.patentdocs.org

MBHB300 South Wacker DriveChicago, Illinois 60606-6709312 913 0001 phone312 913 0002 faxwww.mbhb.com