Are Methods of Diagnosis Still Patentable?

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Methods of medical treatment and methods of medical
diagnosis have long been recognized as patentable subject matter in the United
States. However, recent decisions from the US Supreme Court as well as the
Court of Appeals for the Federal Circuit (the court that hears appeals of
patent cases) have placed restrictions on the scope of such claims.

Patent claims to diagnostic methods typically recite
steps of a) sample collection, b) detection, quantification or analysis of one
or more components of the sample, and c) making a diagnosis or altering a
treatment based on results obtained in step b). However, court decisions over
the years have limited what can be patented. In Mayo Collaborative Services v. Prometheus Laboratories, Inc.[i] the Supreme Court stated that patentable
subject matter does not include certain judicial exceptions, i.e., laws of
nature, natural phenomena, and abstract ideas, and that simply appending
conventional steps, specified at a high level of generality, to a law of
nature, a natural phenomenon or an abstract idea cannot confer patentability.
To be patentable, a claim directed to a judicial exception must contain
additional elements that add something “significantly more” than the law,
phenomenon or abstract idea itself. In a subsequent decision, Alice Corp. v. CLS Bank Int’l, U.S.,[ii] the Supreme Court set out
a two-part test for patent eligibility: first, a court (or the Patent Office)
determines whether a claim is directed to a patent-ineligible concept, i.e., is
the claim drawn to a law of nature, a natural phenomenon or an abstract idea.
If so, the court then asks if the claim includes something “significantly more”
than the patent-ineligible judicial exception.

In Mayo, the independent patent claim the
Court considered was drawn to a method of optimizing therapeutic efficacy for
treatment of an inflammatory bowel disease with a 6-mercaptopurine (6-MP) drug.
The claim included steps of (a) administering a 6-MP drug to a patient and (b)
determining the level of a 6-MP metabolite, 6-thioguanine (6-TG) in red blood
cells from the patient. The claim further included how the levels of 6-TG are
to be interpreted: if below a certain specified minimum, the amount of the 6-MP
drug needs to be increased (presumably to be effective); if above a certain
specified maximum, the dosage needs to be reduced (presumably to avoid
toxicity).[iii]

In Mayo, the scientific insights included understanding that
6-mercaptopurine is metabolized to 6-thioguanine, that 6-TG levels can be used
to determine proper dosage of 6-MP, and the optimal range for 6-TG levels. For
a scientist, how one determines 6-TG levels is of relatively minor interest.
The claim in Mayo thus included no
limitation on the type of assay to
determine the level of 6-TG. However, this led the Supreme Court to state that
“The ‘determining’ step tells a doctor to measure patients’ metabolite levels, through whatever process the doctor or the
laboratory wishes to use.
” (Emphasis added.) The Court added that “because
methods for making such determinations were well known in the art, this step
simply tell doctors to engage in well-understood, routine, conventional
activity previously engaged in by scientists in the field…” The claim was
deemed patent ineligible because the Court considered the conversion of 6-MP by
the body to 6-TG, as well as the effective and toxic levels of 6-TG, to be
non-patentable natural phenomena. Furthermore, the claim preempted all possible
tests for measuring 6-TG, i.e., it covered measuring 6-TG at a high level of
generality—through whatever process the doctor or the laboratory wishes to use.

The patent also issued
with dependent claims specifying a particular test for measuring 6-TG: the use
of high pressure liquid chromatography (HPLC).[iv] However, the Supreme
Court ignored these claims, stating “For present purposes we may assume that
the other claims in the patents do not differ significantly from claim 1.” The
Court did not to consider that alternative methods were available for measuring
6-TG without using HPLC; it also ignored that the patent specification
explicitly described such alternatives (such as thin layer chromatography),
without claiming them.[v] We are thus left without
any guidance as to whether a claim that included a step of “(b) determining the
level of 6-TG by an HPLC assay” would have satisfied the Supreme Court. Put
another way, we do not know if the Supreme Court would have considered a claim
specifying an HPLC assay to measure 6-TG would amount to something
“significantly more” than a claim to the phenomenon itself.

After the Supreme Court’s Mayo decision, the Court of Appeals for the Federal Circuit
decided Ariosa Diagnostics, Inc. v. Sequenom, Inc.[vi] In their patent, the
inventors described and claimed a polymerase chain reaction (PCR)-based method
to detect cell-free fetal DNA (cffDNA) in a plasma or serum sample from a
pregnant woman.[vii]
There is no dispute that the presence of cffDNA in maternal plasma or serum is
a natural phenomenon. There is also no dispute that the invention is useful, as
providing in many cases a simpler, safer alternative to amniocentesis for
analyzing fetal DNA.

The first independent claim considered by the Federal
Circuit included steps of “amplifying” and “detecting” a paternally inherited
nucleic acid of fetal origin. However, the claim did not specify any particular
method of either “amplifying” or “detecting” paternally inherited nucleic acid
from serum or plasma. Because the “amplifying” and the “detecting” steps are
stated at a high level of generality, the Federal Circuit concluded that the
claim was drawn to patent ineligible subject matter under the Mayo framework. In addition, claim 2
depending from claim 1 recited amplification by polymerase chain reaction, and
claim 4 depending from claim 1 recited using “a sequence specific probe.” Other
claims were somewhat more specific. For example, claim 5 referred to detection
of Y chromosome fetal DNA. Nonetheless, claim 1 would have precluded the use of
any DNA amplification technology for detecting a paternally inherited nucleic
acid of fetal origin in maternal blood. Although alternatives to PCR were
mentioned in the specification, such as a ligase chain reaction, nucleic acid
sequence based amplification (NASBA), and branched DNA methods, the Federal
Circuit concluded the claims were patent-ineligible, as they were deemed as
amounting to general instructions to doctors to apply routine, conventional
techniques to detect cffDNA. The Federal Circuit did not consider that a claim
specifying a PCR test would not cover “whatever process the doctor or the
laboratory wishes to use” in view of the availability of alternatives to PCR
assays.

In addition, none of the claims recited specific
sequences of oligonucleotide primers or probes for performing the PCR
amplifications. We do not know if the Federal Circuit or Supreme Court would
deem claims reciting specific sequences for PCR primers as adding something
“significantly more” than the phenomenon itself.

The US Patent and Trademark Office recently released a
guidance on subject matter eligibility, including examples of hypothetical
claims to diagnostic methods and how they would be analyzed in view of Mayo and Ariosa.[viii]
In their guidance, the PTO included claims to methods for diagnosing “julitis”
that involve detection of “JUL-1” protein. The fact pattern included that
anti-JUL-1 antibodies can occur naturally (e.g., a human anti-JUL-1 antibody
from a patient with julitis), or can be generated by human effort (e.g., by
inoculating pigs with JUL-1 to produce a porcine anti-JUL-1 antibody). Included
in the fact pattern is that porcine anti-JUL-1 antibody had not been routinely
used to detect human JUL-1.

The claims analyzed by the PTO included the following:

1. A method of detecting
JUL-1 in a patient, said method comprising:

a. obtaining a plasma sample from a human patient; and

b. detecting whether JUL-1 is present in the plasma
sample by contacting the plasma sample with an anti-JUL-1 antibody and
detecting binding between JUL-1 and the antibody.

2. A method of diagnosing
julitis in a patient, said method comprising:

a. obtaining a plasma sample from a human patient;

b. detecting whether JUL-1 is present in the plasma
sample by contacting the plasma sample with an anti-JUL-1 antibody and
detecting binding between JUL-1 and the antibody; and

c. diagnosing the patient with julitis when the presence
of JUL-1 in the plasma sample is detected.

3. A method of diagnosing
julitis in a patient, said method comprising:

a. obtaining a plasma sample from a human patient;

b. detecting whether JUL-1 is present in the plasma
sample by contacting the plasma sample with a porcine anti-JUL-1 antibody and
detecting binding between JUL-1 and the porcine antibody; and

c. diagnosing the patient with julitis when the presence
of JUL-1 in the plasma sample is detected.

Rather bizarrely, the USPTO decided that claims 1 and 3
are patent eligible, but claim 2 is not. Claims 1 and 2 include identical steps
of a. obtaining a plasma sample, and b. using an anti-JUL-1 antibody to detect
JUL-1 protein. According to the PTO, claim 1 is patent eligible, in that the
steps of obtaining a plasma sample from a patient and detecting whether JUL-1
is present using an anti-JUL-1 antibody do not describe any recognized judicial
exception (i.e., a law of nature, a natural phenomenon or an abstract idea).
The preamble of claim 1 recites a method of detecting JUL-1, and according to
the PTO, claim 1 is “focused on a process of detecting whether JUL-1 is present
in a plasma sample.”

On the other hand, the preamble of claim 2 recites a
method of diagnosing julitis, and according to the PTO, step c of claim 2
describes a correlation or relationship between the presence of JUL-1 in a
patient’s plasma and a diagnosis of julitis. Such a correlation is not patent
eligible under the PTO’s interpretation of Mayo.
According to the PTO, the presence of steps a and b, identical to claim 1, do
not offset that claim 2 as a whole is directed to a judicial exception when
step c is considered.

Does claim 2 include something “significantly more” than
a judicial exception? According to the PTO, “Detecting whether JUL-1 is present
in the plasma sample merely instructs a scientist to use any detection
technique with any generic anti-JUL-1 antibody.” The PTO concluded that claim 2
does not present anything “significantly more” than the phenomenon itself.

In contrast, claim 3 recites diagnosing julitis using a
porcine anti-JUL-1 antibody. According to the PTO, reciting the use of a
porcine anti-JUL-1 antibody, rather than “any” anti-JUL-1 antibody, renders the
claim patent eligible. Because porcine anti-JUL-1 antibodies were not routinely
or conventionally used to detect JUL-1, the PTO considers the detection of
JUL-1 using a porcine antibody to be an unconventional step that is
significantly more than an application of well-understood, routine or
conventional techniques.

Mayo
and Ariosa do not exclude from
patentability all claims to diagnostic methods. To the contrary: the Supreme
Court stated in Mayo and elsewhere
the well-recognized doctrine that a new combination of steps in a process may
be patentable even though all the constituents of the combination were well
known and in common use before the combination was made. Decisions on patent
eligibility in the wake of Mayo
unfortunately focus not on this doctrine, but on whether a claim involves
“well-understood, routine, conventional activity.” The real question should be
if a claim is directed to a (non-patentable) scientific result rather than how
the result is achieved. If results are obtained by unspecified methods—through
“whatever process a doctor or the laboratory wishes to use” —such claims may be
patent ineligible as directed towards a natural phenomenon without adding
something “significantly more.” On the other hand, claims to diagnostic methods
that specify the type of test used, when there are at least conceivable
alternatives, should be deemed patent eligible.

Unfortunately, the Supreme Court recently declined to
review the Ariosa decision. Mayo and Ariosa will remain the law of the land until another case reaches
the Court or Congress acts, and more guidance is provided that better defines
something “significantly more” to make a claim patent eligible. Until the
Supreme Court or Congress decides to take up patent eligibility again, we will
need to live with a standard that a claim to a method that involves
“well-understood, routine, conventional activity” may be patent ineligible,
even when a particular test is specified and alternatives are available so that
the claim is not attempting to cover a diagnostic measurement through “whatever
process a doctor or the laboratory wishes to use.”




[i] Mayo Collaborative Services v. Prometheus
Laboratories, Inc.
, 132 S. Ct. 1289; 182 L. Ed. 2d 321; 2012 U.S. LEXIS
2316; 80 U.S.L.W. 4225; 101 U.S.P.Q.2d (BNA) 1961 (2012).

[ii] Alice Corp. v. CLS Bank Int’l., 134 S.
Ct. 2347; 189 L. Ed. 2d 296; 2014 U.S. LEXIS 4303; 110 U.S.P.Q.2D (BNA) 1976
(2014).

[iii] US
Patent 6,355,623. The independent claim considered by the Supreme Court reads:

1. A method of optimizing therapeutic efficacy for
treatment of an immune-mediated gastrointestinal disorder, comprising:

(a) administering a drug providing
6-thioguanine to a subject having said immune-mediated gastrointestinal
disorder; and

(b) determining the level of
6-thioguanine in said subject having said immune-mediated gastrointestinal
disorder,

wherein
the level of 6-thioguanine less than about 230 pmol per 8×108 red
blood cells indicates a need to increase the amount of said drug subsequently
administered to said subject and

wherein
the level of 6-thioguanine greater than about 400 pmol per 8×108 red
blood cells indicates a need to decrease the amount of said drug subsequently
administered to said subject.”

[iv] Such claims
include, e.g.: 6. The method of claim 5, wherein said level is determined using
high pressure liquid chromatography.

[v] Non-HPLC methods
for measuring 6-MP metabolites listed in the specification include:: capillary
electrophoresis with laser-induced fluorescence detection; anion exchange chromatography
and fluorescent detection; lanthanum precipitation, acid hydrolysis, back
extraction and fluorometric assay; and thin layer chromatography.

[vi] Ariosa
Diagnostics, Inc. v. Sequenom, Inc.
, 788 F.3d 1371,
115 U.S.P.Q.2d (BNA) 1152 (Fed. Cir. 2015).
See also
Genetic Techs. Ltd. v. Merial L.L.C.,
2016 U.S. App.
LEXIS 6407 (Fed. Cir. 2016).

[vii] US Patent 6,258,540.
Independent claim 1 reads:

1.
A method for detecting a paternally inherited nucleic acid of fetal origin
performed on a maternal serum or plasma sample from a pregnant female, which
method comprises

amplifying a paternally inherited nucleic
acid from the serum or plasma sample and

detecting the presence of a paternally
inherited nucleic acid of fetal origin in the sample.

[viii] http://www.uspto.gov/sites/default/files/documents/ieg-may-2016-ex.pdf

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