The Difficulties in Diagnostic Patents, post-Mayo

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Since the Supreme Court issued its opinion in the Association for Molecular Pathology v. Myriad Genetics, Inc. and Mayo Collaborative Services v. Prometheus Laboratories, Inc., it has been increasingly difficult for medical diagnostics to become patented or survive a patentability challenge.  In 2012, the U.S. Supreme Court decisions, which applied to a breast cancer test relying on BRCA1 gene mutations and test determining appropriate dosages of thiopurine drugs that are used in autoimmune diseases, determined that any test that relied upon a correlation between naturally occurring events, such as the presence of a mutated gene or drug metabolite, was related to natural laws and natural phenomena and hence not patent eligible subject matter without more inventive material in the claims.[i]  These decisions also stated that any well-understood, routine, or conventional activity previously engaged in by researchers in the field, would be insufficient to overcome a finding of patent ineligibility.[ii]

Recently, the Federal Circuit released a precedential opinion into a myasthenia gravis diagnostic relying on antibody levels against a membrane protein, muscle-specific tyrosine kinase (MuSK).[iii] Myasthenia gravis is an autoimmune neuromuscular disorder typically caused by antibodies targeting acetylcholine receptors that are responsible for nerve transmission.[iv]  There are three other variations, where antibodies target MuSK, where antibodies target LRP4, and congenital variations that result in defects in nerve transmission, such as in acetylcholine.[v]  In typical muscle nerve transmission, a nerve (presynaptic) releases acetylcholine out of the cell, which is taken up by the next cell (postsynaptic) causing the nerve signal to continue.[vi] LRP4 and MuSK act together to maintain the acetylcholine receptors together and adjacent to the presynaptic cell, which is required for the signaling.[vii]

Myasthenia gravis is diagnosed by physical examinations and various tests, including antibody levels.[viii] In the present case, the inventors of the patent at issue discovered the link between MuSK antibodies and myasthenia gravis.[ix] The patent resulting from this discovery included diagnostic tests that used radiological labeling of MuSK or an antigenic epitope to determine levels of anti-MuSK antibodies in a patient;[x] or adding a reporter or label (usually fluorescent) to MuSK or an antigenic epitope for the same purpose.[xi] The Federal Circuit analyzed the claims, and unsurprisingly found the claims drawn to a correlation between MuSK antibodies and myasthenia gravis.[xii] The court moved to the next step in the analysis, whether the claims include an inventive aspect that elevates the claims to patentable subject matter.[xiii] Despite the fact that the claims included man-made acts of radioactive labeling or other labeling of a molecule, the Federal Circuit found all of these acts to be well known in the field and insufficient to make the claims patentable.[xiv]

Moving on to the multimillion-dollar question; what can be done to provide protection of new discoveries, to thereby move those discoveries into patentable inventions? First, realizing that extremely broad claims for diagnostics are largely dead.  Second, identifying and researching molecules that may bring more man-made aspects into the claims, and specifically man-made aspects that are not commonly used research protocols.  I used radiolabeling and fluorescent labeling of molecules in research in the early 2000’s.  During that time, these labeling procedures were not considered cutting edge, but were regularly employed (though radiolabeling much less so due to administrative and safety concerns with radioactive materials). However, using the MuSK diagnostic as an example, identifying specific epitopes, which are not simply a portion of the MuSK protein, and that bind particularly well to the antibodies and/or provided a very strong signal-to-noise ratio would have been helpful to convince the court of patentability.  For example, a labeled and quenched diagnostic molecule[xv] may have saved this patent, which had a priority date of June 2000.  For medical companies seeking intellectual property protection for their research, especially in diagnostic areas, it is critical to think outside the box. Creative problem solving with a patent attorney provides avenues to protection that would otherwise be unavailable.

[i] See, Assoc. for Molec. Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 133 S.Ct. 2107, 2116-7 (2013); Mayo Collaborative Svcs. v. Prometheus Labs., Inc., 566 U.S. 66, 132 S.Ct. 1289, 1300 (2012).

[ii] Mayo Collaborative Svcs. v. Prometheus Labs., Inc., 566 U.S. 66, 132 S.Ct. 1289, 1294 (2012).

[iii] Athena Diagnostics, Inc. v. Mayo Collaborative Svcs., LLC, No. 2017-2508, slip 4 (Fed. Cir. 2019); Koneczny, et al., The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J Anat. 2014 Jan; 224(1): 29-35.

[iv] Myasthenia Gravis Fact Sheet, Nat’l Inst. Of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Myasthenia-Gravis-Fact-Sheet, last accessed February 13, 2019.

[v] Koneczny, et al., The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J Anat. 2014 Jan; 224(1): 29-35; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867884/, last accessed February 13, 2019.

[vi] Koneczny, et al., The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J Anat. 2014 Jan; 224(1): 29-35; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867884/, last accessed February 13, 2019.

[vii] Koneczny, et al., The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J Anat. 2014 Jan; 224(1): 29-35; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867884/, last accessed February 13, 2019.

[viii] Myasthenia Gravis Fact Sheet, Nat’l Inst. Of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Myasthenia-Gravis-Fact-Sheet, last accessed February 13, 2019.

[ix] Athena Diagnostics, Inc. v. Mayo Collaborative Svcs., LLC, No. 2017-2508, slip 3 (Fed. Cir. 2019).

[x] Athena Diagnostics, Inc. v. Mayo Collaborative Svcs., LLC, No. 2017-2508, slip 5 (Fed. Cir. 2019).

[xi] Athena Diagnostics, Inc. v. Mayo Collaborative Svcs., LLC, No. 2017-2508, slip 6 (Fed. Cir. 2019).

[xii] Athena Diagnostics, Inc. v. Mayo Collaborative Svcs., LLC, No. 2017-2508, slip 9-10 (Fed. Cir. 2019).

[xiii] Athena Diagnostics, Inc. v. Mayo Collaborative Svcs., LLC, No. 2017-2508, slip 15, et seq. (Fed. Cir. 2019).

[xiv] Athena Diagnostics, Inc. v. Mayo Collaborative Svcs., LLC, No. 2017-2508, slip 16 (Fed. Cir. 2019).

[xv] See, Bogdanov, Jr., et al., Cellular activation of the self-quenched fluorescent reporter probe in tumor microenvironment. Neoplasia. 2002 May; 4(3): 228-36; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1531696/