Covid-19 Update

Given the impact of the 2019-nCoV virus (SARS-CoV-2, COVID-19) on everyday life, it made sense to look into what we know about the virus right now and how that knowledge is driving possible treatments and vaccines, to get life moving back to normalcy.  Much of the material was taken from research articles, which are cited at the end, and distilled into a more approachable format.

Scientists working on the 2019-nCoV virus (SARS-CoV-2, COVID-19) have been studying its genome and found a large similarity with the virus responsible for the SARS outbreak of 2003, meaning that the two viruses are related, like cousins.[i]  The virus is a single strand RNA virus that targets the patient’s innate immune system,[ii] and respiratory system.[iii] A fusion spike protein was identified from COVID-19 which binds to proteins on the target cell membrane, angiotensin-converting enzyme 2 (ACE2), resulting in the ejection of a subunit and altering the shape of the fusion spike.[iv]  This allows the virus to merge with the and inject the virus RNA into the cell.[v] ACE2 is a surface enzyme on cells found in the lungs, arteries, heart, kidneys, and intestines,[vi] and is involved in the humoral immune response, recruitment of leukocytes, and generation of reactive oxygen species.[vii]

Once inside a host or patient, the virus is subject to the host’s immune system. However, uncontrolled activation of the host immune response also can cause cytokine release syndrome, where immune response chemicals, cytokines, are over-released into the patient.[viii] Scientists still have an incomplete understanding of cytokine release syndrome, but studies show that activation by an antigen can result in stimulation of secondary cells and non-immune cells, which triggers the humoral and cellular responses, causing further release of immune cytokines that spirals out of control.[ix] Three immune cytokines, IL-6, IL-10, and IFN-γ are the most commonly found in CRS, with IL-6 spiraling the effects of the other cytokines.[x] This can result in fever, hypotension, clotting issues, difficulty breathing, nervous systems dysfunction, fatigue, headache, cough, kidney damage, cardiac dysfunction, neuronal damage which can be mild to severe, such as confusion, hallucinations, difficulty with speech, seizures, and other organ dysfunction.[xi] In COVID-19, the virus attacks cells in the lungs, causing a release on the immune cytokine IL-6.[xii]

COVID-19 has been found to overactivate T-cells,[xiii] which may result in a reduction in T-cells over time.[xiv] In severe COVID-19, immune cytokines can increase even as the T-cell numbers drop.[xv] As such, the effects seen in COVID-19 infection, such as fever, exhaustion, dry cough, aching, nasal congestion, runny nose, sore throat, diarrhea, and difficulty breathing, clotting problems, and septic shock[xvi] may be due to an overactivation of the host immune system.

Once in the patient’s host cells, the virus uses host enzyme, the viral RNA is converted into viral proteins, which are then cut into active parts by viral enzymes, called proteinases.[xvii] The virus uses topoisomerase III-beta, to replicate, akin to Dengue and Zika virus,[xviii] and viral proteins are used to form new virus particles in the cell, eventually resulting in death of the host cell and release of the virus.

 

Work is ongoing on potential treatments for COVID-19, targeting viral access to host cells or replication. Treatment strategies typically revolve around three goals; (1) maintaining an infected patient; (2) stopping virus from entering a cell; and (3) stopping the virus from replicating in the cell.  Strategy (1) includes ventilation,[xix] something that is also seen in cytokine release syndrome (discussed above).[xx] Further, COVID-19 can result the cytokine release syndrome which appears to be similar to other cytokine release syndromes.[xxi] In cancer-based CRS, therapies against IL-6 have been used (toclizumab and siltuximab or clazakizumab, antibodies against the IL-6 receptor and soluble IL-6), as well as immune chemical sponges to remove the cytokines from the patient.[xxii] A such, suggested treatments for COVID-19 include IL-6 inhibitors,[xxiii] low-dose NSAIDs and steroids to control the inflammation and immune response (though ibuprofen was linked to an increase in ACE2 which is used by COVID-19 to enter cells), and immunosuppressants.[xxiv] Strategy (2) includes targeting the fusion spike or covering the virus particle. Initial studies on the fusion spike show that, despite strong similarities between SARS-CoV and COVID-19, antibodies against the SARS-CoV fusion spike did not have significant interaction with the COVID-19 fusion spike.[xxv] However, development is ongoing for antibodies or RNA treatments that target the COVID-19 fusion spike to prevent COVID-19 entry into host cells.[xxvi] Another option is carbohydrate-binding agents that bind to the virus and prevent it from entering a cell.[xxvii] Strategy (3) targets the host cell or enzymes that are used by the virus to commandeer the host. Suggestions include HIV protease inhibitors, chemotherapy to stop cell replication, and stop the virus from using the host cell enzymes to replicate or compounds that prevent the virus from forming new virus particles in the cell.[xxviii]

Hopefully, significant progress is made against COVID-19 through one or more of the therapeutic strategies.  In the meantime, we are doing our best to limit the spread of this pandemic, by having our employees work from home and limit exposure, along with so much of the country.  Stay safe and healthy during these trying times.

[i] https://www.niaid.nih.gov/news-events/atomic-structure-novel-coronavirus-protein, last accessed April 16, 2020; Wrapp, et al., Cryo,EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020 Mar 13; 367(6483): 1260-3.

[ii] Steward, Host pathways in coronavirus replication and COVID-19 pre-clinical drug target identification using proteomic and chemoinformatic analysis. Drug Target Review. Mar. 30, 2020, https://www.drugtargetreview.com/article/58628/host-pathways-in-coronavirus-replication-and-covid-19-pre-clinical-drug-target-identification-using-proteomic-and-chemoinformatic-analysis/, last accessed April 16, 2020.

[iii] Yang & Wang, COVID-19: a new challenge for human beings. Cell Mol Immunol. 2020 Mar 31.

[iv] Wrapp, et al., Cryo,EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020 Mar 13; 367(6483): 1260-3; https://www.drugtargetreview.com/news/56895/scientists-demonstrate-how-covid-19-infects-human-cells/, last accessed April 16, 2020; https://www.drugtargetreview.com/article/58628/host-pathways-in-coronavirus-replication-and-covid-19-pre-clinical-drug-target-identification-using-proteomic-and-chemoinformatic-analysis/, last accessed April 16, 2020.

[v] Wrapp, et al., Cryo,EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020 Mar 13; 367(6483): 1260-3.

[vi] https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_2, last accessed April 16, 2020

[vii] Bernstein, et al., Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol. 2018 May; 14(5): 325-36.

[viii] Xiao, et al., Plasma exchange can be an alternative therapeutic modality for severe cytokine release syndrome after chimeric antigen receptor-T cell infusion: a case report. Clin Cancer Res. 2019 Jan 1; 25(1): 29-34; Zhang, et al., The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020 Mar 29; 105954.

[ix] Shimabukuro-Vornhagen, et al., Cytokine release syndrome. J Immunother Canc. 2018 Jun 15; 6(1):56

[x] Shimabukuro-Vornhagen, et al., Cytokine release syndrome. J Immunother Canc. 2018 Jun 15; 6(1):56

[xi] Xiao, et al., Plasma exchange can be an alternative therapeutic modality for severe cytokine release syndrome after chimeric antigen receptor-T cell infusion: a case report. Clin Cancer Res. 2019 Jan 1; 25(1): 29-34; Shimabukuro-Vornhagen, et al., Cytokine release syndrome. J Immunother Canc. 2018 Jun 15; 6(1):56.

[xii] Zhang, et al., The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020 Mar 29; 105954.

[xiii] Yang & Wang, COVID-19: a new challenge for human beings. Cell Mol Immunol. 2020 Mar 31.

[xiv] Oon, Fighting COVID-19 exhausts T cells. Nat Rev Ummunol. 2020 Apr 6:1

[xv] Zhang, et al., The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020 Mar 29; 105954.

[xvi] https://www.who.int/news-room/q-a-detail/q-a-coronaviruses, last accessed April 16, 2020; Yang & Wang, COVID-19: a new challenge for human beings. Cell Mol Immunol. 2020 Mar 31.

[xvii] Shereen, et al., COVID-19 infection: origin, transmission, and characteristics of human coronaviruses. J Adv Res. 2020 Mar 16; 24:91-8.

[xviii] https://news.fiu.edu/2020/researchers-target-cells-own-machinery-in-fight-against-covid-19

[xix] https://www.aacn.org/education/online-courses/covid-19-pulmonary-ards-and-ventilator-resources, last accessed April 17, 2020.

[xx] Shimabukuro-Vornhagen, et al., Cytokine release syndrome. J Immunother Canc. 2018 Jun 15; 6(1):56

[xxi] Zhang, et al., The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020 Mar 29; 105954.

[xxii] Shimabukuro-Vornhagen, et al., Cytokine release syndrome. J Immunother Canc. 2018 Jun 15; 6(1):56

[xxiii] Zhang, et al., The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020 Mar 29; 105954; Liu, et al., Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrdome (CRS)? J Autoimmunity. 2020 Apr 10; 102452; Russell, et al., Associations between immune-supressive and stimulating drugs and novel COVID-19- a systematic review of current evidence. Ecancermedicalscience. 2020 Mar 27; 14:1022.

[xxiv] Russell, et al., Associations between immune-supressive and stimulating drugs and novel COVID-19- a systematic review of current evidence. Ecancermedicalscience. 2020 Mar 27; 14:1022.

[xxv] Wrapp, et al., Cryo,EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020 Mar 13; 367(6483): 1260-3.

[xxvi] Wrapp, et al., Cryo,EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020 Mar 13; 367(6483): 1260-3.

[xxvii] Russell, et al., Associations between immune-supressive and stimulating drugs and novel COVID-19- a systematic review of current evidence. Ecancermedicalscience. 2020 Mar 27; 14:1022.

[xxviii] Russell, et al., Associations between immune-supressive and stimulating drugs and novel COVID-19- a systematic review of current evidence. Ecancermedicalscience. 2020 Mar 27; 14:1022.

Lego Suit

The toy industry is in a tumultuous time, with many industry experts concerned physical toys are being replaced by digital ones.1  In fact, one of the largest building toy manufacturers, Lego A/S, which manufactures around 75 million bricks each year, suffered an 8% drop in revenue in 20172  Likely as a result of the competition in the toy industry, Lego has been asserting its intellectual property against competitors. One such example reached the Federal Circuit, whom just issued a nonprecedential opinion in Lego A/S v. Zuru Inc.3

Lego obtained patents on its traditional bricks in 1961 (U.S. Pat. 3,005,282) and began facing competition in the 1980’s when its patent expired.  Since then, Lego has used a combination of copyrights, trademarks, and patents to protect its business. Among its copyrights are two pertaining to the Lego figurines, i.e. minifigures.4

Similarly, Lego obtained trademarks on its minifigures and the heads of the minifigures;5

Zuru, a Chinese company, began selling building bricks having a similar structure to the known Lego brick, and included figurines in some of the building kits.  The Zuru figurines were largely as seen below;6

Lego sued Zuru for copyright and trademark infringement of the minifigure copyrights and trademarks.  In part of the suit, Lego successfully sought an injunction to prevent Zuru from selling its figurines.7 During appeal, the Federal Circuit found that the copyright infringement test (where the case was handled) required a finding

[of whether an] ordinary observer, unless he set out to detect the disparities, would be disposed to overlook them, and regard [the] aesthetic appeal as the same.” … The fact-finder must examine the works for their “total concept and feel.”8

The Court, upon looking at the facts, agreed with the trial court that the look and feel was sufficiently similar to justify the injunction.9

The Federal Circuit then addressed Lego’s claims of design patent infringement of patents D688,328, D641,053, and D614,707.  The design patents cover the following ornamentation of brick structures, respectively;

The alleged infringement was due to the sale of building block kits, such as the one depicted below;10

The preliminary injunction issued by the trial court for the bricks was challenged by Zuru, who argued that there was no irreparable harm caused from the further sale of the bricks.11 The Federal Circuit analyzed whether there was irreparable harm to Lego if an injunction were not issued immediately, and found arguments pertaining to forcing Lego to license its brick designs was insufficient and circular, and loss of market share due to those specific bricks were speculative and lacked any evidence.12 However, this will likely be a small victory for Zuru, whom did not challenge many of the findings leading to the injunction and will likely be enjoined at a later date by the trial court.

These results are not surprising, given the claims brought by Lego. However, it does showcase an interesting strategy of Lego, and its use of various types of intellectual property in securing its marketplace. On the other side, what does this mean for Zuru?  Absent a license from Lego, it appears the company’s building block line will be pulled from Walmart shelves and no longer sold in the U.S.  The company does offer various other toy lines,13 and given its extra-U.S. status might still manufacture building toys destined for locations outside the U.S., where Lego lacks IP protection.


1https://www.forbes.com/sites/karstenstrauss/2013/03/15/breaking-rules-in-the-toy-business/#7280a0fd3717, last accessed Jan. 16, 2020.
2https://www.bbc.com/news/business-43298897, last accessed Jan. 16, 2020.
3See, Lego A/S v. Zuru Inc., No. 2019-2122 (Fed. Cir. Jan. 15, 2020).
4Lego A/S, slip opinion at 6; U.S. Copyright Regs. VA0000655230 and VA0000655104
5U.S. Trademark Regs. 4,903,968; 4520327
6Taken from Lego A/S, slip opinion at 7.
7Lego A/S, slip opinion at 5-6.
8Lego A/S, slip opinion at 11.
9Lego A/S, slip opinion at 12, 14.
10https://www.walmart.com/ip/MAX-Build-More-Building-Bricks-Value-Set-759-Bricks-Major-Brick-Brands-Compatible/364375176, last accessed Jan. 16, 2020 (image cropped).
11Lego A/S, slip opinion at 15.
12Lego A/S, slip opinion at 16-17.
13See, https://zuru.com/product-list/?brand=brand&category=category&is_new=false&language=en, last accessed Jan. 16, 2020.

The Difficulties in Diagnostic Patents, post-Mayo

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/