Argument preview: The right to study genes

At 10 a.m. next Monday, the Supreme Court will hold a sixty-five-minute oral argument on the control, through patent ownership, of research studies on human genes taken out of the body.  Arguing against such patents in the case of Association for Molecular Pathology v. Myriad Genetics (docket 12-398) will be Christopher A. Hansen of New York, an attorney with the American Civil Liberties Union, with twenty-five minutes of time.  Following, with ten minutes of time, will be Solicitor General Donald B. Verrilli, Jr., representing the U.S. government as amicus, supporting neither side fully.  Representing Myriad, with thirty minutes of time, will be Gregory A. Castanias of the Washington, D.C., office of the Jones Day law firm.

Background

The human body can be defined by its genetic code — the array, unique to each person, of the genes or basic fragments of DNA that determine the physical characteristics of that person.  A person gets genes from each parent, so they are the basic markers of heredity.  It has been estimated that a human being has as many as 25,000 genes.  They create the proteins that do the work of the body.

Anyone who watches a crime lab drama on television has some, probably incomplete, familiarity with using DNA samples to help solve crimes by potentially identifying the suspect.  The Supreme Court has become legally familiar with DNA sampling through several criminal cases, including one this Term on taking DNA samples from arrested suspects, perhaps to solve some “cold case.”

But now the Court is confronting a more basic legal issue about the science of human genetic study: can one get a patent to gain the exclusive right to do research on specific genes that have been taken out of the body?

Genetic research can be very complex, but it also can be done in simpler form in tests by doctors and clinicians.   This is very important research for treating some diseases because one’s parents, while passing along such benign characteristics as eye color, can also pass on an increased risk of some diseases through a mutated gene.  Knowing that can suggest treatment options for those found to be at risk.

In the case now before the Justices, two genes are involved, and they appear to be markers of susceptibility to two hereditary forms of cancer: of the breasts, and the ovaries.   Testing for the presence in a female patient of these genes — they go by the labels “BRCA1” and “BRCA2” — can tell whether that patient has a higher risk of one of those forms of cancer.  BRCA1 correlates, at an eighty-five-percent risk level, with breast cancer, and BRCA2 does so, at a fifty-percent risk, with ovarian cancer.

Myriad Genetics, Inc., a company based in Salt Lake City, Utah, together with the University of Utah Research Foundation, has obtained several federal patents on “isolated” forms of BRCA1 and BRCA2.   Myriad’s company website describes what it does: “Myriad Genetics is a leading molecular diagnostic company dedicated to making a difference in patient’s lives through the discovery and commercialization of transformative tests to assess a person’s risk of developing disease, guide treatment decisions and assess risk of disease progression and recurrence.”

Using genetic-mapping technology, Myriad learned how to take those genes out of a human body and isolate them for laboratory study.

That sounds simple enough, but it actually is a complex process.  The legal question surrounding the right to study those “isolated genes” also is not simple.

On the one hand, Myriad claims that it was entitled to patents on its isolation technology because it did something that no one previously had been able to do, and its legal papers have claimed that this took “an enormous amount of human judgment, including how to define the beginning and end of these genes.”

On the other hand, those who oppose patenting of isolated genes claim that Myriad did not create anything new, since the genes remained the natural material they had inside the human body, unchanged, and patents cannot legally be given to “natural phenomena” or something that is merely the product of “the laws of nature.”

That is the argument that the Supreme Court said on November 30 that it would seek to settle.  And the true significance of this dispute has become clear in a wide variety of legal briefs taking one side or the other in the fundamental issue.  The Court has had few cases with the potential of this one to make law with such a wide impact across science, medicine, and basic research.

There does remain, however, a possible procedural complication that might lead the Court away from deciding the core question of patentability, however important that question may be and however much the scientific and medical communities may want it decided.   That is related, in fact, to an issue that the Justices refused to grant in their November order: who has a right to be in court to challenge Myriad’s patents?

Potential procedural obstacle

The Court has the authority to decide a case, under Article III of the Constitution, only if there is a live controversy before it, between two opposing sides that have a genuine interest in the dispute, at all times during the lawsuit’s unfolding.  But Myriad’s lawyers, and other attorneys who have filed briefs, have raised questions with the Court on whether there remains a live controversy in this case.

The legal complaint against Myriad’s patents on isolated genes was filed in 2009, by twenty challengers: four national organizations of doctors, researchers, clinicians, and other health professionals, along with six leading geneticists, two genetic counselors, two women’s health and breast cancer organizations, and six patients who had been diagnosed as being at risk for one of the hereditary forms of cancer.

However, when the case reached the specialized federal appeals court that handles patent cases — the Federal Circuit Court in Washington — that court ruled that only one of the individual physicians, Dr. Harry Ostrer, then at New York University, had a genuine interest at stake.

He was the only one, the Federal Circuit ruled, who had faced the potential of an enforcement action against him by Myriad, to protect its patents.  He had been doing research on BCRA genes at NYU, but stopped, he claimed, out of a credible fear of Myriad taking action against him.

The Circuit Court went on to reject Dr. Ostrer’s challenge on the merits, upholding Myriad’s patents.  It found that the company had created “a new chemical entity” that was the product of “human ingenuity,” and was not merely a product of a law of nature.

Dr. Ostrer, along with the twenty other challengers, took the case on to the Supreme Court, and they asked the Justices not only to rule on the patent-eligibility question, but also on whether the challengers other than Dr. Ostrer could be allowed into the case to press the challenge.   They argued that the Federal Circuit took too narrow a view of who could sue to contest a patent.

In granting review, the Court refused to hear that separate issue, thus leaving Dr. Ostrer as the only challenger remaining in the case — and thus the only one supporting Article III jurisdiction for the Court.  There is no doubt, of course, that Myriad, on the other side, has a direct stake in the outcome: its exclusive rights to BRCA1 and BRCA2.

In opposing review, Myriad had argued that the Court should not take the case, because the Justices would first have to face questions about their authority to rule at all — that is, the issue of whether Dr. Ostrer had “standing” to be before the Court.  It noted that he had since left NYU (for the Albert Einstein College of Medicine in New York City), and there was absolutely no controversy between his new employer and Myriad, so Dr. Ostrer had no residual claim.

Allthough the Court granted review only on the validity of Myriad’s patents, and thus declined silently to review the “standing” issue, Myriad in its later filings has continued to press the argument that no live controversy remains, and thus argued that the case should be dismissed for “lack of jurisdiction.”

The procedural argument against a decision now on Myriad’s patents is strenuously supported in an amicus brief filed for a trade group, the Biotechnology Industry Organization.  That brief cited a number of additional complications about Dr. Ostrer’s “standing,” and about whether there remains any controversy at all between him and Myriad, and whether there is any risk that the BCRA testing he might want to do would violate the patents.

That brief, authored by former U.S. Solicitor General Seth P. Waxman, said that “in the face of this daunting task” of sorting out the Article III issue, “the most prudent course” for the Court would be to send the case back to lower courts to explore the situation further.  The “issues addressed in this case,” the brief said, “are too important to be decided” without sorting out these complications.

In a reply brief, the challengers’ lawyers devoted less than two pages of argument to the issue, claiming that Dr. Ostrer retains “standing” because his interests are still opposed to those of Myriad.  That brief noted that the Federal Circuit has rejected Myriad’s “standing” challenge three times.  And the brief made a fleeting attempt to renew its claim that the other challengers, too, should have been found to have “standing.”

Because the question of whether there remains a live controversy is a question about the Court’s authority to rule at all, the Justices at least will have to consider that as they move toward a decision.  It may well be explored at the April 15 argument.

Petition for certiorari

When the challengers filed their petition in the Supreme Court last September, it was their second attempt to get the Justices to answer a simply stated question: “Are human genes patentable?” Previously, in December 2011, they had raised that question (along with the rights of the challengers to pursue their case) after the Federal Circuit had first upheld Myriad’s patents.

In March 2012, the Supreme Court, without ruling on any issue, sent the case back to the Federal Circuit to consider the impact, if any, of a new ruling by the Justices limiting the right to patents on inventions that only reflected the working of the laws of nature.  In response, the Federal Circuit once again upheld the Myriad patents, and the challengers then returned to the Supreme Court.

As has been true of their case since its beginning in 2009, their new petition once again sought a sweeping ruling that “human genes and the information they contain” should never be granted a patent, at least when the genes retain their natural form.

Patent law, the petition noted, allows protection for inventions or discoveries that involved “any new and useful . . . composition of matter.”  But, it said, the Supreme Court had not ruled in more than thirty years on when “composition of matter” was patent-eligible.  “The scientific, medical, and legal communities need guidance” on that, it added.

This case, the challengers said, “is an ideal vehicle” for facing the issue of whether “isolated genes,” unaltered from what they were in the human body, are patentable.  “This is the first case to present and thoroughly litigate the issue of whether isolated DNA is patentable subject matter,” the petition argued.  “At the District Court, all parties agreed on the fundamental characteristics of isolated DNA and disputed only the application of the law to the facts.”

Remarking that the Federal Circuit judges had exhibited the uncertainty about the patent-eligibility issue that now prevails generally, the petition also said that the government had taken different positions, with the Patent Office in favor of patenting “isolated genes” and other government agencies opposed.

“Until the patent eligibility of isolated genes is clarified, important stakeholders will be forced to act — or will be chilled from acting — without clear legal guidance,” the document contended.

Myriad’s claims, the petition asserted, include “every single natural variation of the genes, including those that have not yet been isolated.”  Myriad, it added, has used its exclusive patent rights to the isolated genes “to prohibit standard clinical testing” and the patents have allowed it “to exclude the rest of the scientific community from examining the naturally-occurring genes of every person in the United States.”

Myriad opposed review of the new petition, arguing that the Federal Circuit had done “nothing more than the application of settled law to particular facts.”

On the challengers’ protest, the research company argued that its patents did not cover human genes “or any human being’s DNA,” but rather were limited to “BRCA molecules” that had been isolated from their “naturally occurring environment.”

The Patent Office, Myriad noted, “has long recognized the human ingenuity required to create isolated DNA molecules.”  In the Patent Office’s view, the brief said, ” ‘isolated’ molecules of DNA reflect human-made, patent-eligible inventions.”  Indeed, it added, the Patent Office has issued “thousands of patents directed to isolated DNA molecules,” and it commented that Myriad’s own patents had originated fifteen years earlier.

With the certainty of patentability established over some three decades, Myriad’s filing said, “the investing and inventing communities” have proceeded to “develop significant advancements in human, agricultural, and industrial products” in an “outpouring of scientific creativity.”

It argued that Myriad’s inventions in “molecular sequencing techniques” have been “universally hailed,” and have not “inhibited others from developing additional technologies in this field.”

The challengers’ petition drew the support of a wide array of medical organizations, women’s rights and health advocates, professors of medicine, health policy and genetics, and biotechnology groups from the U.S. and abroad.

The Court’s grant order accepted only the first question, “are human genes patentable,” and bypassed the petition’s separate questions on a disputed Myriad method patent and on the challengers’ “standing” to sue.

Briefs on the merits

The brief on the merits of the challengers (technically, it is the brief of only Dr. Harry Ostrer, the only challenger found to have “standing”) opened with the two themes that it has stressed for the past four years of this unfolding case: first, that human genes are products of nature, and, second, that Myriad’s patents sweep in under its monopoly all of the two genes it has isolated.

“How genes work andwhether variants are harmful or not are laws of nature,” the brief said. Myriad “did not invent any genes or variants or cause their significance.”  What Myriad did so, it noted, was to obtain patents on BRCA1 and BRCA2.

But, the document quickly added, “the claims are not limited to any form, variation, or structure of the BRCA1 or BRCA2 genes, and they cover the BRCA genes of every person in the United States, even genes that Myriad has never seen. . . .  The claims reach all possible uses of the claimed genes. . . .  Myriad has a monopoly on clinical testing of its genes in the U.S.”

If Myriad’s legal argument is sound, the brief contended, one could claim that a kidney “isolated” from the body was eligible for a patent, so would “gold ‘isolated’ from a stream,” and so would “leaves ‘isolated’ from trees. . . . This defense defies common sense and elevates the draftsman’s art over the long-standing prohibition on patenting of products and laws of nature.”

Attempting to keep the case focused on the challengers’ broadest claim, the brief said it does not contest the method Myriad uses for removing the two genes from the body nor the process of testing them for mutations, nor any drugs developed as a result of that study.  “The only question presented by this case is whether human genes can themselves be patented,” the document said.  The target of the challenge, it stressed, are the nine claims Myriad asserts on “the genes themselves,” and all of their “structures and uses.”

The brief also sought to assure the Court that it did not reach what the brief treats as a separate question — that is, whether patents are available for “complementary DNA” (cDNA),” that is, DNA molecules in an artificial form.   The brief did suggest, though, that the patentability of those, too, should be treated as doubtful, at best.

More than a third of the fifty-eight-page brief is devoted to the challengers’ recital of how genes work and the background of the case, in an effort to immerse the Court deeply in their core challenge.

The remainder of the brief is made up of efforts to show that Myriad’s patents fall under any one of the three ways of determining whether a patented invention is actually a claim to “natural phenomena.”  First, the patented DNA fragments are not “markedly different” from any that are found in nature; second, they are not the result of “any inventive concept” but rather resulted from routine isolation activity; and, third, they preempt use of the genes, “foreclosing future innovation out of proportion with” Myriad’s contribution.

The brief’s final point expands somewhat on a point fleetingly made in the challengers’ petition: that Myriad patents violate the Constitution’s First Amendment because they “lock up the body of knowledge about these two genes,” in a form akin to “control over thought and pure information.”

Myriad’s brief on the merits emphasized what it deemed the most critical point: the difference between an article of nature and “invention” that results from the intervention of “human ingenuity.”   The most fundamental characteristic of patent law, the filing argued, is that an invention must be “made by man” in order to be eligible for patent rights.

“It is important,” the brief said, “to define clearly the line between an unpatentable manifestation of nature and a patent-eligible composition.”  The key to the latter, it said, is human activity, “i.e., ‘invention.'”

What it did in isolating BRCA1 and BRCA2, Myriad asserted, was the equivalent of inventing a chemical that, applied to human blood or tissue, would show a mutation that genetically predisposed that person to a risk of hereditary breast or ovarian cancer.  What the world did not have before Myriad presented it, the brief said, were “Myriad’s patented molecules,” the result of the “inventive faculties” of the scientists on its payroll.

“Human design and action,” according to Myriad, transformed the physical structure of its molecules, and changed their chemistry.

Once again, as in its opposition to the original petition, Myriad’s merits brief stressed the importance of the lengthy history of Patent Office approval of “extracts or isolates of natural products,” and the long history of companies and investors taking huge financial risks because they knew they were doing so “under this promise of stable patent protection.”

When the company’s brief moved from its introduction to its full legal argument, it began with the renewed challenged to Dr. Ostrer’s “standing” to bring the case.   As if to keep the focus on Dr. Ostrer alone, the remainder of the brief, in referring to the challengers’ arguments, considers them to be Ostrer’s alone.

“In short,” the brief summed up on that point, “this is a lawyer-driven case with no concrete interest to support a declaratory judgment action.”  (The challengers responded only briefly to that in their reply brief on the merits.)

Beyond that jurisdictional question, the Myriad merits brief once again relied upon the stress that the only analytical measure the Court needs to use in deciding patentability here is whether there has been human intervention, which, of course, it insisted that there has been, at great financial risk to Myriad.

The brief sought to answer the challengers’ likening of Myriad’s isolated genes to kidneys, gold or leaves, saying those suggestions were “factually inapt.”  After removal from their natural environment, each of those items remains what it was before, the brief noted.  What Myriad has created by “human manipulation,” it went on, were “specific chemical compositions that differ structurally from what exists in nature, providing the molecules with new properties that permit them to operate differently than their starting materials.”

Reacting to the challengers’ First Amendment claim of “thought control,” the Myriad brief contended that that argument had been waived.   While their lawsuit had included a First Amendment complaint, Myriad said, the challenge to the composition claims was limited solely to the issue of whether patents could be issued for those.   But, in any event, Myriad added, there is no First Amendment violation: its claims are to physical compositions, not abstract thoughts or information.

The federal government has entered the case at the merits stage.  Nominally, its brief was filed “in support of neither party,” but it robustly challenged Myriad’s claims to patents on the two “isolated” genes.

It parted company with the challengers only on the issue that the challengers said need not be decided: that is, whether synthetic or artificial genetic materials, such as “cDNA,” are eligible for patents.  The government argued explicitly that they do qualify.   In order to draw the contrast crisply, the government brief referred to Myriad’s claimed genes as “native DNA,” and to the synthesized variety as “cDNA.”

“The public’s ability to study and use native DNA,” the brief contended, “would be unduly compromised if changes caused by the extraction of naturally-occurring substances from their native environments were sufficient to trigger patent-eligibility.  And while the process of isolating DNA entails physical changes, those changed do not significantly alter the structure or function of the relevant DNA segments.”

On the question of the Court’s jurisdiction to decide the case, the government brief agreed in a footnote that jurisdiction was present.  It included a single sentence to justify that conclusion: “Dr. Ostrer has standing to challenge the validity of [the] patents because his research activities are constrained by [Myriad’s] assertion of their rights under allegedly invalid patents.”

The challengers retained the amici they had at the petition stage, and picked up others representing the same interests in intellectual property law, medicine, women’s rights, and scientific research.

Myriad has slightly more amici support numerically (thirty to twenty-two), with briefs representing biotech industry and other business trade associations, individual biotech companies, and research entities including drug companies, intellectual property associations, medical associations, and the American Bar Association and Federal Circuit Bar Association.

Analysis

If it were clear that the Supreme Court, in granting review of this case and accepting only the question of patent rights for “isolated genes,” had silently satisfied itself that it has jurisdiction to hear the case, that would be the end of the matter.   It is possible, as Myriad’s brief and the supporting brief by attorney Waxman made clear, that too much can be made of the selection of the merits question.

In the petition in this case, and in the challengers’ first petition, the argument on the “standing” issue was that the Federal Circuit Court had used too narrow a standard. in excluding every one other than Dr. Ostrer, but that is different from the issue that Myriad and its amicus were pressing in their filings: does Dr. Ostrer have standing, and thus, does the Supreme Court itself have jurisdiction?

The most that can be said on this point, perhaps, is that, if no Justice raised the issue of “standing” at oral argument, one could be reasonably — but only tentatively — assured that the Court was prepared to move on to decide this case on the merits of patent-eligibility for “isolated genes.”

On that merits issue, the Court’s first hint had come in March of last year when it returned this case to the Federal Circuit to take into account the impact, if any, of the Court’s decision reinforcing the view that natural processes of the human body cannot be put under patent monopolies.   The Court seemed to be raising at least the possibility that the Justices had created a clearer legal standard, and that the Federal Circuit needed to apply that one.

With the Federal Circuit essentially reaffirming its former conclusion, the issue now becomes: did the Federal Circuit do enough new analysis to satisfy the Court that it took the remand as a strong direction to reconsider, and did it fail to do that?   The Court knows its own standard, and can judge whether it was properly applied.

The briefs of the parties, and the federal government, take such firm positions on just what has happened in Myriad’s laboratories that the Court will be able to see little if any middle ground between them.   It thus may be forced to conclude on its own whether the Myriad scientists did enough to modify nature’s materials to give them the characteristic of now being man-made.   That might well be a scientifically challenging choice for the non-scientist Justices.