Category: Gene Patents

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Biotech Gene Patents Innovation Inventors Uncategorized

How IP-Fueled Innovations in Biotechnology Have Led to the Gene Revolution

scientist looking through a microscopeWe’ve released a new issue paper, The Gene Revolution, by Amanda Maxham, a research associate and writer at the Ayn Rand Institute.

Dr. Maxham explores how innovations in biotechnology, enabled by the intellectual property rights that protect them, have led to the “Gene Revolution,” where scientists use genetic engineering to dramatically improve human life. In order to combat widespread misinformation about genetically modified organisms (GMOs), she traces mankind’s long history of improving plants, animals, and microorganisms to better serve our needs.

We’ve included the Executive Summary below. To read the full issue paper, please click here.

The Gene Revolution

By Amanda Maxham

Executive Summary

Mankind has been improving plants and animals for millennia. Simply by selecting and breeding those they liked best, our ancestors radically improved upon wild species. Today’s biological inventors, with a deeper understanding of genetics, breeding, and heredity, and with the protection of intellectual property rights, are using the technology of genetic engineering to start a “Gene Revolution.”

In the field of medicine, custom-built genetically engineered microorganisms are brewing up rivers of otherwise rare human hormones, life-saving medicines, and much-needed vaccines. In agriculture, scientists are combining their understanding of plant genetics with laboratory techniques of modern molecular biology to “unlock” the DNA of crop plants. By inserting genes from other plants or even common microorganisms, they are able to give plants desirable traits, solving problems that farmers have faced for millennia—faster and more precisely than ever before.

But despite its successes and a bright future, biotechnology is under attack by activists who spread misinformation and foster consumer mistrust. They have been directly responsible for onerous regulations and other hurdles to innovation that are threatening to stifle what could and should be the “third industrial revolution.”

In an effort to combat this misinformation, this paper situates genetic engineering within mankind’s long history of food improvement and then highlights how genetic engineering has dramatically improved human life. In it, you’ll find 29 plants, animals, and microorganisms, from insulin-secreting E. coli to engineered cotton, from cheese-making fungus to chestnut trees, that represent the promise and possibilities that the Gene Revolution holds–if we hold precious and continue to protect the freedom to invent and the power of scientific innovation.

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Biotech Gene Patents Innovation Intellectual Property Theory Inventors Patent Law Patent Litigation Patent Theory Patentability Requirements Supreme Court Uncategorized

Federal Circuit Threatens Innovation: Dissecting the Ariosa v. Sequenom Opinion

By Patent Publius

Earlier this month, the Federal Circuit issued its opinion in Ariosa v. Sequenom, a closely-watched biotechnology case with significant repercussions for patent-eligibility analysis generally. Unfortunately, the Federal Circuit misapplies the Supreme Court’s analytical framework from Mayo v. Prometheus, striking down Sequenom’s important innovation for the prenatal diagnosis of fetal abnormalities. The shame here is that the Mayo opinion itself was unnecessarily broad, and the Federal Circuit has now interpreted it to be even broader.

Section 101 of the Patent Act provides that “[w]hoever invents or discovers any new and useful process, machine, manufacture, or composition of matter . . . may obtain a patent therefor,” but there are judicial exceptions for “laws of nature, natural phenomenon, and abstract ideas.” Those exceptions are relevant here, where the Federal Circuit considers whether the claimed method of using cell-free fetal DNA (“cffDNA”) to make diagnoses is patentable subject matter.

In the Mayo opinion, the Supreme Court established a two-step analysis for determining whether method claims merely “set forth laws of nature” or instead apply those natural laws with “additional features” so as to become patent-eligible processes. The first step looks at whether the claims are directed to a patent-ineligible law of nature, and the second step looks at whether additional elements “transform the nature of the claim” into something that amounts to more than a claim on the law of nature itself.

Applying Mayo to the case at hand, the Federal Circuit’s analysis of the first step is perfunctory:

In this case, the asserted claims of the ‘540 patent are directed to a multistep method that starts with cffDNA taken from a sample of maternal plasma or serum—a naturally occurring non-cellular fetal DNA that circulates freely in the blood stream of a pregnant woman. . . . It is undisputed that the existence of cffDNA in maternal blood is a natural phenomenon. . . . The method ends with paternally inherited cffDNA, which is also a natural phenomenon. The method therefore begins and ends with a natural phenomenon. Thus, the claims are directed to matter that is naturally occurring.

The Federal Circuit’s conclusion that the method “begins and ends with a natural phenomenon” tells us very little of how this principle is to be applied generally. Certainly, the method begins with a biological sample of maternal plasma or serum that contains paternally-inherited cffDNA, and it makes sense to say that it begins with a natural phenomenon. Of course, everything begins with a natural phenomenon, so this is hardly instructive.

But it’s inaccurate to say that the method simply ends with cffDNA. The method itself takes the miniscule amount of cffDNA found in the sample and exponentially amplifies it to detectable levels. The resulting substance, unlike the beginning sample, gains significant and new utility from a diagnostic perspective. What comes out of the process is an artificially-enriched substance that, unlike the maternal plasma or serum fed into the process, can be used for many diagnostic purposes. That is, the method ends with a substance that is anything but a natural phenomenon.

Applying the second step of the Mayo framework, the Federal Circuit finds that Sequenom’s claimed methods are not significantly transformative:

Like the patentee in Mayo, Sequenom contends that the claimed methods are patent eligible applications of a natural phenomenon, specifically a method for detecting paternally inherited cffDNA. Using methods like PCR to amplify and detect cffDNA was well-understood, routine, and conventional activity in 1997. The method at issue here amounts to a general instruction to doctors to apply routine, conventional techniques when seeking to detect cffDNA. Because the method steps were well-understood, conventional and routine, the method of detecting paternally inherited cffDNA is not new and useful. The only subject matter new and useful as of the date of the application was the discovery of the presence of cffDNA in maternal plasma or serum.

The last sentence is the most perplexing: The “discovery of the presence of cffDNA in maternal plasma or serum” is what sets Sequenom’s method apart from that which was “well-understood, routine, and conventional activity in 1997.” The problem here stems from the Federal Circuit’s failure to consider the claimed method as a whole, as it purportedly sets out to do: “[W]e next consider the elements of each claim both individually and ‘as an ordered combination’ to determine whether additional elements ‘transform the nature of the claim’ into a patent-eligible application.”

Undoubtedly, some parts of Sequenom’s method were already well-known. No one denies, for example, that some of the techniques involved in amplifying and then detecting cffDNA were, in their general features, already conventional activity in the field (e.g., PCR). What makes the Sequenom method patentable is the sum of its parts, that is, the method as a whole that the Federal Circuit acknowledges to contain the new and useful discovery of cffDNA in the maternal plasma or serum.

This is the principal feature of Sequenom’s claimed invention and its central argument throughout the litigation. Yet, the Federal Circuit relegates it to one of “Sequenom’s remaining arguments” and addresses it in a brief paragraph near the end of the opinion, where it inexplicably claims: “This argument implies that the inventive concept lies in the discovery of cffDNA in plasma or serum. Even if so, this is not the invention claimed by the ’540 patent.” On the contrary, this discovery is anything but conventional, and the method as a whole transforms a natural phenomenon into something both artificial and patentable.

Overbroad (and Dangerous) Principles

The overbreadth of the Federal Circuit’s analysis threatens diagnostic methods across the board. If a method of detecting a natural phenomenon is always “directed to” that natural phenomenon, as the Federal Circuit suggests, then all such methods are prima facie patent-ineligible under the first step of the Mayo framework and must fight the uphill battle under its second step. This is particularly troubling since virtually all diagnostic tests detect natural phenomena. Moreover, the Federal Circuit’s application of the second step of the Mayo framework looks at each part of the method individually, ignoring the claimed method as a whole.

Not only is this principle breathtakingly broad in the damage it could cause to the diagnostics industry, it is neither required by, nor even consistent with, the controlling case law. Only claims to natural phenomena are per se patent-ineligible; however, applications of natural phenomena are generally patentable. Detecting a natural phenomenon is not the same thing as the phenomenon itself. It is instead a specific application of that phenomenon. While the Federal Circuit states that applications of natural phenomena are patent-eligible, it quickly proceeds to categorically suggest a principle under which all diagnostic inventions may have one foot in the Section 101 grave.

Another overly-broad principle from the Federal Circuit opinion comes from this statement: “For process claims that encompass natural phenomenon, the process steps are the additional features that must be new and useful.” This may at first seem obvious and uncontroversial, but in the context of the rest of the opinion, it proves quite problematic. The Federal Circuit cites Parker v. Flook as support: “The process itself, not merely the mathematical algorithm, must be new and useful.” But note the subtle distinction between the two quotes. The Supreme Court discussed the “process itself,” while the Federal Circuit discusses the “process steps.”

This distinction has two important effects. First, it is one of many signals in the opinion that demonstrates the Federal Circuit’s improper dissection of the claimed method into its components parts. Rather than consider whether the “process itself” is “new and useful,” as the Flook opinion had done, the Federal Circuit analyzes each step individually. There’s no consideration of how the steps integrate into the process as a whole, and there’s no mention of whether that entire process claims something other than the natural phenomenon itself.

Second, the Federal Circuit looks at each step in a very general way and ignores the details of the steps that confer patent eligibility. For example, the opinion spends much time discussing how routine the PCR method was at the time of filing. But Sequenom never claimed the PCR method itself. The Federal Circuit fails to address Sequenom’s central argument: The claimed method is a new process of detecting cffDNA by devising a novel sample source from which to extract it, namely, maternal plasma or serum. The application and adaptation of known techniques in this inventive way to a newly-discovered sample source is not conventional.

Finally, the most problematic and new principle that may emerge from this opinion is a subtle, yet very significant, extension of Mayo to invalidate claims directed to routine and conventional applications of natural laws. Mayo teaches that the mere addition of what is purely routine and conventional at the time of filing cannot save a claim directed to a law of nature: “In particular, the steps in the claimed processes (apart from the natural laws themselves) involve well-understood, routine, conventional activity previously engaged in by researchers in the field.”

The Federal Circuit appears to exclude from the patent system a routine application of a law of nature, rather than, as Mayo requires, a law of nature to which merely routine activities have been appended. That is, if one skilled in the art could, after being informed of a newly-discovered law of nature, use routine skill to arrive at the claimed invention, then that claimed invention may be invalidated under the Federal Circuit’s reasoning.

This is contrary to Mayo, and it could conceivably invalidate huge swaths of meritorious inventions. Once the principles underlying a new method are known, application of those principles to devise that method will very often be obvious. The Supreme Court has been very consistent in saying that applications of laws of nature are patent-eligible, including those applications that would have been obvious in view of newly-discovered laws of nature. It is a subtle, but important, point to recognize that Mayo did not say the opposite, as the Federal Circuit now interprets it.

The Preemption Question

One potential bright spot in the Federal Circuit’s opinion is its treatment of preemption. Instead of being a test for patent eligibility, preemption is properly understood as being solely a policy underlying eligibility exclusions. It can at most serve as an after-the-fact check on whether an already-reached conclusion of eligibility is consistent with this policy. The Federal Circuit here mostly validates this position:

The Supreme Court has made clear that the principle of preemption is the basis for the judicial exceptions to patentability. Alice, 134 S. Ct at 2354 (“We have described the concern that drives this exclusionary principal as one of pre-emption”). For this reason, questions on preemption are inherent in and resolved by the § 101 analysis. . . . Where a patent’s claims are deemed only to disclose patent ineligible subject matter under the Mayo framework, as they are in this case, preemption concerns are fully addressed and made moot.

This may ultimately be a hollow victory, however. The Federal Circuit also says: “While preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility.” The problem here is that it is impossible to ever show complete preemption because it is impossible to know at the time of filing whether something outside the claims could also be conceived. Inventions are, by definition, unforeseeable.

Moreover, allowing anything less than complete preemption to be sufficient to invalidate a claim threatens to invalidate far too much subject matter. By their very nature, patents are preemptive. Allowing courts and patent examiners to freely draw the line between allowable and prohibited levels of preemption invites unpredictable and arbitrary decisions based on personal value judgments. That very problem arose here, where the district court held the claims invalid, at least in part, because they covered what the judge deemed to be “the only commercially viable way of detecting” the embodiment of the law of nature.

The Promising Potential in Judge Linn’s Concurrence

Judge Linn’s concurrence is promising, but it falls short of its full potential. Judge Linn does a better job than the majority in recognizing and understanding the legal significance of the important facts of this case:

[N]o one was amplifying and detecting paternally-inherited cffDNA using the plasma or serum of pregnant mothers. Indeed, the maternal plasma used to be “routinely discarded,” . . . because, as Dr. Evans testified, “nobody thought that fetal cell-free DNA would be present.”

It is encouraging to see that a Federal Circuit judge has finally gone on record to point out the problems caused by ever-broadening applications of Mayo:

I join the court’s opinion invalidating the claims of the ‘540 patent only because I am bound by the sweeping language of the test set out in Mayo Collaborative Services v. Prometheus Laboratories, Inc. . . . In my view, the breadth of the second part of the test was unnecessary to the decision reached in Mayo. This case represents the consequence—perhaps unintended—of that broad language in excluding a meritorious invention from the patent protection it deserves and should have been entitled to retain.

Judge Linn errs, however, in his acquiescence that Mayo requires the majority’s conclusion. Judge Linn’s concurrence generally reads more like a dissent, but he undercuts his own criticism of Mayo and its effects by calling his opinion a “concurrence.” As he laments:

The Supreme Court’s blanket dismissal of conventional post-solution steps leaves no room to distinguish Mayo from this case, even though here no one was amplifying and detecting paternally-inherited cffDNA using the plasma or serum of pregnant mothers.

But the second half of this sentence shows the critical distinction that makes Sequenom’s claims patent-eligible, even in view of Mayo. Unlike the claims analyzed in Mayo, Sequenom’s process is new and not routinely engaged in by researchers in the field. Judge Linn even states the point better elsewhere in his own concurrence:

Unlike in Mayo, the ‘540 patent claims a new method that should be patent eligible. While the instructions in the claims at issue in Mayo had been widely used by doctors—they had been measuring metabolites and recalculating dosages based on toxicity/inefficacy limits for years—here, the amplification and detection of cffDNA had never before been done.

Judge Linn should be praised for critiquing Mayo as bad law that has led to the invalidation of untold meritorious patent claims. Unfortunately, however, he may have unintentionally contributed to the expansive scope of Mayo about which he complains by failing to factually distinguish (and hence cabin) the Supreme Court’s opinion when presented with such a good opportunity to do so.

All told, the Federal Circuit’s opinion in Ariosa v. Sequenom is a predictable, yet unfortunate, application of the Supreme Court’s disastrous reasoning in Mayo. The unintended consequences of the Supreme Court’s opinion have been further realized in the Federal Circuit’s denial of Sequenom’s innovative claimed method for diagnosing fetal abnormalities. Only time will tell how many other innovations will suffer under the Supreme Court’s careless expansion of Section 101’s patent eligibility analysis.

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Biotech Commercialization Gene Patents Innovation Patent Law Patentability Requirements Uncategorized

The Critical Role of Patents in the Development, Commercialization, and Utilization of Innovative Genetic Diagnostic Tests

Last week, CPIP released an important new policy brief, The Critical Role of Patents in the Development, Commercialization, and Utilization of Innovative Genetic Diagnostic Tests, by Professor Chris Holman.  Professor Holman explains the important role that patents play not only in attracting the capital investment needed to bring genetic tests to market, but also in incentivizing companies to invest in educating patients and their doctors about new tests and in facilitating insurance reimbursements for new tests. Professor Holman addresses the common mistaken assumption that patents negatively impact patient access to genetic diagnostic testing, concluding instead that patent protection is a critical spur for the innovation and commercialization of next-generation genetic diagnostic tests.

The full document (including endnotes) is available here, and we’ve also included the text (without endnotes) below.

The Critical Role of Patents in the Development, Commercialization, and Utilization of Innovative Genetic Diagnostic Tests

Christopher M. Holman

Genetic diagnostic testing is an increasingly high-profile subject in the minds of the public, academia, and policymakers.  This increased attention was prompted in part by highly publicized events such as Angelina Jolie’s decision to undergo a preemptive double mastectomy based on the results of a genetic diagnostic test, followed shortly thereafter by a U.S. Supreme Court decision invalidating patent claims held by the company (Myriad Genetics) that developed the test used by  Ms. Jolie.   Although traditionally viewed as a relatively unglamorous sector of the healthcare market (accounting for less than 2% of total health care spending), genetic analysis and other innovative molecular diagnostics seem poised to become “a powerful element of the healthcare value chain,” playing an increasingly important role in the prediction, detection, and treatment of disease. “Personalized medicine,” a new term that refers to the pairing of a molecular diagnostic test with a patient-specific course of pharmaceutical treatment, represents a particularly promising avenue through which molecular diagnostics might improve therapeutic outcomes while containing healthcare costs.

Those involved in the development and commercialization of innovative molecular diagnostics stress the important role of effective intellectual property rights in attracting the substantial capital investment required to bring these products to market.  Influential voices outside the innovation community, however, have argued strongly against patent protection for molecular diagnostics, claiming that such patents are overly broad, reduce patient access, and inhibit research that might otherwise lead to new and improved diagnostic tests. Most of these critics would acknowledge that strong patent protection is appropriate, and indeed critical, for the development of innovative drugs, in view of the huge cost of developing drugs and securing FDA marketing approval. They argue, however, that the same considerations do not apply to diagnostic tests.  Unfortunately, their argument is based largely on the outdated and now-incorrect belief that diagnostic tests are developed by publicly-funded academics who are primarily motivated by non-patent incentives, and that commercialization of these tests is cheap and easy.

The critics have been heard and are finding resonance in the legislative, judicial, and executive branches.  Legislation to limit the patentability of genetic inventions and the enforceability of genetic patents has been introduced in Congress, although not yet enacted. Omnibus patent reform legislation enacted in 2011 does contain a section requiring the U.S. Patent and Trademark Office (“PTO”) to conduct a study examining the “impact that current exclusive licensing and patents on genetic testing activity has on the practice of medicine, including but not limited to the interpretation of testing results and performance of testing procedures,” and to report back to Congress with recommendations as to how to deal with presumed problems with respect to the ability of health care providers “to provide the highest level of medical care to patients” and of innovators to improve upon existing tests. In the courts, the alleged impact of genetic diagnostic patents on genetic research and the availability of diagnostic testing played an important role in litigation brought by the ACLU against  the genetic testing company Myriad Genetics, challenging the validity of Myriad’s so-called “gene patents.” The ACLU won before the Supreme Court.  The Obama administration filed amicus briefs in the Myriad litigation arguing against patent eligibility for patent claims allegedly relating to genetic testing, and National Institutes of Health (NIH) Director Francis Collins has been an outspoken critic of patents on genetic tests.

The plaintiff’s victory in Myriad has not lessened the call for more severe restrictions on the availability of effective patent protection for innovative molecular diagnostics. When the Supreme Court invalidated some of Myriad’s patent claims relating to the BRCA breast cancer genes, a number of Myriad’s competitors were emboldened to enter the BRCA testing market, and Myriad responded by filing lawsuits alleging infringement of some of its remaining patent claims (patent claims that were not at issue in the previous litigation). In response, Sen. Patrick Leahy (D-Vt.) sent a letter to Francis Collins asking NIH to “use its march-in rights under the Bayh-Dole Act to force Myriad Genetics Inc. to license its patents related to testing for genetic mutations associated with breast and ovarian cancer.”

This essay addresses some of the criticisms that have been leveled against genetic diagnostic testing patents.  It identifies the critical role that patents play not only in the discovery and development of new molecular diagnostic tests, but also in making these tests more accessible to the patients who can benefit from them. When we move beyond the improperly restricted and crabbed view of patents as incentivizing only discovery of new medical drugs or tests, we recognize that patents also have a fundamental role in incentivizing companies like Myriad to create markets for these new discoveries by investing in educating patients and their doctors and in facilitating the reimbursement of patients for the cost of the test via their insurance plans.

Molecular Diagnostic Tests and Personalized Medicine

To understand the important role of patents in molecular diagnostic testing, it is important to have a basic understanding of what these tests are and where they come from. This is important if only because there is substantial misinformation in the public policy debates about these innovative medical discoveries.  Thus, a brief primer on the topic is in order.

Molecular diagnostic tests involve the detection and/or analysis of a molecular biomarker in a patient in order to discern clinically relevant information about that patient. Molecular biomarkers come in many forms – prostate-specific antigen (PSA), for example, is a protein biomarker used to diagnose prostate cancer, while high levels of glucose in the blood can serve as a biomarker for diabetes. Today some of the most promising biomarkers are genetic variations, which are detected by analyzing an individual’s genomic DNA. Some genetic variations in the human breast cancer genes BRCA1 and BRCA2, for example, can be used to predict the likelihood that an individual harboring that variation will develop breast or ovarian cancer. Although significant progress already has been made, scientists are just beginning to scratch the surface of the potential of molecular diagnostic testing. Research continues in the quest to identify and validate new biomarkers correlated with a host of diseases and disease outcomes.

Testing for molecular biomarkers is not only useful in the diagnosis and prognosis of disease; it can also be used to guide doctors in the best course of treatment tailored to the needs of an individual patient. Personalized medicine, for example, encompasses the use of molecular diagnostic testing to identify the best course of drug therapy for an individual patient by (1) identifying the best drug for that individual, or (2) predicting the optimal drug dosage for that particular patient in terms of safety and efficacy.  In a case involving determining personalized levels of drug dosage, Mayo v. Prometheus, the Supreme Court recently invalidated patent claims covering a non-genetic molecular diagnostic test that enables doctors treating patients for Crohn’s disease to prescribe a drug dosage at a level that maximizes efficacy while minimizing the horrible side effects too often endured by patients before the test became available. In doing so, the Court overturned a decision by the Court of Appeals for the Federal Circuit which upheld the validity of the claims – the Federal Circuit’s decision explicitly acknowledged that the claims relate to methods of medical diagnosis and treatment which have until recently been assumed to constitute patentable subject matter.

The fundamental challenge in developing molecular diagnostic tests is identifying and validating clinically significant molecular biomarkers.  The magnitude of this challenge is vastly underappreciated by those who argue against patent protection for these tests. It is true that some relatively rare genetic diseases such as sickle cell anemia, cystic fibrosis and Tay-Sachs are associated with specific genetic variations (sometimes referred to as mutations), and once those variations have been identified it is relatively straightforward for any competent clinical laboratory to test for the presence of a mutation that has been unambiguously associated with the disease. But these are the low hanging fruit. For the vast majority of human diseases which have a genetic component, the correlation between biomarker and clinically relevant information is much less straightforward, and substantial investment is necessary to support the lengthy and labor-intensive research efforts required to discern and validate the clinical significance of novel biomarkers.

With respect to any two individual humans there typically exists about 6 million genetic variations (referred to as polymorphisms) spread across the genome. Most comprise single nucleotide variations that occur on average about once in every 1000 nucleotides. Significantly, almost all of these polymorphisms are believed to be clinically irrelevant.  Thus, the challenge is to identify that small cohort of human genetic variations that can function as useful biomarkers, and to assign and validate their clinical significance.

Compounding the difficulty is the fact that the clinical significance of most genetic variations is substantially affected by the influence of other genetic variations residing throughout the rest of the genome, oftentimes in a manner that is not additive, and by interactions with non-genetic environmental factors. For example, there is often an observed synergistic amplification of susceptibility to disease caused by the interaction of variations at multiple locations in the genome, or, conversely, a dampening of the effect of one variation caused by variations at other locations. It can be extremely difficult to identify and validate correlations for multifactorial genetic diseases of this type, which in large part explains the relatively modest progress that has been made in molecular diagnostic testing in the decade subsequent to the initial sequencing of the human genome.

For example, some genetic variations in the BRCA1 and BRCA2 breast cancer genes have been shown to be associated with an extremely high likelihood of developing cancer, while others are associated with a likelihood of developing cancer only somewhat higher than the general population.  Many of the observed variations in the BRCA genes are believed to be neutral, having no cancer-related implications. In fact, even after years of research and millions of dollars in investments, we are still finding patients with variations in the BRCA genes for which the significance is currently unknown. These “variations of uncertain significance,” or VUSs, constitute a major limitation on the clinical usefulness of molecular diagnostic tests. Patents provide the incentive for the substantial up-front investment in gathering and analyzing the clinical data necessary to assign a predictive value to a VUS.

Shrinking Patent Protection for Molecular Diagnostics and Personalized Medicine

For years, innovative scientists and physicians working in diagnostics and personalized medicine have sought and obtained patent protection for diagnostic tests that are based on the detection and/or analysis of molecular biomarkers. While patent claims covering isolated and synthetic DNA molecules can play some role in this regard, the most direct and effective means of patenting a diagnostic test is by claiming the method itself.  Unfortunately, the Supreme Court’s recent decisions in Mayo and Myriad have substantially impaired the ability of innovators to obtain effective patent protection for DNA molecules used in diagnostic testing and for diagnostic testing methods per se.  Although Myriad has garnered more public attention, Mayo is likely a much more significant decision with respect to the patentability of diagnostic tests, since it most directly implicates the method claims which are so important for effective patent protection in this area of technology.

Three aspects of Mayo could prove extremely problematic for future patenting of molecular diagnostics in general. First, the Court adopted a very broad definition of the term “natural phenomena” as it is applied in the context of patent eligibility for discoveries in medical treatments. The Mayo Court’s definition of this term, which refers to facts of nature that are unpatentable, appears to encompass the discovery of clinically significant biomarkers that is the essence of innovation in diagnostics and personalized medicine. Second, the Court held that in order to be patent eligible, a method claim must include some “inventive concept” above and beyond the discovery of a natural phenomenon. And third, the Court declared that a method claim is patent ineligible if it “preempts” all practical applications of a natural phenomenon.

A recent district court decision, Ariosa Diagnostics v. Sequenom, illustrates the profoundly troubling implications of Mayo for patents on molecular diagnostic methods. On a motion for summary judgment, the judge invalidated all of the genetic diagnostic testing method claims at issue in the case for failure to satisfy the requirements of patent eligibility as set forth in Mayo. In particular, the judge held that the claims failed the “inventive concept” test because they encompassed conventional methods of DNA analysis, and failed the “preemption” test based on a determination that the claims would cover all “commercially viable” methods of performing the test as of the filing date of the patent.

If this is indeed the standard by which the validity of molecular diagnostic claims will be assessed, the prospect for effective patent protection appears bleak.  Innovation in molecular diagnostics resides primarily in the identification and characterization of biomarkers of clinical significance, e.g., genetic variations useful in the diagnosis and prognosis of disease. Once the biomarker and its clinically significant correlation has been identified, conventional forms of DNA analysis involving techniques such as PCR amplification and/or labeled hybridization probes are employed for diagnostic testing. A patent eligibility test that bars the inventor from claiming the use of conventional DNA analysis techniques will render the patent ineffective in blocking competitors from entering the market and thereby free-riding on the initial inventor’s substantial investments in the discovery of this molecular biomarker.

This troubling concern is not mere prophecy. In Ariosa Diagnostics,the judge held that Mayo prohibits any patent claim that encompasses all “commercially viable” means of testing for a biomarker. This decision renders any protection afforded by a valid diagnostic patent illusory.  After all, how many venture capitalists are interested in investing hundreds of millions of dollars in a start-up diagnostic company whose patents are unable to preclude competition by free-riders using alternate, unpatented (but still commercially viable) methods for detecting the same biomarkers that the start-up invested in identifying?

Furthermore, in Myriad, the Supreme Court held that isolated DNA molecules corresponding to naturally occurring DNA are patent ineligible, absent some significant structural difference compared to the naturally occurring molecule. This holding is problematic for innovators in genetic testing because the DNA molecules used in the course of genetic diagnostic testing, such as DNA primers for PCR and hybridization probes, are inherently highly similar in chemical structure to naturally occurring DNA molecules, and thus apparently patent ineligible under Myriad. A district court recently adopted this view in a decision denying the patentee’s motion for preliminary injunction against an alleged infringer in a lawsuit commenced post-Myriad, finding that product claims directed towards DNA primers useful in BRCA genetic testing are likely invalid under Myriad.  The PTO recently issued guidance adopting the same restrictive interpretation of Myriad with respect to DNA primer claims.

The Role of Patents in Molecular Diagnostic R&D

The Unfounded Assumption that Patents Inhibit Research

The plaintiffs in Myriad argued that Myriad’s patents inhibit research that might otherwise lead to improvements in BRCA testing.  Unfortunately, many share this pessimistic view of the role of patents in the research and development of molecular diagnostic tests, and this deeply mistaken notion found support in a number of amicus briefs filed with the Supreme Court in support of the Myriad plaintiffs. A typical example was an amicus brief filed by the American Medical Association, which argued that patents are not only unnecessary to incentivize the optimal level of innovation in genetic diagnostic tests, but that genetic diagnostic patents allegedly inhibit research that could develop improved tests.

The argument that patents inhibit research in genetic diagnostics is based largely on an unfounded assumption that the existence of a patent necessarily precludes research on the patented subject matter. In fact, empirical studies have shown that basic researchers follow a norm of ignoring patent infringement, and that patent owners do not enforce their patents against basic researchers, resulting in a de facto research exemption from liability. Patent owners have little if any incentive to enforce patents against basic researchers – to the contrary, patent owners often welcome third-party basic research on patented subject matter, since it tends to promote and enhance the value of the patented subject matter.

Myriad’s policy toward basic research on the BRCA genes is a good case in point. During the time in which Myriad’s BRCA patents have been in force, basic research on the BRCA genes has flourished in both the US and abroad. While patent-skeptics assume that Myriad’s patents preclude research on the genes, in fact thousands of research articles relating to the genes have been published, many by researchers at leading US academic institutions such as the University of Pennsylvania, the University of Chicago, Emory University, and the University of Rochester. While it has been widely publicized that Myriad has on occasion threatened lawsuits against academic institutions that engaged in genetic diagnostic testing, it is important to bear in mind that these academic institutions were invariably engaged in commercial genetic testing, not basic research – i.e., they were charging patients for the testing services and thus competed with Myriad.

In attempting to support their assertion that patents harm research and development of diagnostic tests, patent-skeptics often point to the “SACGHS Report,” a 2010 report on the impact of patents on patient access to genetic tests that was prepared by the Secretary of Health and Human Services’ Advisory Committee on Genetics, Health, and Society. Despite these citations to the SACGHS Report, the case studies presented in the SACGHS Report for the most part show exactly the opposite. For example, the Report’s case study on the impact of patents and patent licensing practices on access to genetic testing for hereditary hemochromatosis concluded not only that “concerns regarding inhibition of research due to the HFE gene patents do not seem to be supported,” but that substantial basic research aimed at identifying new genes and genetic variations associated with hemochromatosis, along with new methods of testing for these biomarkers, were proceeding in spite of third-party patents.  Similar findings were reported with respect to genetic tests investigated in other case studies, including the tests for cystic fibrosis, hearing loss, and Alzheimer’s disease.

The Important Role of Patents in the Development and Commercialization of Diagnostic Tests

While patents do not inhibit basic research, they do play a critical role in incentivizing the substantial investment required to translate the results of basic research into high-quality, commercially available diagnostic tests that meaningfully impact people’s lives. In a recent report, the President’s Council of Advisors on Science and Technology found that the “ability to obtain strong intellectual property protection through patents has been, and will continue to be, essential for pharmaceutical and biotechnology companies to make the large, high-risk R&D investments required to develop novel medical products, including genomics-based molecular diagnostics.” Similarly, commentators familiar with the challenges associated with the development and commercialization of diagnostics have concluded that patents are vital “to incentivize the significant investment required” for clinical research in personalized medicine. And while the AMA came out against genetic diagnostic testing patents in Myriad, the Association of American Physicians and Surgeons (“AAPS,” a national nonprofit association representing thousands of physicians) filed an amicus brief in support of Myriad’s patents, explaining that “advancing patients interests means supporting and defending incentives for medical innovations.”

Innovators in molecular diagnostics rely heavily on venture capital to fund the years of research, development, and validation necessary to bring a novel diagnostic product to market, and the decision of whether to invest is heavily dependent upon the availability of effective patent protection. Weakening of patent protection for molecular diagnostics will inevitably cause venture capitalists to shift their investments to other sectors of the economy. Not surprisingly, the National Venture Capital Association filed an amicus brief with the Supreme Court in support of Myriad.

One of the most compelling amicus briefs submitted to the Supreme Court insupport of Myriad was filed by Lynch Syndrome International (“LSI”), an all-volunteer organization founded and governed by Lynch syndrome survivors, their families, and health care professionals who treat Lynch syndrome.  Lynch syndrome is a genetic condition caused by genetic variations in certain genes that result in a greatly increased risk of developing colon cancer. Lynch syndrome and BRCA mutations are highly analogous, with one important difference – patents in the area of Lynch syndrome have been nonexclusively licensed, so there has been no single provider to invest in developing and improving genetic tests for Lynch syndrome, nor in making the test widely available to the patients who could benefit from it. In its brief, LSI argues passionately for greater patent protection in the area of genetic diagnostic testing, in the hope that patent exclusivity might incentivize a patent owner to invest in Lynch syndrome in a manner comparable to Myriad’s investment in BRCA testing.

LSI explains that:

The development and commercialization of genetic tests require significant amounts of capital, but capital sources will not provide the necessary funding unless the newly developed tests will have patent protection. Only patent protection will assure the capital sources of sufficient investment return to make the provision of funding worthwhile.

LSI’s brief goes on to urge the Supreme Court to maintain patent eligibility for genetic tests in the hope that patents might provide incentives for the development of high-quality tests comparable to those available for BRCA thanks to the investments made by Myriad. LSI points to the long odds against success facing start-up companies like Myriad, noting that most start-up companies fail, particularly in the area of diagnostics. In the words of LSI:

Myriad’s survival, due largely to patent eligibility for genetic tests, has been a miracle for BRCA1 and BRCA2 patients: without Myriad, it is possible that only fragmented and potentially unregulated testing would be available. Lynch syndrome patients desperately need access to the quality testing that Myriad has been able to provide to BRCA1 and BRCA2 patients.

While the SACGHS Report found little evidence that patents impede basic research, it also found (incorrectly) that patents are largely unnecessary for genetic research, based largely on an assumption that genetic research is primarily conducted by academics who are not particularly interested in obtaining patents. The Report opines that while patents incentivize some private investment in genetic research, this private funding is “supplemental to the significant federal government funding in this area.” In conclusion, the Report states that “patent-derived exclusive rights are neither necessary nor sufficient conditions for the development of genetic test kits and laboratory-develop tests.”  But these conclusions are seriously flawed, as explained below.

When the Report assumes that most genetic research is conducted by academic researchers, it is specifically referring to the identification of genes associated with genetic disease. While finding a gene associated with genetic disease is an important first step, the Report fails to take into account the much more difficult and costly research required to discern and validate the clinical significance of genetic variations.  The Report’s conclusions, based on an analysis of the relatively straightforward genetic diseases that have been the basis for the first round of genetic diagnostic tests, are largely inapplicable to the next generation of diagnostic tests, where the correlation between genetic variation and clinical significance will be much more attenuated and difficult to establish.

The BRCA genes provide a good example of this. While the discovery of the genes in the 1990s was an important first step, the real work began after the genes were identified, as Myriad and others sought to distinguish the clinically significant variations in the BRCA genes from the clinically insignificant, and to quantify and validate the likelihood of cancer for patients having clinically significant variations. Some variations have been shown to correspond with only a marginal likelihood of cancer, others with a very high likelihood. Myriad reports that even today 3% of the variations it finds when it tests patients are still of unknown significance, and this is after performing thousands of tests and compiling enormous amounts of data. In Europe, where for years Myriad has as a practical matter not enforced its patents, many independent laboratories perform BRCA tests. The number of variations of uncertain significance in Europe is much higher than in the US, not surprising since without an exclusive provider there is less incentive and ability to gather and analyze the data necessary to assign significance to ambiguous variations.

Celera Diagnostics, a private-sector developer of advanced diagnostic tests, made this point in a comment submitted in connection with the SACGHS Report:

Even though the Draft Report suggests that scientists who search for gene-disease associations may not be motivated by the prospect of receiving a patent, they cannot conduct this type of research without considerable capital and resources. In our experience, meaningful gene-disease associations are confirmed only if the initial discoveries are followed by large scale replication and validation studies using multiple sample sets, the costs of which are prohibitive for many research groups. Private investors who provide funding for such research invariably look to patents that result from such work as a way of protecting their investment.

The SACGHS Report concluded that patents are unnecessary for the development and commercialization of diagnostic test, but that conclusion was based on an unrealistic assumption that the cost of developing a sequencing-based diagnostic test is in the range of $8,000-$10,000. While this paltry sum might have been sufficient for the development and commercialization of the simple diagnostic tests considered by SACGHS in preparing its Report, it is orders of magnitude short of the investment required for the critical next generation of diagnostic tests being developed by companies such as Myriad, Celera, and Genomic Health.

Furthermore, patents also promote innovation by facilitating collaboration and coordination between firms, which will be particularly important in the development of personalized medicine. For example, the pairing of the cancer drug Herceptin with a companion genetic diagnostic test that identifies patients likely to benefit from treatment with Herceptin represents one of the first successful implementations of personalized medicine. Herceptin, a biotechnology drug developed by Genentech, is only effective for a subpopulation representing about 30% of breast cancer patients, but for those for which it is effective it can reduce the recurrence of a tumor by 52%. Another pharmaceutical company, Abbott, developed the companion genetic diagnostic test used to distinguish between patients who will benefit from Herceptin and those who will not. The distinction is important because it allows doctors to rapidly begin Herceptin treatment for patients who will benefit from it, while avoiding the high cost and delay that result from trying Herceptin on a patient that, for genetic reasons, will not respond to the treatment. Patents play an important role in incentivizing companies like Abbott to develop a companion diagnostic, as well as facilitating the collaboration necessary to effectively pair one company’s diagnostic with another company’s drug.

Now that Myriad’s patent protection has been weakened, some argue that the company should make its proprietary data freely available in order to allow competitors to improve their tests. At one time Myriad did share this data, but in recent years it has adopted a policy of maintaining much of it as a trade secret. Of course, this is exactly the response one would predict in the face of weakened patent protection. No company is likely to invest in the creation of a valuable database if competitors are free to appropriate the value of the data. An important attribute of patents is that they encourage the disclosure of information that in the absence of the patent would likely be kept as a trade secret. Indeed, the SACGHS Report explicitly recognized that an absence of patent protection promotes secrecy, and that such “secrecy is undesirable because the public is denied new knowledge.”

The Important Role of Patents in Promoting Access

One of the main complaints leveled against patents on genetic diagnostic tests is that a patent owner like Myriad is able to charge a higher price as the exclusive test provider, which limits access for patients who cannot afford the test.  A study included in the SACGHS Report attempted to assess this allegation by comparing the cost for Myriad’s BRCA test with the genetic test for Lynch syndrome.  When normalized for the relative sizes of the genes, the Report found that Myriad charges “little if any price premium” for its exclusively controlled BRCA testing relative to the price charged for nonexclusively licensed testing of the Lynch genes. The Report concluded that this “surprising” finding “suggests that the main market impact of the BRCA patents is not on price but rather on volume, by directing BRCA full-sequence testing in the United States to Myriad, the sole provider.”

While the prices of BRCA and Lynch syndrome testing are comparable, many more BRCA tests are performed in the US compared to Lynch syndrome testing, suggesting that, at least with respect to these two tests, patent exclusivity actually serves to enhance patient access. Epidemiologically the two syndromes are quite similar – both have a similar prevalence in the overall population and in cancer populations, both can result in drastic increases in the risk of developing cancer, and breast and colon cancer are two of the leading causes of cancer death in the country. Prior to the Myriad decision there were 15 providers of full sequence Lynch syndrome testing in the US, and only one authorized provider of full sequence BRCA testing (Myriad).  However, in the period from June 2010 through March 2013 nearly 5 times as many patients in the US received BRCA testing than testing for Lynch syndrome (339,294 vs. 70,294).

One explanation for the discrepancy could lie in the relative quality of the tests. The turnaround time for Lynch syndrome testing results is reportedly longer than that of Myriad’s BRCA tests, and the VUS rate is much higher for Lynch syndrome (15-30% for non-Myriad Lynch testing vs. 3% for Myriad BRCA testing). The amicus brief filed by LSI specifically noted the superiority of Myriad’s BRCA test, which LSI attributed to the patent exclusivity enjoyed by Myriad with respect to the BRCA genes.

Increased public awareness of BRCA testing relative to Lynch syndrome testing is likely to account for much of the discrepancy in usage of the tests. The SACGHS Report specifically found that the “incentive to advertise the service and broaden the market is stronger for a monopoly provider than in a shared market because a monopolist will gain the full benefit of market expansion.”  According to the Report, one of the social benefits of patents is that they incentivize an exclusive test provider like Myriad to invest in creating more public knowledge of the availability of genetic tests.  The Report acknowledges a clear “link between [Myriad’s] status as a single provider and incentives for direct-to-consumer advertising, with single provider status in this case associated with exclusive patent rights for BRCA testing.”

A Center for Disease Control (CDC) survey found an increase in BRCA test requests and questions about testing among women, and an increase in test-ordering among physicians and providers, in cities where Myriad invested in direct-to-consumer “public awareness campaigns.”  The SACGHS Report noted that “[t]he overall impact of a DTC advertising campaign on the Kaiser Permanente health system in Denver was a more than two-fold increase in number of women in the high risk category getting tested, a more than three-fold surge in contacts about testing.”  Another study showed that high-risk women—those eligible for BRCA testing based on family history—were three times as likely to get tested following a physician recommendation as those who did not get such a recommendation.

Ironically, while Myriad fought to inform patients and healthcare providers about the availability of BRCA testing, many policymakers argued in favor of restricting patient access to the results of these tests. For example, the Working Group of Stanford’s Program in Genomics, Ethics and Society recommended that ‘for most people, testing for BRCA1 and BRCA2 mutations is not appropriate.’  Similarly, NIH director Francis Collins testified before Congress that the results of genetic testing for BRCA mutations should generally not be made available to patients. With respect to BRCA testing, patents have played an important role in empowering patients to take control of their own their own genetic information, in the face of a medical establishment that sought to limit patient access to this information.

One of the most formidable obstacles facing patients in need of genetic diagnostic testing services is insurance reimbursement. Patents play an important role in overcoming this obstacle, by providing an incentive for patent owners to work with insurance companies to ensure that a maximum number of patients will be able to get insurance reimbursement for testing. For example, in 1995 only 4% of insurance providers allowed reimbursement for BRCA genetic testing. By 2008 Myriad was able to report that it had established contracts or payment agreements with over 300 carriers and has received reimbursement from over 2500 health plans, reducing the number of self-pay patients to single-digit percentages of its clientele. By 2010 BRCA genetic testing in the U.S. was covered for roughly 95% of those requesting tests, and reimbursed to cover 90% of their charges.  In contrast, non-profit diagnostic testing services in many cases charge patients upfront for genetic testing, and require patients to seek their own reimbursement from their insurance company, which can be slow in coming, assuming it comes at all.

Conclusion

Arguments in favor of reining in the availability of effective patent protection in the area of genetic diagnostic testing are based largely on two fundamental misconceptions regarding the role of patents in this important area of technological innovation. The first is the mistaken assumption that patents negatively impact patient access to genetic diagnostic testing by preventing research that might lead to new or improved versions of a genetic test and by increasing the cost of testing services. The second is the failure to appreciate the substantial positive role patents play in in the development and utilization of genetic diagnostic tests. In fact, patents have little if any negative impact on basic research, and have been proven to significantly improve patient access to advanced diagnostic testing services by incentivizing the substantial investment that is necessary not only to bring these tests to market, but also to educate patients and their doctors with respect to the availability of the tests, and to work with third-party payers to expand patients’ eligibly for reimbursement. Next-generation technologies are poised to dramatically improve healthcare and patient outcomes, but this will only occur if effective and enforceable patent protection is available as the necessary spur for innovation and commercialization.

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Biotech Gene Patents Patent Law Uncategorized

A Critique of a Recent Article Which Found That Sequence Patents Cover the Entire Human Genome

By Professor Christopher Holman

[The following is a blog posting by Christopher Holman, a patent law scholar at UMKC School of Law, that he originally posted on April 5, 2013 at his blog, Holman’s Biotech IP Blog, where Professor Holman regularly blogs on important issues in biotech and IP law.  Professor Holman kindly gave us permission to repost his blog posting here.]

A Critique of a Recent Article Which Found That Sequence Patents Cover the Entire Human Genome
By Christopher Holman

I recently fielded a phone call from a reporter with a leading international scientific journal, asking for my opinion of an article entitled “Pervasive Sequence Patents Cover the Entire Human Genome,”recently published in a publication called Genome Medicine. I have published several articles debunking the myth that 20% of human genes are patented, and the reporter thought that the article in Genome Medicine, authored by a researcher affiliated with Yale Law School’s The Information Society Project, contradicted the results of my study. I took a look at the “Pervasive Sequence Patents” article and found it to be a fundamentally flawed empirical study that will sadly be used to further support the widespread misperception that access to a large percentage of the human genome is precluded by a thicket of gene patents.

The “Pervasive Sequence Patents” article does cite to my 2012 Nature Biotechnology article Debunking the Myth That Whole Genome Sequencing Infringes Thousands of Gene Patents, but the authors apparently missed the main point I was trying to make. The myth that 20% of human genes are patented was born out of a 2005 article published in Science by Jensen and Murray that found that the sequence of 20% of human genes (or in some cases the protein encoded by human gene) is mentioned in a US patent claim. The problem arose when people assumed that the mention of a gene’s DNA sequence in a patent claim is equivalent to the patenting of the gene, which led to an assumption that any use of or research on any of these genes would result in patent infringement. In my article, I explained that in patent law “the name of the game is the claim “(to quote Judge Rich), and that when one actually reads the patent claims in the patents identified by Jensen and Murray it is clear that few if any of the patents would be infringed by many forms of research or genetic testing, including diagnostic testing and whole genome sequencing.

Unfortunately, the authors of “Pervasive Sequence Patents” have apparently fallen into the same trap, assuming that mention of a gene’s DNA sequence in a patent claim results in the patenting of the gene in a manner that totally blocks access to the gene. Even more problematically, the authors seem to assume that every patent with a claim mentioning a gene sequence also claims every 15mer present in the sequence, i.e., every contiguous 15 nucleotide sequence appearing in the gene. Presumably they made this assumption because the Myriad gene patent litigation includes a patent claim directed to 15mers of the BRCA1 encoding sequence, including Claim 5 from US patent number 5,747,282:

An isolated DNA having at least 15 nucleotides of the DNA of claim 1.

There are two fundamental problems with this empirical approach. One is that it does not necessarily follow that the mention of a gene’s DNA sequence in a claim equates with the patenting of the gene – that was the main point of my Nature Biotechnology article. The other is to assume that all of these patents include claims analogous to Claim 5 of the ‘282 patent.

In my experience, claims of this type are extremely rare. I looked at hundred patents identified as gene patents in the Jensen Murray study and found that most only claim the full-length gene sequence, and if fragments were claimed the fragments are much larger than 15 nucleotides. In fact, I looked through hundreds of gene patents trying to find another 15mer claim analogous to those in the Myriad patents and could not find one. The patent claims at issue in the Myriad case will be expiring within the next few years I believe, and I doubt that this sort of broad 15mer claim has been issued by the patent office in recent years, or if it has it seems to be extremely rare.

In any event, in 2010 Keppler et al. published an article entitled “Metastasizing Patent Claims in BRCA1” which showed that if the BRCA 15mer claims are interpreted so broadly as to cover any DNA sequence comprising any 15mer appearing in a BRCA gene, there appears to be a wealth of prior art that would invalidate the claim regardless of the claims patent eligibility.

The flawed methodology used in the “Pervasive Sequence Patents” article is readily apparent from the results of their empirical study. Here is what they reported as the result of their study:

[W]hen we took existing gene patents and matched their 15mers to known genes, we found that 100% of known genes have at least one 15mer claimed in a known patent. Current gene patents were observed to match each gene many times, with 1,295 matches to other genes on average (standard deviation 1,208). When we examined the amount of total sequence space in human genes that is covered by 15mers in claims from current patents (Additional file 2), we found 58 patents whose claims covered at least 10% of the bases of all human genes. The top patent was US7795422, whose claims’ sequences matched 91.5% of human genes. Interestingly, we also observed a patent for improving bovine traits (US7468248) with explicit claims for 15mers that matched 84% of human genes. This patent was not even aimed at any human sequence, yet covered a majority of human genes once we examined the claim’s matches at the 15mer scale.

First off, let’s look at the “top patent” they found, US7795422, “whose claims sequences matched 91.5% of human genes.”  The ‘422 patent has only one independent claim:

1.       A chemically modified short interfering nucleic acid (siNA) molecule, wherein: (a) the siNA molecule comprises a sense strand and an antisense strand, each strand having one or more pyrimidine nucleotides and one or more purine nucleotides; (b) each strand is independently 18 to 27 nucleotides in length, and together comprise a duplex having between 17 and 23 base pairs; (c) the antisense strand is complementary to a human Hypoxia Inducible Factor 1 (HIF1) RNA sequence comprising SEQ ID NO:567; (d) a plurality of pyrimidine nucleotides present in the sense strand are 2′-deoxy-2-fluoro pyrimidine nucleotides and a plurality of purine nucleotide present in the sense strand are 2′-deoxy purine nucleotides; and (e) a plurality of pyrimidine nucleotides present in the antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and a plurality of purine nucleotides present in the antisense strand are 2′-O-methyl-puine nucleotides.

When one reads the claim, it is apparent on the face that the claim is limited to “chemically modified” molecules comprising 2′-deoxy-2-fluoro pyrimidine nucleotides and 2′-deoxy purine nucleotides.  DNA does not contain 2′-deoxy-2-fluoro pyrimidine nucleotides and 2′-deoxy purine nucleotides, these are synthetic analogues to the nucleotides that appear in DNA. This patent that the authors found to match 91.5% of human genes does not cover any gene or any DNA molecule, only chemically modified synthetic molecules for use in RNA interference.

Next the authors reported that US7468248 contains “explicit claims for 15mers that matched 84% of human genes.” In fact, the ‘248 patent has only two independent claims, both of them method claims:

1.       A method for inferring a trait of a bovine subject from a nucleic acid sample of the bovine subject, comprising identifying in the nucleic acid sample, a nucleotide occurrence of a single nucleotide polymorphism (SNP) at position 300 of SEQ ID NO:21645, thereby inferring the trait, wherein the trait is marbling, tenderness, fat thickness, red meat yield, or average daily weight gain.

22. A method for determining a nucleotide occurrence of a polymorphism in a bovine sample, comprising: a) contacting a bovine polynucleotide in the sample with an oligonucleotide that binds to a target region, wherein the target region comprises a position at position 300 of SEQ ID NO:21645 or wherein the target region is within 3000 nucleotides of a nucleotide at position 300 of SEQ ID NO:21645, and b) determining the nucleotide occurrence of a single nucleotide polymorphism (SNP) at position 300 of SEQ ID NO:21645, wherein the determination comprises analyzing binding of the oligonucleotide or detecting an amplification product generated using the oligonucleotide, thereby determining the nucleotide occurrence of the polymorphism.

Both of these claims would only be infringed by someone performing a specific genetic test on a bovine subject (colloquially a cow). The patent does not include any claim covering any DNA sequence, and the authors’ assumption that the patent “explicitly claims 15mers that matched 84% of human genes” implies that they either did not read the claims or do not understand the basics of claim interpretation.

The problems with this article are pretty apparent once one reads the claims of the patents that were identified as “matching” human genes. Unfortunately, it is just the latest installment of a prolific stream of fundamentally flawed academic articles that are being cited in support of the notion that human gene patents are a pervasive problem.  I don’t doubt that the authors meant well, but it’s dangerous to conduct empirical patent studies without appreciating and understanding the critical role of the patent claim. And the publication of the article highlights the limitations of peer review (assuming Genome Medicine engages in peer review).