In a resounding manner, members of the medical device industry recently filed comments reacting to the Food and Drug Administration’s proposed rule to strengthen its oversight of overseas clinical studies of medical devices. The proposed rule would replace the current practice, which does not require review by an independent ethics committee. Currently, FDA accepts data from clinical trials conducted outside the U.S. if the data are valid and the studies are conducted in conformance with the 1983 Declaration of Helsinki or the laws and regulations of the country in which the research is conducted, whichever accords greater protection to human subjects. 

The proposed rule, however, would impose new reporting requirements when data from clinical studies for medical devices conducted outside the U.S.are submitted as support for an  device exception, a 510(k) premarket notification submission, a premarket approval application, a product development protocol application, or a humanitarian device exemption application. In such cases, applicants would have to demonstrate to FDA that the study was conducted in accordance with “good clinical practice.” Under the proposed rule, proof of good clinical practice includes obtaining “the review and approval of the study by an independent ethics committee,” as well as a record of the informed consent of study participants. FDA would further require applicants to provide records detailing the qualifications of ethics committee members, their approval process, information about the research facility, and descriptions of how researchers obtained informed consent and monitored their subjects.

Comments submitted to FDA by the medical device industry have resoundingly critiqued the new rule as imposing stricter regulations than those required for domestic clinical trials, while ignoring barriers presented by other countries’ laws. Some propose that before implementing the proposed rule, FDA should first create consistency between international and U.S.definitions and guidelines, as currently not all foreign countries permit disclosure of the information required for compliance with the proposed rule. Others point out that studies are oftentimes conducted overseas without plans to apply for approval from the U.S., and the data from such studies should not be summarily excluded. As to potential alternative solutions, it was proposed by at least one commenter that the FDA should instead adopt the standard ISO-14155:2011, which is already recognized by all members of the International Medical Device Regulators Forum. After the overwhelming response by industry, many are anticipating that FDA may initiate additional changes to the regulations before a final rule is implemented.

Stay tuned as we continue to follow this important legal and regulatory issue.

David L. Rosen, Nathan A. Beaver and Jennifer M. Forde are legal experts advising clients on regulatory issues and are resident in Foley & Lardner’s Washington, DC office.

Guest Post By David L. Rosen, Nathan A. Beaver and Jennifer M. Forde

In a remarkable move, the Food and Drug Administration recently indicated that it plans to take new steps to regulate laboratory-developed tests (“LDTs”). FDA Commissioner Margaret Hamburg made the significant announcement during a speech on June 2, 2013, at an annual meeting of the American Society of Clinical Oncology. Historically, FDA has exercised enforcement discretion when regulating LDTs and generally exempted them from regulatory requirements because LDTs have often consisted of low-risk diagnostics or tests for rare diseases with a physician evaluating the test results in the laboratory. Consequently, LDTs oftentimes have been marketed without premarket review by FDA.

In recent years, LDTs have become increasingly complex, with physicians relying on LDTs for clinical decision-making in personalized medicine and cancer screening. Because many LDTs are currently marketed without premarket review, Commissioner Hamburg announced that FDA is developing a risk-based framework to regulate LDTs and evaluate their safety and efficacy. In doing so, according to Commissioner Hamburg, FDA plans to “provide medical professionals with a critical baseline for confidence in the tests they order for their patients.”

Though Commissioner Hamburg did not elaborate on when FDA plans to carry out this new enforcement policy with respect to LDTs, Commissioner Hamburg’s comments are expected to have a forceful impact on the diagnostics industry, where many historically have not been compelled to undergo the rigors of premarket review for LDT products. It is possible that FDA will pursue a stratified approach and begin its enforcement efforts by targeting the more complex tests relied upon for clinical decision-making. Renewed enforcement efforts by FDA would also likely raise questions as to whether new fields, such as DNA sequencing, would be treated as LDTs. In light of these remarkable implications, the diagnostic industry will be closely watching for more detailed guidance by FDA on its planned changes to the current scheme of LDT regulation.

Stay tuned as we continue to follow this important legal and regulatory issue.

David L. Rosen, Nathan A. Beaver and Jennifer M. Forde are legal experts advising clients on regulatory issues and are resident in Foley & Lardner’s Washington, DC office.

In this case, … Myriad did not create anything. To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention. Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the Section 101 inquiry. (citing Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. 127 (1948)).

In contrast to isolated DNA, altered or modified DNA, the Court explained, remain patent-eligible as well as applications of any information gleaned from the isolation of the gene or a new method used to isolate the DNA. The Court in footnote 8 also noted that the possibility that an unusual and rare phenomenon that might randomly create a molecule similar to one created synthetically, such as a synthetic cDNA molecule made through human ingenuity, would not render the synthetic molecule unpatentable.

Thus, the Supreme Court has removed from patent-eligibility a class of discoveries that has been the backbone of the biotechnology industry for the last few decades. Isolated DNA molecules, such as isolated genes that describe the gene as it exists in nature, microRNA and interfering RNA, if claimed as isolated molecules, now fail the Supreme Court’s patent-eligibility test. To meet the new standard, the patent claim must contain an element that explicitly shows human intervention, such as a modification to the DNA sequence or the addition of an element useful in the application of the technology. Unlike the Supreme Court’s Prometheus decision which incorporated patent concepts of novelty and non-obviousness into the patent-eligibility standard, this Myriad decision did not intermix the separate criteria for patentability. Therefore it is likely that if the isolated DNA molecule is novel and non-obvious, the addition of the element showing human intervention into the claim would qualify the claim for patent-eligibility under the new standard.

On the same day that the Supreme Court issued its decision, the USPTO issued guidelines (attached) for its examiners instructing them that isolated DNA molecules that are unaltered should be rejected for failing to satisfy 35 U.S.C. Section 101. Synthetic or altered DNA molecules remain patent-eligible.

Inadvertent Use of Self-Replicating Technologies

Appellants originally sought declaratory judgments of non-infringement and invalidity with respect to twenty-three patents owned by Monsanto Co. and Monsanto Technology, LLC (“Monsanto”) that cover Monsanto’s genetically modified seeds and plants that are resistant to the herbicide glyphosate, the active ingredient in Monsanto’s popular herbicide sold under the trade name Roundup. The appellants were joined in the suit by the Public Patent Foundation of the Benjamin N. Cardoza School of Law.

Monsanto sells the patented technology and licenses others to grow and sell seed under a limited-use license permitting licensees to plant, harvest and sell a single generation of the patented seeds. It was undisputed that Monsanto enforced its intellectual property. Between 1997 and 2010, Monsanto pursued over 800 claims for unauthorized use of its patented seeds.

The appellants did not want to use the patented seeds but were concerned that their crops and seeds would be contaminated with the patented seeds and that as a result, they would be sued by Monsanto for patent infringement. The appellants alleged that they their fear of suit prevented them from planting crops that may have become contaminated by Monsanto’s seeds. At one point, appellants asked Monsanto for a written covenant not to sue. Monsanto refused their request and directed appellants to its website wherein Monsanto noted that it would not exercise its patent rights where trace amounts of the patented seeds or traits are present in farmer’s fields as a result of inadvertent means. The district court ruled in favor of Monsanto who argued that the court had no jurisdiction because appellants lacked an essential element of standing – a live case or controversy.

Appellants’ Subjective Fear of Suit Is Not Enough

The Federal Circuit affirmed the district court’s holding that appellants had not demonstrated that their fear of suit does not rise to an actual controversy between the parties having adverse legal interests, of sufficient immediacy and reality to warrant the issuance of a declaratory judgment. The court noted that even though some of the appellants could be liable for infringement if they used or sold the patented seeds or plants (even very small quantities of the patented technology) Monsanto’s explicit representations not to take legal action against inadvertant use of the technology is essentially equivalent to a covenant not to sue. The appellants also failed to show that their possible use would fall outside the disclaimed minimal use.

Thus this case provides patentees a road map to avoid unwanted validity challenges from potential plaintiffs who may seek to invalidate patents that are unlikely to be asserted against them sans a covenant not to sue.

The ’103 Patent

U.S. Patent No. 6,573,103 (the ’103 Patent) entitled “Antenatal Screening For Down’s Syndrome” issued on June 3, 2003. All twenty-four claims relate to methods for determining whether a pregnant woman is at an increased risk of having a fetus with Down’s syndrome. Claim 1 is representative:

1. A method of determining whether a pregnant woman is at an increased risk of having a fetus with Down’s syndrome, the method comprising the steps of:

measuring the level of at least one screening marker from a first trimester of pregnancy by:

 (i) assaying a sample obtained from the pregnant woman at said first trimester of pregnancy for at least one first biochemical screening marker; and/or

 (ii) measuring at least one first ultrasound screening marker from an ultrasound scan taken at said first trimester of pregnancy;

measuring the level of at least one second screening marker from a second trimester of pregnancy, the at least one second screening marker from the second trimester of pregnancy being different from the at least one first screening marker from the first trimester of pregnancy, by:

 (i) assaying a sample obtained from the pregnant woman at said second trimester of pregnancy for at least one second biochemical screening marker; and/or

 (ii) measuring at least one second ultrasound screening marker from an ultrasound scan taken at said second trimester of pregnancy; and

determining the risk of Down’s syndrome by comparing the measured levels of both the at least one first screening marker from the first trimester of pregnancy and the at least one screening marker from the second trimester of pregnancy with observed relative frequency distribution of marker levels in Down’s syndrome pregnancies and in unaffected pregnancies.

The Federal Circuit’s Asserted Errors

Intema argues that the Federal Circuit erred when it ignored material differences between the claims of the ’103 Patent and the claims held invalid by the Supreme Court’s Mayo decision. Such errors include, for example:

• the failure of the Federal Circuit to recognize the claims of the ’103 Patent are more than the use of a law of nature – the claims embody the use of data gathered was completely non-standard when developed, and improved screening efficacy;
• the failure of the Federal Circuit to acknowledge that the measuring step, achieves a simple and useful test result using statistical analysis when it wrongly characterized the measuring steps as conventional and obvious presolution activity;
• the failure of the Federal Circuit to give proper weight to the steps of selecting the measured marker levels during two separate trimesters of pregnancy and the integration of that in a carefully specified manner;
• the Federal Circuit’s finding that the determining step is insufficient as being a “known and conventional” algorithm;
• the Federal Circuit’s interpretation of the “assaying” portion of the measuring steps to be insufficient to impart patent-eligibility to the claims because it could be performed without transforming the sample should science develop a totally different system for assaying for a biochemical marker that did not involve such a transformation; and
• the Federal Circuit’s error in concluding that a transformation, if it existed, would be insufficient relying on another rigid rule excluding all transformations from consideration under Section 101.

Personalized Medicine and Diagnostic Patents

The Supreme Court’s Mayo ruling has created uncertainty for diagnostic technologies that support and promote personalized medicine. Inventions simply defined by correlating a natural biomarker with a clinical outcome or therapeutic treatment are now ineligible for patent protection as a result of the Mayo decision. For inventions that offer more than a simple correlation, patent protection may still be available. However, how much “more” is necessary to move an invention involving a biomarker and correlation to patent-eligibility is still an open question. With that in mind, more clarity and direction would be welcome, provided the Supreme Court does not take the opportunity to further restrict patent protection for these important technologies.

A copy of Intema’s petition is attached.  PerkinElmer’s reply is due June 19, 2013.

This report is interesting not only from a patent analyst’s perspective of tracking the evolution of IP in a particular technology, but also because it shows a clear evolution of the technology and processes for achieving the same result using different techniques.

The particular facts of the case relate to self-replicating soybean seeds that are resistant to Roundup, a popular herbicide. Bowman, a soybean farmer, purchased patented soybean seeds from a company affiliated with Monsanto. Monsanto holds the patent on the herbicide-resistant seeds. When purchasing the original seeds, Bowman agreed to Monsanto’s restriction against the use of seeds created from the planting and harvesting of them.

The Doctrine of Patent Exhaustion Does Not Apply

After planting, harvesting and selling the resulting seeds from the original purchase, Bowman purchased second generation seeds from a party not authorized by Monsanto to sell the patented seeds. He planted the second generation seeds and sold the resultant soybeans for a profit. Monsanto sued Bowman for for the unauthorized use of the patented (second generation) seeds. Bowman raised as his defense the doctrine of patent exhaustion. 

The Supreme Court held that the defense of doctrine of patent exhaustion does not apply to the facts of this case. Under the doctrine, the initial authorized sale of a patented item terminates all patent rights to that item. However, consistent with that rationale, the Supreme Court noted that the doctrine restricts a patentee’s rights only as to the particular article sold; it leaves untouched the patentee’s ability to prevent a buyer from making new copies of the patented item. Slip Op. at 4-5. The exhaustion doctrine does not enable Bowman to make additional patented soybeans without Monsanto’s permission whether expressly or impliedly granted. Slip Op. at 5.

Limited Application of the Doctrine

While the holding of the case could be applied to self-replicating technologies such as stem cells, recombinant genes and monoclonal antibody-producing hybridoma cells, the Supreme Court was careful to limit its holding to the particular facts of the case and expressly cautioned against its application to other self-replicating technologies such as in biotechnology and computer science.

“Our holding today is limited – addressing the situation before us, rather than every one involving a self-replicating product. We recognize that such inventions are becoming ever more prevalent, complex, and diverse. In another case, the article’s self-replication might occur outside the purchaser’s control. Or it might be a necessary but incidental step in using the item for another purpose.”

Slip Op. at 10.

A Careful Balance

That is not to say, however, that the Supreme Court would not hold similarly for self-replicating inventions in the field of biotechnology with a few tweaks. In explaining the rationale for its holding, the Supreme Court noted that purchaser of the patented soybean seed gets full value in the initial purchase by planting and harvesting the seeds and that the purchaser of the patented seeds has full control over its initial use. The Court indicated that this might not be the case where the article’s self-replication occurs outside the purchaser’s control. As an example, the Court noted that making a copy might be an essential step in the utilization of the patented technology. One could see how the purchase of a population of stem cells, such as a population of induced pluripotent stem cells for drug screening, might need to replicate or copy the originally purchased cells to use them for drug screening. The same facts could apply to the use of a plasmid or recombinant gene in the laboratory or for therapy. Thus, the Supreme Court has kept open the question of how far a patentee can extend the patent monopoly over self-replicating technologies in biotechnology. Even so, it is clear that the Supreme Court is aware that current innovations in biotechnology and information technology are raising difficult questions over the proper scope of patent rights, and that the rights of patent owners and the public must carefully balanced.

Gregory A. Castanias noted the importance of gene patents in general to the evolving business of personalized medicine. Justice Kagan questioned Mr. Castanias regarding the application of the product of nature doctrine to the patent-eligibility of isolated naturally occurring materials. Justice Kagan asked:

“Well, the plant in the forest can’t be used for any purpose either. It only has a use when it’s taken out – you know, when it’s uprooted and taken out of the forest. But it’s still the same thing. And I guess what you haven’t gotten me to understand is how this is different than that. It’s still the same thing, but now that you’ve isolated it, it in fact has lots of great uses.”

Mr. Castanias replied:

“Well, I think there are two ways – two ways to look at that. First of all, if you want to look at it from the – the perspective of the so-called product of nature doctrine, which I think has some very dangerous consequences if it’s not cabined and understood correctly – but if you look at it strictly from a product of nature doctrine, you could say, well, that’s the same plant and it says in the 1930 legislative history of the Plant Patent Act that plants that are unmanipulated by the hand of man are not eligible for patents, and that’s fine, in terms of their breeding and genetics and that sort of thing.

But the product of nature doctrine is troublesome for this reason: Modern medicine – go beyond just the isolated DNA patents here. Modern medicine, particularly the area of personalized medicine, is trying to get to a point where what we are administering to individual patients is giving them the opportunity to mimic the actions of the body. And – so actually, the goal of medicine is to get closer to nature, rather than farther away. And anything that takes the product of nature doctrine beyond the simple truism that the product of nature is something that is not a human invention, then that’s very dangerous, not just for our case…”

A copy of the complete transcript is attached. A decision from the Court is expected this summer.

What is a “Human Gene?”

“Are human genes patentable” is the sole question before the Supreme Court. Hidden within this deceptively simple question is what is specifically meant by the phrase “a human gene.” During this dispute, the patent claims at issue have been argued to cover a complete human gene (including contiguous coding and non-coding regions), artificial, human-generated, contiguous DNA sequences (cDNA and recombinant DNA) and functional gene fragments being identical to portions of a human gene. In its recent Reply Brief, the ACLU argues that the term “a human gene” includes isolated human DNA, cDNA and fragments, but excludes recombinant DNA. The ultimate construction of the term “a human gene” is key to whether or not gene patents preempt the use of laws and products of nature; a policy issue that has been heavily briefed and argued by the parties and amici.

Naturally-Occurring Genes

In its Reply Brief, the ACLU responds to Myriad and its amici’s concern that a ruling in petitioner’s favor might prevent useful patents on tests, drugs, other DNA-related compositions such as recombinant DNA, or patents limited to particular uses by opining that the question before the Supreme Court does not touch recombinant DNA (DNA that results from choosing fragments from genes or chromosomes that do not appear together in nature and “stitching them together”), recombinant therapeutic proteins, or genetically engineered antibodies. (Page 2 of Reply Brief.)

The ACLU argues that in contrast to recombinant DNA, DNA isolated or purified from a human (complete gene sequences and fragments of genes) should not be patent-eligible because the acts of finding, separating and characterizing a DNA molecule do not present structural distinctions between the DNA or gene as it exists in the human body. The ACLU also dismisses Myriad’s new uses of isolated DNA over DNA in the human body, on the ground that these arguments only speak to methods for using materials (relevant only to method or use patents) and not patents claiming compositions such as isolated DNA.

Patent-Eligibility of cDNA

The ACLU takes the position that the patent-eligibility of cDNA is not at issue, but should the Supreme Court decide to take on this issue, it should find that cDNA is not patent-eligible. cDNA (an abbreviation of complementary DNA) is synthesized in a laboratory from a messenger RNA (“mRNA”) template. Certain of Myriad’s patent claims at issue are limited to cDNA by reference to a specific nucleotide sequence which was determined by a process of reverse transcribing messenger RNA. The ACLU first takes issue with Myriad’s construction of the cDNA claim because, in its opinion, the claim does not identify the sequence as cDNA. The ACLU opines that thus, the claim arguably covers any isolated DNA with that nucleotide sequence. Moreover, the act of creating cDNA is, in the ACLU’s opinion, as simple as linking the mRNA fragments to form one template that codes a functional protein like magnets on a string.

Interestingly, in the ACLU’s view, cDNA is distinct from recombinant DNA, “which is created when a geneticist selects cDNA or DNA fragments from different sources and intentionally stitches them together. (Page 10 of Reply Brief). Any cDNA that “simply mirrors naturally-occurring mRNA is a product of nature and a basic scientific tool” and therefore is argued to be patent-ineligible. (Page 10 of Reply Brief).

A Question of Claim Construction

The history of this dispute is unusual in that the patent claims at issue were never construed, a process by which the parties and at times the court interpret patent claims to determine their scope and meaning. Indeed, any patent analysis, whether to determine patent infringement or patent invalidity, requires a construction of the patent claims. Construction of Myriad’s patent claims would have served as clear notice to the amici and public as to what subject matter was objectionable and why. Without this fundamental analysis, the parties and amici have appeared to struggle with what is clearly at issue here – the patenting of any DNA that has some sequence identity to a human gene or only purified whole gene sequences? Indeed, one sensible approach for the Supreme Court would be to remand for construction of the patent claims.  

The ACLU in its Reply Brief has moved from its prior policy-heavy arguments of preemption and public health to a more traditional analysis of the claim language and whether that language satisfies the statute that governs patent-eligible subject matter. Whether and how the Supreme Court handles the same issue will be telling as to its ultimate decision and more importantly, the effect if any, of the possible exclusion of human DNA or genes from the U.S. patent system.