Aria Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2013)

By Kevin E. Noonan --

The Federal Circuit vacated and remanded a District Court decision denying a preliminary injunction to patentee Sequenom over the claims of U.S. Patent No. 6,258,540.  While the Court rendered its decision based on traditional principles of claim construction and the lower court's balancing of the equitable factors considered for granting preliminary injunctions in patent cases, the decision also bears consideration in view of the panel's mention of whether the claims at issue were patent eligible under the Supreme Court's recent AMP v. Myriad Genetics decision.

The claims of the '540 patent (owned by Isis Innovation Limited and exclusively licensed to Sequenom) are directed towards detecting paternal DNA sequences derived from a fetus in maternal circulation from a pregnant woman.  Claim 1 is representative:

A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises
    amplifying a paternally inherited nucleic acid from the serum or plasma sample and
    detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.

(emphasis in the opinion).  Sequenom's commercial product (and Aria's) is directed to diagnosing trisomy disorders (Down's, Edwards and Patau) in the fetus by detecting these disorders from "non-nucleated free-floating fetal DNA (cffDNA) in maternal blood.  This test is much less invasive than traditional amniocentesis (and poses no risk to the developing child, unlike amniocentesis) and avoids the necessity of isolating the "rare nucleated [fetal] cells" that can be found in maternal blood.  Fortuitously, it appears that women bearing a trisomy-affected child have more cffDNA in their blood than women bearing an unaffected child.  As the result of these biological phenomena the test is not only safer but also more reliable in providing a diagnosis.

Aria (now, Ariosa) Diagnostics filed a declaratory judgment action that its genetic test, termed "Harmony," did not infringe Sequenom's claims, and Sequenom counterclaimed for patent infringement and asked for a preliminary injunction, which the District Court denied.

The Federal Circuit opinion, by Chief Judge Rader, joined by Judges Dyk and Reyna, begins with the standard for appealing denial of a preliminary injunction:  not only that at least one of the District Court's factual finding was clearly erroneous, but that the court abused its discretion in denying the injunction, citing Reebok Int'l Ltd. v. J. Baker, Inc., 32 F.3d 1552, 1555 (Fed. Cir. 1994).  While the parties disagreed over the extent to which claim construction is determinative in the preliminary injunction context (the opinion invites a comparison between Chamberlain Group, Inc. v. Lear Corp., 516 F.3d 1331, 1340 (Fed. Cir. 2008), and Int'l Cmty. Materials v. Ricoh Co., 108 F.3d 316, 318-19 (Fed. Cir. 1997)), here "the court need not reach out to comment on those alternative approaches to the question" because "[e]ven under the ostensibly more relaxed standard, the district court erred in its claim construction" and "[a]s a consequence, the district court erred in finding a substantial question of noninfringement."  In this regard the panel reviewed construction of the terms "paternally inherited nucleic acid" and "amplifying" in the claims.  With regard to the term "paternally inherited nucleic acid," the District Court held the term to mean "DNA sequence known [in advance] to be received only from the father which is not possessed by the mother."  (Note that while the District Court did not include the bracketed [in advance] in its claim construction order it is undisputed that it must be known "in advance" that the sequence is derived from the father and not the mother for the test to be diagnostic.)  Thus, for infringement to arise the user must know the father's genotype, and this requirement renders the District Court's claim construction incorrect according to the panel.

The reason for this determination by the Court is that this requirement is not part of the plain meaning of the term "paternally inherited nucleic acid," nor is it supported by the specification; indeed, the panel opinion asserts that this interpretation is based on a single sentence from the '540 patent specification:  the "method according to the invention can be applied to the detection of any paternally-inherited sequences which are not possessed by the mother."  The opinion does not find this sentence to be limiting but rather an expansive statement "reflect[ing] the broad meaning of 'paternally inherited nucleic acid' that is found in the claims -- a meaning which does not limit them to those known in advance to have come from the father."  In the panel's opinion the term encompasses any paternal characteristics by comparison to maternal characteristics (emphasis in opinion), not a limitation only to those paternal nucleic acids identified in advance.

The Court also found that this construction was not consistent with other portions of the specification, particularly the examples.  For instance, Example 3 expressly recites a prior determination of the mother's RhD negative status but is silent as to a similar determination of the father's RhD gene; although this example detects the RhD gene allele inherited by the fetus from the father there is no teaching that the father's RhD gene was known in advance.  Thus, even if the claims were limited to what was expressly disclosed in the examples (an outcome the panel specifically points out is not the claim construction standard), Example 3 illustrates embodiments of the invention falling outside the District Court's construction of the term.

Regarding the prosecution file history, the Court also found no support for limiting the "paternally inherited nucleic acid" term to paternal DNA known in advance.  The panel assessed three incidents asserted in support of the District Court's construction.  First, the claims were amended to recite the "paternally inherited nucleic acid limitation" during prosecution to secure an allowance, but the Court found that this portion of the prosecution history does not require prior knowledge of the paternally inherited sequence.  Second, during prosecution of a related continuation application Isis argued that the claims should not be limited to paternally inherited nucleic acids, citing instances where DNA distinct for the fetus (such as due to "spontaneous" or "chance" changes or mutations or other fetus-specific differences between fetal and maternal nucleic acids.  However the Court did not find these arguments to "approach the clear and unequivocal statement needed before prosecution history can operate to extinguish subject matter otherwise within the claims."  Third, with regard to those continuation application claims, the examiner asserted that the specification did not enable detection of chromosome 21 "caused by maternal inheritance or genetic mutation," but the panel found these statements to be too ambiguous to support Ariosa's arguments or the District Court's claim construction (as well as being directed to an issue, enablement, not considered by the District Court).

Because the District Court erred in imposing this limitation on the claims, the Federal Circuit held that the District Court erred in finding that Ariosa had raised a substantial question of noninfringement precluding grant of a preliminary injunction to Sequenom.

Regarding the term "amplifying," the District Court construed the term to mean "increasing the concentration of a paternally inherited nucleic acid relative to the other DNA in the sample."  Under this construction, only paternally derived DNA would be amplified, not the fetal DNA as a whole.  This was error, according to the Federal Circuit, because the plain meaning of the claims require that paternally derived nucleic acid is amplified "without any mention of an effect on the quantity of other nucleic acid" and thus the claims would be infringed "whether, or not, other nucleic acid is amplified."  The specification is contrary to the District Court's construction, according to the panel, citing passages from the specification that distinguish between "amplification" and "enrichment" of paternally inherited nucleic acid.  The panel concluded that "the specification does not support, but instead points away from the district court's claim construction, which already is at odds with the plain language of the claim."  And the prosecution file history is no less availing:  the examiner's statements cited to support the District Court's construction of the "amplifying" term are directly related to enrichment rather than amplification according to the panel because "[t]he examiner could not have been objecting to lack of support for amplification, because amplification was described through traditional PCR and other methods."  As with its erroneous construction of the "paternally inherited nucleic acid" term, the Federal Circuit found that the District Court had incorrectly construed the "amplifying" term and thus erred in concluding that Ariosa had raised a substantial question of noninfringement.

Finally, the District Court had found that there was "a substantial question over whether the subject matter of the asserted claims was to eligible subject matter."  Noting the intervening decision by the Supreme Court in the Myriad case, the panel's remand instructs the District Court to consider the subject matter eligibility question.  However:

To be clear, this court offers no opinion as to whether there is or is not a substantial question regarding the subject matter eligibility of the asserted claims.  This court merely concludes that in light of Myriad and the different claim construction, this court would benefit from the district court's initial and further consideration.  On remand, the district court may once again consider this issue, as well as whether there is a substantial question of validity of the asserted claims under other defenses raised by Ariosa but not reached previously by the district court.

To be equally clear, the claims of the '540 patent do not claim isolated paternally inherited nucleic acid per se and thus should fall outside the ambit of the Supreme Court's Myriad decision.  The question that will need to be addressed is whether these claims recite diagnostic method claims that remain patent eligible under the Court's Mayo v. Prometheus Labs. decision, both a different question and one for which it is much harder to predict an outcome.

The Court also provided "additional guidance" to the District Court with regard to its application of the other equitable factors (irreparable harm, balance of the hardships and the public interest) should the lower court find in Sequenom's favor on the "likelihood of succeeding on the merits" prong of the preliminary injunction test.  Concerning the "irreparable harm" prong, the District Court found that "price and market erosion would occur," these being factors that can be used to support a preliminary injunction (for example, under Celsis in Vitro, Inc. v. CellzDirect, Inc., 664 F.3d 922, 930 (Fed. Cir. 2012)).  The District Court cited four reasons why Sequenom's showing of harm was not sufficient to satisfy this prong of the test.  First, the Court found that the market and price erosion were not "irreparable" because Sequenom's superior product (if it turned out to be so) would recover the market and receive damages for any infringement.  The panel found this to be an assumption rather than a fact and said that "[i]n the face of that kind of universal assumption, patents would lose their character as an exclusive right as articulated by the Constitution and become at best a judicially imposed and monitored compulsory license."  Second, the Court found that Sequenom's expert witness had not demonstrated the "degree" of price and market erosion adequately, because he had not considered other, potentially rival tests.  In addition to the contingent and speculative nature of this assessment, the panel noted that the "'fact that other infringers may be in the marketplace does not negate irreparable harm,"' citing Pfizer, Inc. v. Teva Pharm. USA, Inc., 429 F.3d 1364, 1381 (Fed. Cir. 2005).  Next, the District Court found that granting a preliminary injunction "would put Ariosa out of business."  While such a showing can be a factor (see Intel Corp. v. ULSI Sys. Tech., Inc., 995 F.2d 1566, 1568, 1570 (Fed. Cir. 1993)) it does not control the "balance of the hardships" prong of the standard, citing Bell & Howell Document Mgmt. Prods. Co. v. Altek Sys., 132 F.3d 701, 708 (Fed. Cir. 1997).  The panel indicated that the District Court will need to educe evidence of the balance of the hardships (i.e., on Sequenom if the injunction is denied as well as Ariosa if it is granted) to properly establish where the balance of the hardships lies.  Finally, the Court noted that at least some of the grounds used by the District Court in finding in favor of Ariosa on the public interest prong was that Ariosa marketed its Harmony test to both "high- and low-risk women" (approximately 3.5 million) while Sequenom made its test available only to high-risk women (e.g., over 35 years of age and amounting to about 750,000 women).  The panel noted that more recently "an expert organization had warned that cffDNA tests should not, yet, be used in low-risk women. Am. Coll. of Obstetricians and Gynecologists Comm. on Genetics, Noninvasive Prenatal Testing for Fetal Aneuploidy, Op. No. 545 (Dec. 2012).  This report raises questions that the panel should consider when rendering its decision on Sequenom's preliminary injunction motion on remand.

Aria Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2013)
Panel: Chief Judge Rader and Circuit Judges Dyk and Reyna
Opinion by Chief Judge Rader

Comments

[Jorma Narrone]

Kevin: "The question that will need to be addressed is whether these claims recite diagnostic method claims that remain patent eligible under the Court's Mayo v. Prometheus Labs. decision"

The Federal Circuit's claim construction would seem to be rather problematic for the patentee and the denial of a preliminary injunction would still be a very reasonable choice. The only steps in the method claim are these two:

1) amplifying a paternally inherited nucleic acid from [a pregnant woman's] serum or plasma sample and

2) detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.

Given the broad construction of the terms "amplifying" and "paternally inherited nucleic acid", there seems to be little doubt that step (1) is old, i.e., serum from pregnant women was subjected to PCR prior to the discovery by the inventors (circa 1997) that the serum contained small amounts of fetal DNA.

Step (2) can be practiced by merely recognizing that some of the amplified DNA from step (1) is of fetal origin.

The issue in Prometheus, then, is front and center in Sequenom's claims. It would seem that having discovered that fetal DNA exists in PCR-detectable levels in the serum of pregnant women, Sequenom sought to prevent anyone else from exploiting that fact or recognizing that fact in its only relevant practical context (I haven't checked the prosecution history but I gather from the summary above that they tried repeatedly to obtain claims broader than the very broad claims that ultimately issued). The Supreme Court has left no doubt that attempts to use the patent system to retain control of facts -- particularly facts about biology -- must be checked.

If the issue remains elusive to you (or anyone else) consider the following:

1. A method comprising:
determining if a sequence of DNA in the serum of a pregnant woman comprises SEQ ID NO:1.

2. The method of claim 1, where the sequence is obtained using any sequencing method known in the art.

Claim 1 is undeniably ineligible in view of Prometheus (and the Federal Circuit's decision in Myriad, applying Prometheus to Myriad's method claims). Claim 2, of course, adds nothing to claim 1 that would save it.

The analysis and conclusion remains unchanged, of course, if instead of a specific sequence (BRCA1) being detected, we substitute a generic description of a class of undefined sequences (e.g., "fetal DNA of paternal origin"). And that non-distinguishing difference appears to be the only difference between Sequenom's claim and the method claims of Prometheus and Myriad that have been deemed ineligible.

I say "appears" because it might be the case, in fact, that serum from a pregnant woman was never subjected to PCR amplification before the filing of this application. That seems highly unlikely but, if true, it would turn the first step in the claim from an "old step" into a new step and would thus mitigate the Prometheus issue. Of course, if that first step was indeed new and non-obvious, one wonders why Sequenom bothered to include the subsequent "detecting" step ...

[Kevin E. Noonan]

Dear Jorma:

I suspect the "detecting" part of the claim was included for utility purposes - a method for amplifying fetal DNA in maternal blood has to actually do something, and detecting it provides a utility that satisfies the other requirements of Section 101.

I agree that the patent eligibility of the claim will depend on whether detecting fetal DNA in maternal blood was "new" when the patent application was filed. I do think that we (and the Court) need to be careful with broad pronouncements of reducing patent eligibility of diagnostic method claims. Claims that overreach (like the Myriad claims struck down by the district court) are one thing, but a broad preclusion is bad policy, for at least this reason: as our understanding of molecular biology of disease having a genetic component becomes more extensive the opportunity to "hide the ball" by not disclosing the basis of the diagnosis will increase. Non-disclosure is worse for everyone that patenting diagnostic methods, a fact the Court does not appear to appreciate.

Thanks for the comment.

[Skeptical]

Patent eligibility and patentability ('newness') are different things. This was emphasized by the Prometheus Court in no uncertain terms.

[Jorma Narrone]

Good points, Kevin. I disagree wiht a couple aspects:

You wrote: "I suspect the "detecting" part of the claim was included for utility purposes - a method for amplifying fetal DNA in maternal blood has to actually do something"

I don't think the utility requirement is that burdensome (for lack of a better word). A bona fide new method for amplifying fetal DNA in maternal blood does actually "do something" -- it amplifies fetal DNA in maternal blood, which could be useful for any number of reasons.

Your observation does highlight a recurring problem with broad claims to discoveries of natural phenomenon: if your claim is so broad that another party using old tools can become an infringer merely be detecting the phenomenon you described first, the claim is at very high risk of being ineligible. It's easy to understand why this is the case if you consider situations where "looking trhough a microscope" is the only step in the claim and the "new" element is the identification of the importance of what you are looking at, or the counting of some pre-existing material that "correlates" with some likelihood of disease, or the identification of where to point the microscope. I believe such claims are ineligible. I also don't see a policy reason for distinguishing between the use of a microscope or any other old methodology. Do you?

"as our understanding of molecular biology of disease having a genetic component becomes more extensive the opportunity to "hide the ball" by not disclosing the basis of the diagnosis will increase. Non-disclosure is worse for everyone that patenting diagnostic methods, a fact the Court does not appear to appreciate"

I think that's debatable (and we will surely be debating the issues for a long, long time!). First, valuable genetic information is going to be obtained and made public more quickly than ever because (1) sequence information is going to become easier to obtain (in part, with the help of worthy patents on new methods of obtaining that information); (2) because the ever-shrinking cost of computer storage and processing is going to make it easier to analyze the information about sequences; and (3) because the pressure to make that information available to everyone (doctors and patients, especially) is going to be enormous. The ball may be "hidden" for short periods of time but those times will likely be extremely short, at least with respect to any "balls" that matter. Take the alleged discovery in this case, for instance, i.e., the discovery that fetal DNA exists in detectable quantitities in the serum of pregnant women. Let's say that the discoverers knew that they could not get a patent so broad that it prevented others from making the discovery independently. How could that discovery possibly have been hidden from the public for any substantial length of time?

As for "non-disclosure being worse than patents on diagnostic methods", that would certainly depend on the methods being claimed. Given the increasing ease of obtaining medical information (sequence information in particular) and processing that information to identify *some* correlation between *some* sequence and *some* condition (whether it be classified as a "disease" or not), it doesn't seem prudent to give the "discoverers" of such "correlations" 20 years of exclusivity whereby people are prevented from using old, publicly available (or, in some cases, patent ineligible) methods to obtain the information themselves.

So there is no confusion on this key point, I do not disagree that patents can successfully promote progress in any useful art, including the medical arts. I do think it's important to recognize, however, that the progress that is promoted by worthy patents (on, say, new methods of gathering information) may not itself always be patent-able or deemed practical to patent (either for statutory reasons or any other reason). That would certainly apply to information about disease correlations and genetics obtained, in part, through the aid of new sequencing methodologies (which will continue to progress, with the help of patents).

[Jorma Narrone]

Skeptical: "Patent eligibility and patentability ('newness') are different things."

Indeed they are. However, the claims we are discusssing here, just like the claims that were found ineligible in Prometheus, involve only two steps. The Supreme Court made clear that in these sorts of claims, at least, where one step is old and conventional and the other step is ineligible subject matter (e.g., the recitation of a natural phenomenon or correlation or some other ineligible step), the claim is very likely to be ineligible.

The bottom line is that whether eligibility and "newness" are different things, the analysis for determining patent ineligibility under Prometheus requires determining what steps, if any, are "old and conventional." If you know a way of performing the Prometheus analysis without addressing the "newness" of any claim element, you should tell everybody about it.

[Skeptical]

I see at Patently-O that Jorma Narrone has been linked with the entity formally known as Malcolm Mooney.

While I asked a similar question before, that question went unanswered.

Jorma Narrone, have you posted on this or other blogs using any (or all) of the following pseudonyms (or derivations thereof):
Malcolm Mooney,
MM,
Keeping It Real,
Robert,
Francis,
Shrivan,
Vivika M., or
Friend of the Court?

Will I get an honest and straightforward answer?

I remain...