Abstract
Synopsis
On motion for summary judgment, a district court invalidated for lack of patent eligibility claims directed towards PCR-based methods for detecting antibiotic resistant forms of pathogenic bacterium Mycobacterium tuberculosis (M. tuberculosis or MTB), and also claims reciting primers that would be used in performing the method. The Federal Circuit affirmed. With respect to the primer claims, the court found that, because the claimed primers had genetic sequences identical to those found in nature, their patent eligibility was precluded by the Federal Circuit's 2014 decision in In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litig., 774 F.3d 755, 760 (Fed. Cir. 2014) (BRCA1), which found similar primer claims patent ineligible. The court was not persuaded by Roche's argument that the claimed primers were chemically and structurally distinct from naturally occurring MTB DNA, in particular due to the presence of both a 3-prime end and a 3-prime hydroxyl group on the primer DNA which is not present in naturally occurring DNA. Turning to the method claims, the Federal Circuit applied the Alice/Mayo test and found that under step one of the test the claims were directed towards a natural phenomenon, i.e., the relationship between “signature” nucleotide sequences unique to MTB and the presence of MTB in a sample. The court then concluded that the method claims lacked sufficient inventive concept to satisfy step two of the Alice/Mayo test, given that the “main action step” of the claimed methods is polymerase chain reaction (PCR) amplification, and that PCR implication and detection were “routine” when the patent application was filed in 1994. Judge O'Malley filed a concurring opinion agreeing with the majority that the BRCA1 decision compelled its conclusion that the claims are patent ineligible, but then urging the court to revisit BRCA1 en banc. In the view of Judge O'Malley, BRCA1 was a poor vehicle for deciding the patent eligibility of DNA primers due to the procedural posture of the case (review of a denial of patent owner's motion for preliminary injunction), and the court should reconsider en banc whether the chemical and structural differences between naturally occurring chromosomal DNA and synthetic PCR primers might be sufficient to render PCR primers patent eligible under the test set forth by the Supreme Court in Myriad.
Appellant Roche Molecular Systems, Inc. (“Roche”) owns U.S. Patent No. 5,643,723 (“the '723 patent”), titled “Detection of a Genetic Locus Encoding Resistance to Rifampin in Microbacterial Cultures and in Clinical Specimens.” The United States District Court for the Northern District of California found that the asserted claims of the '723 patent are directed to patent-ineligible subject matter and are therefore invalid under 35 U.S.C. § 101. Roche appeals from a grant of summary judgment of invalidity. We affirm.
I. The '723 Patent
The '723 patent is directed to methods for detecting the pathogenic bacterium Mycobacterium tuberculosis (“M. tuberculosis” or “MTB”). MTB infection is a major cause of tuberculosis. In 1994, before the priority date of the '723 patent, the general method of MTB detection in a tuberculosis patient was known as sputum examination by the acid-fast bacilli smear. For this test, a biological sample taken from a patient is subjected to cell culture in a process that can take three to eight weeks. This test has limitations: it can identify the presence of bacterial cells in a biological sample, but cannot identify the cells as MTB. There is a need to know whether the MTB from a patient is resistant to antibiotics. The standard of care for MTB treatment at the time involved a regimen of antibiotics, with rifampin being a first-line anti-tuberculosis drug. Tuberculosis outbreaks, however, still resulted because of delays in diagnosis and reporting of rifampin-resistant tuberculosis due to the inability to rapidly identify MTB strains that are resistant to rifampin and put a patient on an appropriate alternative therapy.
Prior to the '723 patent, scientists in the field had been working on diagnostic tests for faster detection of MTB, particularly rifampin-resistant MTB strains. It was speculated that “[g]enotypic detection of multi-drug resistant MTB [strains] directly from clinical specimens is theoretically the fastest and most direct step toward determining effective therapy for patients.” It was known in the art that rifampin has a unique site of action on a particular gene that encodes the β subunit of bacterial RNA polymerase (“the rpoB gene”). The rpoB gene is present in MTB and other bacterial species, and its deoxyribonucleic acid (“DNA”) sequences were known to be highly conserved, with little variation from one bacterial species to another. In 1994, single site mutations in the rpoB gene that confer rifampin resistance in some bacteria, such as Escherichia coli (“E. coli”), were well characterized, making rpoB a prime candidate for studying rifampin resistance in MTB.
The inventors of the '723 patent—scientists from Roche and the Mayo Foundation for Medical Education and Research (“Mayo”)—sequenced the rpoB gene from various bacteria species, including MTB, obtained from a commercial vendor. After comparing rpoB DNA sequences across different species, the inventors discovered that the rpoB gene in MTB contains eleven “position-specific ‘signature nucleotides’” (i.e., naturally occurring single nucleotide mutations) that are only present in MTB but not in other bacteria. In other words, these naturally occurring signature nucleotides are like finger-prints of MTB: if an investigator detects one of the eleven signature nucleotides from a biological sample, she knows the sample contains MTB, and vice versa. These signature nucleotides, therefore, could be used to identify MTB using genetic testing, which is both faster and more accurate than the traditional MTB detection methods.
Based on these eleven MTB-specific signature nucleotides, the Roche inventors devised a diagnostic test that could (1) identify whether or not a biological sample contains MTB, and (2) if MTB is present, predict whether that MTB is a strain that is resistant to rifampin treatment. The diagnostic test of the '723 patent involves subjecting DNA extracted from a biological sample taken from a patient (e.g., a tissue or fluid sample) to amplification by polymerase chain reaction (“PCR”) using a short, single-stranded nucleotide sequence (a “primer”) that can hybridize (i.e., bind) to at least one of the eleven position-specific signature nucleotides in the MTB rpoB gene.
PCR is a method of amplifying DNA exponentially. In PCR, a pair of primers effectively “flanks,” or marks the start and finish of, the DNA segment—e.g., the rpoB gene or a portion of it—to be copied. Strands of DNA are then replicated between the primer pair by a DNA polymerase. This process is repeated until a sufficient number of copies of the desired DNA segment are generated. These copies, known as “amplification product,” make it possible to detect whether a specific type of DNA is present. It is undisputed that by the time of the invention in 1994, PCR had become a well-understood, routine, and conventional technique.
After PCR is performed, the presence of DNA amplification product in sufficient copies from the reaction indicates that MTB is present in the biological sample. The absence of DNA amplification product (i.e., below the detection limit using standard assays) indicates that MTB is absent from the biological sample. The amplified rpoB DNA segment from the PCR can, in turn, be tested for the presence of known genetic mutations associated with rifampin resistance. Thus, the '723 patent represents an improvement over the traditional sputum examination method for detecting MTB, as its genetics-based diagnostic method is faster and more accurate.
The '723 patent provides two types of claims: (1) composition-of-matter claims for the primers used in the PCR, which could hybridize to the rpoB gene of MTB at a site that includes at least one of the eleven signature nucleotides (“the primer claims”); and (2) process claims for methods for detecting MTB that include amplifying target sequences by PCR and detecting amplification products, which, if present, indicate the presence of MTB (“the method claims”).
Claims 1–13 are the method claims. Claim 1, the sole independent method claim, recites:
A method for detecting Mycobacterium tuberculosis in a biological sample suspected of containing M. tuberculosis comprising:
subjecting DNA from the biological sample to polymerase chain reaction [PCR] using a plurality of primers under reaction conditions sufficient to simplify a portion of a M. tuberculosis rpoB [gene] to produce an amplification product, wherein the plurality of primers comprises at least one primer that hybridizes under hybridizing conditions to the amplified portion of the [gene] at a site comprising at least one position-specific M. tuberculosis signature nucleotide selected, with reference to FIG. 3 (SEQ ID NO: 1), from the group consisting [of] a G at nucleotide position 2312, a T at nucleotide position 2313, an A at nucleotide position 2373, a G at nucleotide position 2374, an A at nucleotide position 2378, a G at nucleotide position 2408, a T at nucleotide position 2409, an A at nucleotide position 2426, a G at nucleotide position 2441, an A at nucleotide position 2456, and a T at nucleotide position 2465; and detecting the presence or absence of an amplification product, wherein the presence of an amplification product is indicative of the presence of M. tuberculosis in the biological sample and wherein the absence of the amplification product is indicative of the absence of M. tuberculosis in the biological sample.
Claims 17–20 are the primer claims. Independent claim 17 is representative and recites:
A primer having 14–50 nucleotides that hybridizes under hybridizing conditions to an M. tuberculosis rpoB [gene] at a site comprising at least one position-specific M. tuberculosis signature nucleotide selected, with reference to FIG. 3 (SEQ ID NO: 1), from the group consisting of [the same 11 nucleotides at the positions disclosed in claim 1].
II. District Court Proceeding
Appellee Cepheid makes and sells “Xpert® MTB/RIF Assay,” an assay that can detect MTB in a biological sample and can identify rifampin-resistant MTB. Roche brought a patent infringement case against Cepheid asserting that Cepheid's product infringed the '723 patent. Cepheid filed a motion for summary judgment, arguing that all of the asserted claims claim patent-ineligible subject matter under 35 U.S.C. § 101.
The district court granted Cepheid's motion. The district court found that the primer claims of the '723 patent, “which have genetic sequences identical to those found in nature, are indistinguishable from those held to be directed to nonpatentable subject matter” and are thus invalid. The district court also found that the method claims are invalid because they are directed to “nonpatentable laws of nature or natural phenomena” and “the use of newly developed, nonpatentable primers to bind to newly identified naturally occurring signature nucleotides … using the well-known, routine process of PCR in a conventional way does not transform the claimed methods into” patent-eligible subject matter.
Roche timely appealed.
III. Discussion
The only issues on appeal are whether the aforementioned primer claims and the method claims of the '723 patent are patent-ineligible within the meaning of § 101. Section 101 provides that “[w]hoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.” 35 U.S.C. § 101. There are certain exceptions to this provision: laws of nature, natural phenomena, and abstract ideas are not patent-eligible subject matter. Alice Corp. v. CLS Bank Int'l, 573 U.S. 208 (2014) (collecting cases).
The Supreme Court has established a two-step framework for distinguishing patents that claim laws of nature, natural phenomena, and abstract ideas from those that claim patent-eligible applications of those concepts. Under the Alice/Mayo two-step framework, we first “determine whether the claims at issue are directed to one of those patent-ineligible concepts.” “[T]he ‘directed to’ inquiry applies a stage-one filter to claims, considered in light of the specification, based on whether ‘their character as a whole is directed to excluded subject matter.’” At step one, “it is not enough to merely identify a patent-ineligible concept underlying the claim; we must determine whether that patent-ineligible concept is what the claim is ‘directed to.’”
If a claim is directed to one of those patent-ineligible concepts, we move to step two of the Alice/Mayo inquiry to “examine the elements of the claim to determine whether it contains an ‘inventive concept’ sufficient to ‘transform’ the claimed abstract idea into a patent-eligible application.” At step two, there must be a further inventive concept to take the claim into the realm of patent-eligibility. For claims that encompass natural phenomena, the method steps are the “additional features that must be new and useful.” Following the Alice/Mayo framework, we address the primer claims and the method claims in turn.
A. The primer claims
Roche argues that at Alice/Mayo step one, the primer claims (claims 17–20) are patent-eligible because they are directed to artificial, man-made primers that are different from naturally occurring DNA. Specifically, Roche argues that the claimed primers have both a 3-prime end and a 3-prime hydroxyl group, while the naturally occurring bacterial MTB DNA contains neither of these. The district court rejected Roche's arguments and found that “the primer claims in this case, which have genetic sequences identical to those found in nature, are indistinguishable from those held to be directed to nonpatentable subject matter in In Re BRCA1.” (citing In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litig., 774 F.3d 755, 760 (Fed. Cir. 2014) (“BRCA1”)). We agree.
BRCA1 forecloses Roche's arguments. There, this court examined the subject matter eligibility of similar primer claims and held that those primers “are not distinguishable from the isolated DNA found patent-ineligible in Myriad” and thus are not patent-eligible. It is well established that primers are short, single-stranded nucleic acid molecules that bind to their complementary nucleotide sequence. As this court found in BRCA1, “[p]rimers necessarily contain the identical sequence of the [nucleotide] sequence directly opposite to the [DNA] strand to which they are designed to bind. They are structurally identical to the ends of DNA strands found in nature.”
The court further held:
A DNA structure with a function similar to that found in nature can only be patent eligible as a composition of matter if it has a unique structure, different from anything found in nature. Myriad, 133 S.Ct. at 2116–17. Primers do not have such a different structure and are patent ineligible.
It is undisputed that the primers before us have the identical nucleotide sequences as naturally occurring DNA, just like the primers found subject matter ineligible in BRCA1. Nothing in the '723 patent suggests that the Roche inventors introduced any mutations that would have made the primers' nucleotide sequences different from those found in nature. Thus, Roche's primers are indistinguishable from their corresponding nucleotide sequences on the naturally occurring MTB rpoB gene.
Roche argues that the claimed primers are nonetheless patent-eligible because they “are chemically and structurally distinct from any nucleic acid that occurs in nature or that can be isolated from naturally occurring DNA.” According to Roche, its claimed primers have a 3-prime end and a 3-prime hydroxyl group, which are absent in naturally occurring DNA. This distinction is unavailing. The same argument was raised in the opening brief in BRCA1. This court rejected this argument, holding that the primers at issue were patent-ineligible subject matter. As we held in BRCA1, “it makes no difference that the identified gene sequences are synthetically replicated.” It was undisputed that the primers in BRCA1 contain 3-prime ends and 3-prime hydroxyl groups, exactly as Roche's primers in this case. Thus, except for the nucleotide sequences, the primers before us are not chemically or structurally different from the primers that we held patent-ineligible in BRCA1.
Roche next argues that its primers can be distinguished from the patent-ineligible primers of BRCA1 because they can hybridize to only one of eleven position-specific signature nucleotides on the MTB rpoB gene. This is an Alice/Mayo step two argument: Roche is arguing that the specificity of its primers to the eleven signature nucleotides would “transform” the claimed naturally occurring phenomenon into patent-eligible subject matter. But Roche's emphasis on hybridizing to particular DNA sequences is unavailing. A primer that is otherwise patent-ineligible does not gain subject matter eligibility simply because it can selectively hybridize to a certain position of naturally occurring DNA, because a primer having an identical nucleotide sequence to naturally occurring DNA without further chemical modification is a natural phenomenon. Here, the primers before us have no further chemical modification.
The eleven position-specific signature nucleotides on the MTB rpoB gene that Roche's primers are designed to hybridize to are naturally occurring; the Roche inventors identified these eleven positions after sequencing MTB DNA. In other words, Roche identified these pre-existing position-specific signature nucleotides; it did not create them. There is no doubt that Roche's discovery of these signature nucleotides on the MTB rpoB gene and the designing of corresponding primers are valuable contributions to science and medicine, allowing for faster detection of MTB in a biological sample and testing for rifampin resistance. However, “[g]roundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Myriad, 569 U.S. at 591; Ariosa, 788 F.3d at 1379. The primers are not patent-eligible because they can be found in nature, not because they are not valuable scientific discoveries.
We hold that the primers before us are indistinguishable from their corresponding nucleotide sequences on the naturally occurring DNA, and that the primer claims, therefore, are patent-ineligible within the meaning of § 101. We next address the asserted method claims.
B. The method claims
At Alice/Mayo step one, the plain language of the asserted method claims, viewed in light of the written description, demonstrates that they are directed to naturally occurring phenomena. The method claims disclose a diagnostic test based on the observation that the presence of the eleven position-specific signature nucleotides of the naturally occurring MTB rpoB gene indicates the presence of MTB in a biological sample. Claim 1, the sole independent method claim, provides “[a] method for detecting Mycobacterium tuberculosis in a biological sample” and contains two steps: (1) PCR amplification of DNA (“the amplification step”), and (2) determination of the presence of MTB based on the presence or absence of PCR amplification product (“the detecting step”). The amplification step subjects DNA from a biological sample—naturally occurring matter—to amplification by PCR using primers that are designed to hybridize to at least one of the eleven naturally occurring position-specific signature nucleotides on the MTB rpoB gene. The primers, as discussed above, are indistinguishable from their corresponding naturally occurring segments on DNA. The detecting step of claim 1 is a mental determination step: if a PCR amplification product is detected, MTB is present in the biological sample, and vice versa.
Claim 1 establishes that the method claims are directed to a relationship between the eleven naturally occurring position-specific signature nucleotides and the presence of MTB in a sample. In other words, the method claims assert that if an investigator detects a signature nucleotide from a sample, she knows the sample contains MTB. This relationship between the signature nucleotides and MTB is a phenomenon that exists in nature apart from any human action, meaning the method claims are directed to a natural phenomenon, which itself is ineligible for patenting. Because these signature nucleotides are naturally occurring, we conclude that the method claims, as informed by the written description, are directed to a patent-ineligible natural phenomenon. We turn to Alice/Mayo step two.
We hold that the method claims do not contain an inventive concept that transforms the eleven position-specific signature nucleotides of the MTB rpoB gene into patent-eligible subject matter. PCR amplification of DNA is the main action step of the method claims. The district court found, and Roche does not challenge, that “the background techniques of PCR amplification and detection were ‘routine’ when the patent application was filed in 1994.” Neither the claims nor the written description of the '723 patent disclose any “new and useful” improvement to PCR protocols or DNA amplification techniques in general. The detecting step of claim 1 is similarly devoid of an inventive concept because it involves a simple mental determination of the presence of MTB based on the presence or absence of a PCR amplification product.
While it may be true that Roche inventors were the first to use PCR to detect MTB in a biological sample, being the first to discover a previously unknown naturally occurring phenomenon or a law of nature alone is not enough to confer patent eligibility. Many groundbreaking, innovative, and brilliant discoveries have been held patent-ineligible.
Roche argues that to use its primers to detect MTB “is no less an inventive act than to make a specific artificial drug that is effective to treat an MTB infection.” We disagree. [Unlike] a method of treating a disease with a new drug, Roche's method claims do not involve “a significantly new function” for the primers.
This case is distinguishable from CellzDirect, where this court vacated a district court's decision that the method claims at issue were ineligible for patenting. 827 F.3d at 1052. This court held that while the claims were based on the discovery of a natural phenomenon (the ability of certain liver cells, or hepatocytes, to survive multiple freeze cycles), they were “directed to a new and useful laboratory technique for preserving hepatocytes”—namely, freezing and thawing hepatocytes twice even though the prior art taught away from this process. This court held that “[t]his type of constructive process, carried out by an artisan to achieve ‘a new and useful end,’ is precisely the type of claim that is eligible for patenting. … [The inventors] employed their natural discovery to create a new and improved way of preserving hepatocyte cells for later use.” Id. at 1048 (emphasis added) (quoting Alice, 134 S.Ct. at 2354). Unlike the method claims of the '723 patent, the invention in CellzDirect went beyond applying a known laboratory technique to a newly discovered natural phenomenon, and instead created an entirely new laboratory technique that “is not simply an observation or detection” based on the natural phenomenon. In contrast, the '723 patent claims a method of detection based on a natural phenomenon and employs only conventional, well-known laboratory techniques, which are the opposite of those at issue in CellzDirect.
Roche attempts to distinguish its invention from the patent-ineligible method claims in BRCA1. In BRCA1, this court invalidated claims 7 and 8, which were directed to methods of diagnosing genetic mutations of the BRCA1 gene in patients, as subject matter ineligible. Relevant here, BRCA1 distinguished the subject matter ineligible method claims 7 and 8 from the potential subject matter eligibility of a different method claim, claim 21, which was not asserted and was thus not at issue; in dicta, the court pointed out that claim 21
claims a method of detecting alterations in which the alterations being detected are expressly identified in the specification by tables 11 and 12. These tables expressly identify ten predisposing mutations of the BRCA1 gene sequence discovered by the patentees. Thus, the detection in claim 21 is limited to the particular mutations the inventors discovered: detecting ten specific mutations from the wild-type, identified as “[p]redisposing [m]utations,” for the specific purpose of identifying increased susceptibility to specific cancers. Claims 7 and 8 are significantly broader and more abstract, as they claim all comparisons between the patient's BRCA genes and the wild-type BRCA genes.
Roche argues that its method claims are analogous to claim 21, and distinguishable from claims 7 and 8 in BRCA1, because they require primers hybridizing to one of eleven signature nucleotides expressly identified in the claims, and thus would not preempt or limit use of other DNAs for detecting MTB. To be clear, BRCA1 did not find claim 21 subject matter eligible; in response to the parties' arguments, this court emphasized that “we express no view” on whether claim 21 is subject matter eligible, and simply noted that “claim 21 is qualitatively different from” claims 7 and 8. Roche is mistaken that limiting the scope of an otherwise ineligible method claim would necessarily confer subject matter eligibility. Roche's attempt to limit the breadth of the method claims by showing alternative uses of MTB DNA outside of the scope of the claims “does not change the conclusion that the claims are directed to patent ineligible subject matter.” See Ariosa, 788 F.3d at 1379. “While preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility.” Id. Thus, the method claims before us cannot gain subject matter eligibility solely because they are limited to specific signature nucleotides.
Therefore, we hold that the asserted method claims of the '723 patent are patent-ineligible because they are directed to a natural phenomenon and lack any inventive concept that transforms them into patent-eligible subject matter.
IV. Conclusion
For the foregoing reasons, we affirm the district court's summary judgment ruling.
AFFIRMED
I agree with the majority that our decision in In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litigation, 774 F.3d 755, 758 (Fed. Cir. 2014) (“BRCA1”) compels the conclusion that the primer and method claims of U.S. Patent No. 5,643,723 (“the '723 patent”) are not eligible for patent protection.
I write separately to express my belief that we should revisit our holding in BRCA1 at least with respect to the primer claims. Specifically, I believe that our holding there was unduly broad for two reasons: (1) the question raised in BRCA1 was narrower than our holding in that case; and, (2) our interpretation of the nature and function of DNA primers lacked the benefit of certain arguments and evidence that the patent owner presents in this case.
First, the question before us in BRCA1 was not whether the primer claims were patent-ineligible, but, rather, whether the district court abused its discretion when it denied the patent owner's motion for a preliminary injunction. We affirmed by expressly concluding that the primer claims were directed to patent-ineligible subject matter. But that was not the question before us; it was only whether the district court abused its discretion when it found that the accused infringer raised a substantial question regarding invalidity under § 101.
Because of the procedural posture in BRCA1, it is hardly surprising that we did not have the benefit of certain arguments and evidence that the patent owner presents in this case when we decided BRCA1. In BRCA1, we found that “[p]rimers necessarily contain the identical sequence of the BRCA sequence directly opposite to the strand to which they are designed to bind,” and that “[t]hey are structurally identical to the ends of DNA strands found in nature.”
But it is not clear from the BRCA1 opinion or record why we reached this conclusion. The lack of record evidence underlying BRCA1's conclusion on this point is important in light of the record in this case. Specifically, BRCA1 concludes that primers have “identical sequences” to the natural DNA strands directly opposite the strands to which they bind, but, as the record in this case reveals, a finding that the two have identical sequences does not entirely resolve the question of whether they are structurally identical because structure is not defined solely by nucleotide sequence. Nor is it clear how primers “are structurally identical to the ends of DNA strands found in nature.” As I explain below, the additional facts in this record, viewed in the light most favorable to Roche, give rise to genuine issues of material fact regarding whether the claimed primers have a “unique structure, different from anything found in nature,” and therefore, challenge the conclusion that this entire class of molecules is ineligible under § 101.
Roche developed a record in this case demonstrating the ways in which the claimed primers differ structurally from anything that occurs in nature. Roche first submitted evidence supporting a finding that the claimed primers differ from primers that naturally occur in the bacteria of the M. tuberculosis complex (“MTB”). Roche's expert explained that, unlike the claimed primers, the naturally occurring MTB primers are never single-stranded. Roche's expert also explained that the naturally occurring MTB primers are comprised of RNA whereas the claimed primers are comprised of DNA. This means that naturally occurring MTB primers differ chemically from the claimed primers “both (i) in the type of sugar they contain (ribose [in MTB primers] v. deoxyribose [in the claimed primers]) and (ii) the sets of bases that they use (A, C, G, U [in the MTB primers] v. A, C, G, T [in the claimed primers]).” Finally, Roche's expert explained that “[n]aturally occurring MTB primers are 3–10 nucleotides long, and thus differ structurally from the claimed primers, which are at least 14 nucleotides long.” This record evidence supports a finding that the claimed primers differ from naturally occurring MTB primers.
Roche also explained that the claimed primers differ structurally from the native MTB rpoB gene. Roche explained that because “the DNA of MTB occurs in the form a circular chromosome,” the native MTB rpoB gene lacks a 3-prime end with a 3-prime hydroxyl (-OH) group. In contrast, the parties agree that the claimed primers necessarily have hydroxyl groups at their 3-prime end, and that skilled artisans would recognize as much. Roche's expert explained that “[a] free hydroxyl group at the 3′ end of the primer or extension product is essential for DNA replication, because it provides a free end to which the next nucleotide can be attached.” Indeed, “[a] DNA that lacks a free hydroxyl group at the 3′ end cannot support replication and thus cannot serve as a primer.”
Moreover, because the DNA of MTB found in nature occurs in the form of a circular chromosome, and therefore lacks any sort of end, the claimed primers cannot be “structurally identical to the ends of DNA strands found in nature,” as we concluded in BRCA1. And, even if the DNA in MTB occurred in linear strands, Roche's expert testified that, in linear strands of native DNA, only the last nucleotide in the entire strand typically has a hydroxyl group at its 3-prime end. Thus, based on the above evidence, Roche's expert concluded that, while a portion of the native MTB rpoB gene has the same nucleotide sequence as the claimed primers, the two differ chemically vis-à-vis the presence of a 3-prime end with a 3-prime hydroxyl group at a nonnaturally occurring location.
Said another way, although it is undisputed that all the claimed primers here have nucleotide sequences that are identical to segments of the naturally occurring rpoB gene found in MTB, a genuine factual dispute exists as to whether they have a materially different structure than any DNA molecules typically found in nature.
Not only does the record demonstrate that the claimed primers could be structurally different from that which exists in nature, but the claims here also appear to be distinguishable from the molecule that would result from isolating the sequence of the strand directly opposite the strand to which the claimed primers hybridize. This is critical because, in Myriad, the Court explained that claims directed to isolated DNA sequences “are not saved by the fact that isolating DNA from the human genome severs the chemical bonds that bind gene molecules together.” But, unlike the claims in Myriad, which were neither “expressed in terms of chemical composition, nor” reliant “in any way on the chemical changes that result from the isolation of a particular section of DNA,” the primer claims here, by virtue of being directed to the well-known, structural term “primer” and by virtue of including “14-50 nucleotides that hybridize[ ] under hybridizing conditions” to at least one signature nucleotide, are expressed in terms of chemical composition and are reliant on the presence of a 3-prime end and a 3-prime hydroxyl group at a nonnaturally occurring location. Therefore, Roche's evidence regarding the presence of a 3-prime end with a 3-prime hydroxyl group, coupled with the claim language, support a finding that the claims here are distinguishable from the DNA claims in Myriad.
These structural differences between the claimed primers and that which exists in nature are not my only concerns with our conclusion in BRCA1, however: we also held that primers “do not perform a significantly new function” than does naturally occurring DNA. 774 F.3d at 761. In reaching this conclusion, we rejected the patentee's contention that DNA, when part of the naturally occurring genetic sequence, “stores the biological information used in the development and functioning of all known living organisms,” but when isolated as a primer, the DNA fragment “prime[s], i.e., … serve[s] as a starting material for a DNA polymerization process.”
Here, not only is there at least a genuine issue of material fact as to whether the claimed primers have a different structure from anything found in nature, the record also suggests that the claimed primers may have a different function from that of native DNA. Particularly, record evidence shows that, unlike native DNA, which merely stores genetic information and serves as a template for replication, the claimed primers can selectively hybridize, or bind, to specific nucleotides of a target gene—here, the “signature nucleotides” of the MTB rpoB gene. This function is reliant on the presence of the free 3-prime hydroxyl group at a nonnaturally occurring location and allows scientists, among other things, to amplify and detect the MTB rpoB gene using techniques such as polymerase chain reaction (“PCR”). The fact that claimed primers, once synthesized, “utilize the innate ability of DNA to bind to itself” to achieve this selective hybridization should not render them wholesale patent-ineligible. In Myriad, the Supreme Court explained that, although “[t]he nucleotide sequence of cDNA is dictated by nature, not by the lab technician,” this is irrelevant for § 101 purposes because “the lab technician unquestionably creates something new when cDNA is made.” Similarly, this record contains evidence that the lab technician creates something new when the claimed primers are made, even though, once made, the primers “utilize the innate ability of DNA to bind to itself.”
Cepheid argues on appeal that the patent owner in BRCA1 pointed to the same differences that Roche points to here. Specifically, Cepheid contends that the patent owner in BRCA1 raised the same 3-prime hydroxyl group argument that Roche makes here, and that we squarely rejected that argument. But, that is not an accurate characterization of the record in BRCA1. Perhaps because of the procedural posture in which the issue was developed, the patent owner in BRCA1 did not develop a record demonstrating that primers differ structurally from native DNA based on the presence of a hydroxyl group at a nonnaturally occurring location. Nor did we expressly address this hydroxyl group “argument” in BRCA1 or include language indicating that we had considered, but rejected, any such argument.
The patent owner in BRCA1 also never argued that its claimed primers were structurally distinct from naturally occurring primers. Simply, the patent owner in BRCA1 did not make the specific arguments Roche makes here. These points were also not raised or addressed in Myriad. While the patent owner there argued that native DNA differs from isolated DNA because “[n]ative DNA cannot be used as a molecular tool, such as a probe or a primer,” it did not explain that isolated DNA differs structurally from native DNA vis-à-vis a 3-prime end and a 3-prime hydroxyl group at a nonnaturally occurring location. Significantly, and as explained above, the claims at issue in Myriad were not reliant on the presence of this 3-prime hydroxyl group at a nonnaturally occurring location. Accordingly, Myriad could not have properly raised, and the Supreme Court could not have considered, the particular points that Roche now raises.
Therefore, unlike the appellants in Myriad and in BRCA1, here, Roche submitted evidence of record that, at the very least, raises genuine issues of material fact as to whether there exists anything in nature that both has the structure and performs the function of the claimed primers. For these reasons, while I agree with the majority that the broad language of our holding in BRCA1 compels the conclusion that the primer claims in this case are ineligible under 35 U.S.C. § 101, I believe that holding exceeded the confines of the issue raised on appeal and was the result of an underdeveloped record in that case. I believe, accordingly, that we should revisit our conclusion in BRCA1 en banc.