PTO Subject Matter Eligibility Guidance: An Ill-Advised Overextension of Myriad

Nucleic Acids

Although the Court's holding in Myriad was seemingly straightforward in its application to nucleic acid sequences, it failed to satisfactorily clarify what is required for a nucleic acid sequence to be patent eligible. The Guidance provides some clarity, at least from the viewpoint of the PTO, but it does little to clarify how various types of alterations to nucleic acid sequences would affect patent eligibility.

The Guidance makes clear that the type of nucleic acid and the biological source of claimed nucleic acid sequence do not change the patent eligibility analysis.30 This interpretation is consistent with Myriad. Although the nucleic acid sequences at issue in Myriad were sequences corresponding to human genes and portions of human genes, there is nothing in the Court's opinion that limits its holding to human DNA or to coding regions of the genome, and the reasoning underlying the Court's holding would logically apply equally to other types of nucleic acids as well. Thus, other naturally occurring nucleic acid sequences such as individual primers, promoters, enhancers, repressors, mRNAs, and microRNAs—whether from humans or another source—will likely no longer be patent eligible if they are merely “isolated.”

The Guidance also makes clear that mere manipulations of claim language will be insufficient to confer eligibility.31 Consistent with this, it seems clear from Myriad that limiting language in claims such as “purified,” “amplified,” “synthetic,” or “recombinant” is not automatically going to confer eligibility. Nevertheless, an argument has been made by Myriad in a recently settled lawsuit against Ambry Genetics that synthetic DNA is patent eligible by virtue of being created synthetically instead of being simply extracted or isolated.32 The crux of Myriad's argument in these lawsuits is that “it is not the nature of the nucleotide sequence that determines whether a particular DNA molecule is patentable, but rather the extent to which the molecule constitutes a ‘naturally occurring’ compound versus one created in a laboratory.”33 Further potential arguments have been put forth by commentators who have drawn attention to the fact that synthetic DNA often lacks epigenetic modifications, such as methylation, that are found in natural DNA.34 These differences are not just structural, but arguably informational: methylation patterns and epigenetic regulation can selectively activate or inactivate gene expression in cells.35

A more-plausible interpretation of Myriad, however, is the Guidance's interpretation that the sequence of DNA and its structure are more important in the patent eligibility inquiry than the manner in which the DNA is made. Although the Court held that “cDNA is patent-eligible because it is not naturally occurring,” contextual clues indicate that this refers to the fact that the nucleotide sequence of the cDNA is not found in nature, rather than the mere fact that the cDNA was synthetically created. In holding isolated DNA patent ineligible, the Court noted that “Myriad did not create or alter any of the genetic information” and that the “order of the nucleotides existed in nature before Myriad found them.”36 Similarly, in holding cDNA patent eligible, the Court emphasized that the cDNA at issue in Myriad had a non-naturally occurring nucleotide sequence. Specifically, the Court noted that cDNA “omits portions within the [natural] DNA segment that do not code for proteins,”37 and this “results in an exons-only molecule that is not naturally occurring.”38 The Court's emphasis on the removal of the non-coding sequences suggests that it is the resulting non-naturally occurring sequence that is critical for patent eligibility rather than the synthetic origin. This interpretation is supported by the Court's dicta suggesting that cDNA may not be patent eligible when it is identical in sequence to naturally occurring DNA.39 Thus, synthetic, purified, or amplified nucleic acid sequences are unlikely to be patent eligible unless they encompass a non-naturally occurring sequence.

The Guidance also interpreted Myriad as holding that the differences in structure between isolated DNA and naturally occurring DNA (i.e., broken chemical bonds) are not significant enough changes by themselves to confer patent eligibility, regardless of how that isolated DNA is claimed.40 This goes against the speculation of various commentators that claims relying more directly on the chemical changes resulting from isolation of DNA might be sufficient. The basis for this proposition is found in the Court's opinion in Myriad:

Nor are Myriad's claims saved by the fact that isolating DNA from the human genome severs chemical bonds and thereby creates a nonnaturally occurring molecule. Myriad's claims are simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA. Instead, the claims understandably focus on the genetic information encoded in the BRCA1 and BRCA2 genes.41

Despite this apparent opening, it is unlikely that this strategy would work. Myriad's claims did in fact rely on the chemical changes that resulted from isolation, such as the severing of chemical bonds, as these changes were inherent in the definition of “isolated” in Myriad's patents:

An ‘isolated’ or ‘substantially pure’ nucleic acid (e.g., an RNA, DNA or a mixed polymer) is one which is substantially separated from other cellular components which naturally accompany a native human sequence or protein, e.g., ribosomes, polymerases, many other human genome sequences and proteins. The term embraces a nucleic acid sequence or protein which has been removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogs or analogs biologically synthesized by heterologous systems.42

Because the Court disregarded this language in its analysis, the implication is that the structural differences between isolated DNA and an identical, naturally occurring sequence of genomic DNA are too trivial to render the isolated DNA patent eligible, regardless of how the isolated DNA is claimed.

Absent a more significant structural change than those caused by mere isolation or by synthetic creation of DNA, what will likely be required for patent eligibility are sequence alterations. What is not clear, however, is how much of a change to a naturally occurring DNA sequence will be considered by a court to be sufficient under Myriad or will be considered to be a “marked difference in structure” under the Guidance. The one thing that is certain is that eukaryotic cDNA will be patent eligible in most cases. However, the Myriad Court reasoned in dicta that there may be an exception if a cDNA is derived from a gene having no intervening introns, such as a prokaryotic gene.43 Thus, a prokaryotic cDNA would likely not be patent eligible because its sequence of nucleotides would be indistinguishable from the naturally occurring genomic DNA sequence from which it was derived.

The other near certainty is that specifically defined, non-naturally occurring, physically linked combinations of DNA sequences are still patent eligible. It is unquestionable that combining a naturally occurring DNA sequence with a heterologous DNA sequence, such as a regulatory sequence or tag, creates a composition that does not occur in nature. These changes in structure should also be considered “significant” under the Guidance because they confer additional functionality. The same is true for DNA sequences that have been modified with labels, such as fluorophores or haptens. Thus, specifically defined, recombinant DNA sequences or labeled DNA sequences should remain patent eligible.

Unfortunately, neither Myriad nor the Guidance provides much clarity on what other alterations to DNA sequences are sufficient to confer patent eligibility. Nucleotides within the DNA sequence of a gene can be divided into codons. Would a mutation of one nucleotide within a codon be sufficient for patent eligibility if the mutation did not change the encoded amino acid, as is done when optimizing codons for expression in another organism? What if multiple codons were changed in this manner? What if the mutation changed the encoded amino acid to a different amino acid? What if the mutation altered the function of the protein? In patents that have issued after the Myriad decision, the PTO has allowed claims to isolated genes with codons optimized throughout for expression in another organism,44 but it still is not yet clear how much alteration is needed for patent eligibility.

Proteins and Antibodies

The Guidance takes the position that Myriad applies with equal force to all other naturally occurring products. For proteins and antibodies, this means that patent eligibility at the PTO will turn on whether the protein or antibody is (1) non-naturally occurring and (2) markedly different in structure from naturally occurring counterparts. Although proteins with significantly altered amino acid sequences—such as humanized antibodies or fusion proteins—should remain patent eligible under this test, proteins that are merely isolated will likely no longer be patent eligible. This interpretation of the law expands the holding of Myriad and goes against years of precedent upholding claims to isolated proteins.

More weight should have been given by the PTO to the functional differences between isolated proteins and their naturally occurring counterparts. Similar to the purified epinephrine (trade name Adrenalin) in Parke-Davis & Co. v. H.K. Mulford Co.,45 an isolated protein has a significant utility (e.g., utility in treating a particular disease) that its naturally occurring counterpart does not.46 Consideration of these types of functional differences in patent eligibility determinations is consistent with the Supreme Court precedent cited favorably in Myriad. For example, in Chakrabarty, the claimed bacterium was held to be patent eligible because it was “a product of human ingenuity ‘having a distinctive name, character [and] use.’ ”47 Likewise, in refusing to uphold the validity of the claimed mixtures of bacteria in Funk Brothers Seed Co. v. Kalo Inoculant Co.,48 the Supreme Court reasoned that “[n]o species acquire[d] a different use.… The combination of species produces … no enlargement in the range of their utility.”49

The Guidance's focus on the structural similarity of isolated natural compounds without adequately considering functional differences goes against this precedent. If important non-structural differences are overlooked, it is almost unavoidable to conclude that the fact that a naturally occurring protein is isolated will not be enough to confer patent eligibility. Unlike isolation of a DNA sequence, which requires breaking of covalent bonds to separate the DNA sequence from surrounding genomic DNA, isolation of a protein does not require any comparable chemical changes. Consequently, isolated proteins are more structurally similar to their natural counterparts than isolated DNA is to naturally occurring genomic DNA. Recombinant proteins—those that are produced through expression of recombinant DNA in a host cell—will often differ in additional ways from their naturally occurring counterparts, particularly if a prokaryotic host cell is used. Glycosylation patterns, phosphorylation patterns, and other functionally significant post-translational modifications will often be altered in that case. It is hard to see how these differences would be sufficient, however, because comparable differences in isolated DNA—for example, differences in epigenetic modifications in synthetic DNA—were ostensibly ignored by the Court in Myriad in its dicta explaining that a synthetically created cDNA with a nucleotide sequence identical to a genomic DNA sequence may not be patent eligible.50

Although it seems likely that isolated proteins generally will no longer be patent eligible under the Guidance, the eligibility of antibodies is less clear. Some “isolated” antibodies that are often claimed in patents are antibodies generated by immunizing an animal with an antigen (such as a fragment of a pathogenic human protein) that the animal would not otherwise encounter (and that a human would not generally generate against itself ). Consequently, these antibodies do not exist in nature without human intervention. Although they are “naturally occurring” in the sense that they are produced by the immune system in response to a foreign antigen, the foreign antigen is present only because of the human intervention of injecting that antigen into the target animal. Thus, a good argument can be made that such antibodies should remain patent eligible.51 Just as a hybrid plant is eligible subject matter despite being created by manipulation of the naturally occurring processes of pollination and fertilization,52 an isolated antibody as described above should be patent eligible despite being made by immunizing an animal with a specific antigen to take advantage of natural biological processes within the animal. This is consistent with the Guidance, which states that “[t]he fact that a marked difference came about…via human manipulation of natural processes does not prevent the marked difference from weighing in favor of patent eligibility.”53 Moreover, although there is a theoretical possibility that a human could have generated an antibody against a human antigen (e.g., the fragment of a pathogenic human protein in the example above), that remote possibility should not be enough to negate patent eligibility. The PTO training slides provide an analogous example in a hybrid plant, which is eligible subject matter despite the “theoretical possibility that nature might have randomly created a hybrid plant similar to the claimed hybrid plant.”54

Other antibodies that are often claimed in patents are fragments of antibodies, such as Fab fragments or nanobodies. Even if these fragments came from antibodies that were truly naturally occurring, there is a good argument that they should remain patent eligible despite fragments of naturally occurring DNA no longer being patent eligible. Just as DNA consists of a sequence of nucleotide subunits dictated by nature, proteins (such as antibodies) consist of a sequence of amino acid subunits dictated by nature. Thus, the PTO might be tempted to use analogous reasoning to find that fragments of naturally occurring antibodies are ineligible. However, a DNA sequence is unique because although it is a chemical compound, it is more importantly an informational blueprint. Thus, most of the value of isolated DNA lies in its genetic information as dictated by the sequence of nucleotides, and the sequence of nucleotides is unaltered by the process of isolation. In contrast, the informational content of a protein (i.e., its amino acid sequence) is subsidiary to the protein's three-dimensional structure, which is where most of the value of an isolated protein lies because this structure dictates the protein's function. Although a protein fragment has the same amino acid sequence as a portion of its naturally occurring counterpart, the three-dimensional structure of the naturally occurring protein is significantly changed when a portion of it is removed to create the fragment, just as the structure of a small-molecule compound would be significantly changed if a particular side chain were removed.

In essence, fragments of proteins or antibodies are comparable to the 5-methyl amazonic acid in Example B in the Guidance. This 5-methyl amazonic acid was determined to be patent eligible because it is structurally different from the naturally occurring amazonic acid in the addition of a methyl group, and this structural difference results in the functional difference of giving the compound hair-growth-stimulating activity.55 Analogously, fragments of proteins are structurally different (part of the naturally occurring protein is removed), and these structural differences result in functional differences. For example, in the case of antibody fragments, the structural changes can result in better stability and serum half-life, better tissue penetration, lower immunogenicity, expression advantages, and/or suitability for oral administration. Based on this reasoning, antibody fragments (and protein fragments in general) should generally be patent eligible. Whether the PTO agrees remains to be seen.

A lawsuit between St. Jude Children's Research Hospital and Amgen could provide some additional clarity on the patent eligibility of isolated proteins and antibodies.56 Among the patent claims being asserted by St. Jude are claims to isolated polypeptides and isolated antibodies.57

Organisms

The Guidance provides two examples demonstrating how the patent eligibility of a claimed isolated organism would be analyzed. These examples are based on Funk Brothers and Chakrabarty.

In Funk Brothers, the claimed invention was mixtures of naturally occurring, mutually non-inhibitive strains of bacteria that aid plants in fixing nitrogen.58 This ability of these bacteria was previously known. Each strain could be used only with certain plants, and previously attempted mixtures of strains were unsuccessful because the bacterial strains had mutually inhibitive effects.59 The discovery that led to the claimed invention was that certain bacterial strains did not exert mutually inhibitive effects. Despite this useful discovery, the majority held the combinations of mutually non-inhibitive strains to be ineligible subject matter. In contrast, the well-reasoned concurrence by Justice Frankfurter recognized that the mixtures had “the new property of multi-service applicability,” making them patent eligible, but were not patentable because the particular compatible strains discovered by the inventor were not adequately identified, and the claims encompassed all mixtures of mutually non-inhibitive strains in the Rhizobium genus.60 Portions of the majority opinion are consistent with the idea that claims to specifically defined mixtures of strains might have fared better. For example, the majority opinion was concerned with generally foreclosing others from using the naturally occurring, mutual non-inhibition properties of the bacteria when it emphasized how these properties are “manifestations of laws of nature, free to all men and reserved exclusively to none,” and that inventions from such discoveries “must come from application of the law of nature to a new and useful end.”61 Claims to specific combinations of bacteria—specific applications of the law of nature that do not substantially foreclose others from using the properties of mutual non-inhibition in other combinations of bacteria—would seem to address those concerns. Nevertheless, the majority opinion went further and held that the mixtures of bacteria were not patent eligible because they produced no new bacteria, and none of the bacteria acquired a different use.62 Because the mixtures were “no more than the discovery of some of the handiwork of nature,” they were not patent eligible.63

Example D from the Guidance mirrors the Myriad Court's holding in Funk Brothers, and it includes the following sample claim: “An inoculant for leguminous plants comprising a plurality of selected mutually non-inhibitive strains of different species of bacteria of the genus Rhizobium, said strains being unaffected by each other in respect to their ability to fix nitrogen in the leguminous plant for which they are specific.”64 The Guidance indicates that such a claim would not be patent eligible because the claimed bacteria are structurally identical to naturally occurring bacteria and are therefore not markedly different.65

By contrast, the claimed invention in Chakrabarty was a bacterium that was genetically engineered through the addition of plasmids so it would break down components of crude oil.66 Because the bacterium had properties created through human intervention that were not possessed by any naturally occurring bacteria, the Supreme Court held that the modified bacterium was patentable.67

Example A from the Guidance mirrors the Supreme Court's holding in Chakrabarty, and it includes the following sample claim: “A bacterium from the genus Pseudomonas containing therein at least two stable energy-generating plasmids, each of said plasmids providing a separate hydrocarbon degradative pathway.”68 The Guidance indicates that such a claim would be patent eligible, even if there are naturally occurring Pseudomonas bacteria containing a stable energy-generating plasmid capable of degrading a single type of hydrocarbon. As the Guidance explains, the claimed bacterium is markedly different because it is both structurally different (genetically modified) and functionally different (capable of degrading at least two hydrocarbons instead of one).69

Although the PTO had been allowing claims to isolated, naturally occurring microorganisms in patents that issued after Myriad but prior to the publication of the Guidance,70 the examples provided in the Guidance make it seem unlikely that this practice will continue. This interpretation aligns with the favorable discussion of both Chakrabarty and Funk Brothers in Myriad, making it likely to be upheld by the courts.

The Guidance provides no examples directed to the application of Myriad to multicellular animals, but this issue was later addressed in In re Roslin Institute (Edinburgh).71 A sample claim is claim 155 from U.S. Patent Application No. 09/225,233: “A live-borne clone of a pre-existing, non-embryonic, donor mammal, wherein the mammal is selected from cattle, sheep, pigs, and goats.”72

The appellant argued that such a clone is patent-eligible subject matter notwithstanding the holding in Myriad. To support this argument, the appellant points to numerous differences between the claimed clones and donor mammals. For example, the claimed clones are necessarily younger than the donor mammals based on the language of the representative claim.73 In addition, the claimed clones have several phenotypic differences such as different color patterns, different pigmentation of the iris, and behavioral differences.74 Contributing factors to these differences include differences in mitochondrial DNA from the oocyte, as well as environmental factors, such as uterine environment.75

However, the Federal Circuit held that, “as in Myriad, Roslin ‘did not create or alter any of the genetic information’ of its claimed clones, ‘[n]or did [Roslin] create or alter the genetic structure of [the] DNA’ used to make its clones.”76 The court dismissed the appellant's arguments about differences in mitochondrial DNA and phenotypic differences due to environmental factors because such differences were unclaimed,77 and because any phenotypic differences due to environmental factors came about “quite independently of any effort of the patentee.”78 The court did concede, however, that “having the same nuclear DNA as the donor mammal may not necessarily result in patent ineligibility in every case. Here, however, the claims do not describe clones that have markedly different characteristics from the donor animals of which they are copies.”78a

Antibiotics and Other Naturally Occurring Compounds

The Guidance provides one example demonstrating how the patent eligibility of a naturally occurring chemical compound other than nucleic acids or proteins would be analyzed. The following two sample claims are provided in that example: (1) “Purified amazonic acid” and (2) “Purified 5-methyl amazonic acid.”79 Amazonic acid is a cancer-fighting chemical purified from the leaves of a tree, and 5-methyl amazonic acid is a synthetically created derivative that is structurally different (addition of a methyl group) and functionally different (it can also be used to stimulate growth of hair).80 The Guidance indicates that claim 1 would not be patent eligible because there is no structural difference between the claimed purified acid and the acid as it exists in the leaves.81 In contrast, claim 2 would be patent eligible because 5-methyl amazonic acid is both structurally different and functionally different from naturally occurring amazonic acid.82

It is simple to understand how the PTO arrived at these conclusions, given the Guidance's emphasis on structural differences and corresponding lack of emphasis on functional differences. Unlike isolation of DNA, isolation of other naturally occurring chemical compounds, such as naturally occurring antibiotics, does not involve breaking chemical bonds. Thus, isolated chemical compounds have more structural similarity to their naturally occurring counterparts than isolated DNA does to native DNA. Likewise, although typically, no pharmacological benefit will be seen with a naturally occurring, small-molecule pharmaceutical until it has been isolated and purified from nature, the same can be said about the utility of DNA in most cases.

This misguided interpretation, however, goes against 100 years of precedent by ignoring important non-structural distinctions between isolated or purified compounds and their naturally occurring counterparts.83 Compounds that are isolated are purified from natural sources, such as the amazonic acid in Example B of the Guidance, have been patent eligible for so many years because such compounds do not naturally exist in isolated or purified form—a form in which they have new functions and utilities that are not possessed by their non-isolated or non-purified naturally occurring counterparts. For instance, in Example B, a patient has to eat 30 pounds of leaves per day for at least four weeks to receive the pharmacological benefit of amazonic acid.84 This is not possible as a practical matter, meaning that the naturally occurring version of amazonic acid does not have the pharmacological benefit of the claimed purified version. The Guidance inappropriately discounts this significant difference in functional utility, thereby overextending Myriad in ways that were not intended. Even the attorney who argued for the petitioners against the patent eligibility of isolated DNA in Myriad believes that this would be an improper application of the law, as evidenced by his testimony regarding a hypothetical virtually identical to that recited in Example B:

No, that may well be eligible because you have now taken what was in nature and you've transformed it in two ways. First of all, you've made it substantially more concentrated than it was in nature; and second, you've given it a function. If it doesn't work in the diluted form but does work in a concentrated form, you've given it a new function. And…by both changing its nature and by giving it a new function, you may well have patent.85

Unfortunately, the ultimate impact of Myriad on this commercially important area will not be resolved until the PTO's new position is challenged, and courts provide additional guidance.

Combinations of Natural Products

The Guidance provides three examples demonstrating how the patent eligibility of composition claims directed to combinations of natural products would be analyzed. The first is within Example C, which explains that gunpowder falls within the natural product judicial exception to patent eligibility because it is a mixture of naturally occurring saltpeter, sulfur, and charcoal, and these components are not markedly different from how they exist in nature.86 The second, Example D, is based on Funk Brothers and is discussed above.87

The third, Example E, is based on a pair of DNA primers, with the following representative claim: “A pair of primers, the first primer having the sequence of SEQ ID NO: 1 and the second primer having the sequence of SEQ ID NO: 2.”88 The Guidance indicates that such a claim would not be patent eligible because neither of the primers recited in the claim is markedly different from the corresponding naturally occurring DNA.89 The Guidance explains that the structural differences (broken bonds) caused by isolation are not significant enough to make the primers markedly different, and the primers have the same function as naturally occurring DNA (i.e., to hybridize to complementary sequences).90

The Guidance overextends Myriad in this example by taking too narrow a view of the function of primers, as demonstrated by some of the arguments in Myriad's litigation with Ambry Genetics.91 A representative claim is claim 29 from U.S. Patent No. 5,837,492:

A pair of single-stranded DNA primers of at least 15 nucleotides in length for determination of the nucleotide sequence of a BRCA2 gene by a polymerase chain reaction, the sequence of said primers being isolated from human chromosome 13, wherein the use of said primers in a polymerase chain reaction results in the synthesis of DNA comprising all or at least 15 contiguous nucleotides of the BRCA2 gene.92

Myriad's primary argument is that a pair of primers that is functionally coordinated to synthesize a particular DNA molecule is patent eligible because such a functionally matched pair does not exist in nature.93 Unlike the claims in Myriad, which did not “rely in any way on the chemical changes that result from the isolation of a particular section of DNA,”94 the claimed primers at issue here “have utilities, explicitly recited in the claims, that are not present in naturally occurring DNA.”95 In other words, the claims do in fact rely on the chemical changes that result from the isolation of the two sections of DNA that make up the primers. For example, in the representative claim above, only the functionally matched, isolated primers—not naturally occurring DNA—would be capable of being used “in a polymerase chain reaction [resulting] in the synthesis of DNA comprising all or at least 15 contiguous nucleotides of the BRCA2 gene.”96

However, like the Guidance, Ambry is arguing that the sequence information in DNA is the key,97 and “[t]he primer claims contain subject matter that comprise DNA segments with [nucleotide sequences that are] identical to natural DNA,” making them patent ineligible under Myriad.98 An argument could also be made that functionally matched DNA primers are analogous to the subject matter found to be unpatentable in Funk Brothers. In Funk Brothers, which was cited favorably by the Court in Myriad, the unpatentable invention consisted of groups of nitrogen-fixing bacteria that were functionally matched so that they did not exert the typical mutually inhibitive effects on each other.99 Here, the invention consists of a pair of naturally occurring DNA sequences that are functionally matched to amplify a particular DNA sequence, so there are some parallels with Funk Brothers. How a court would ultimately rule on this issue remains to be seen, but an order denying Myriad's motion for a preliminary injunction in Myriad's litigation against Ambry Genetics appears to align with the viewpoint of Ambry Genetics.100

Manufactures Comprising Natural Products

The Guidance provides one example demonstrating how the patent eligibility of a manufacture claim reciting natural products would be analyzed. The claim in Example C is as follows:

A fountain-style firework comprising: (a) a sparking composition, (b) calcium chloride, (c) gunpowder, (d) a cardboard body having a first compartment containing the sparking composition and the calcium chloride and a second compartment containing the gunpowder, and (e) a plastic ignition fuse having one end extending into the second compartment and the other end extending out of the cardboard body.101

In this example, the calcium chloride and gunpowder are assumed to be natural products. Although the Guidance indicates that the calcium chloride and gunpowder recited in the claim are not markedly different from what exists in nature, such a claim would be patent eligible because of the additional claimed elements. These elements narrow the scope of the claim so that others are not foreclosed from using the calcium chloride and gunpowder in other ways, relate to the calcium chloride and gunpowder in a significant way because they are physically integrated, and do more than describe the calcium chloride and gunpowder with general instructions to use them because the claim effectively provides instructions about one specific application.102

In effect, this type of analysis requires focusing on the claim elements that are not naturally occurring instead of considering the claim as a whole. Examples published in PharmaPatents demonstrate why this type of analysis, which extends well beyond the holding in Myriad, could be troublesome.103 A common type of claim to a pharmaceutical drug is one such as the following: “A pharmaceutical composition comprising Drug X in a pharmaceutically acceptable carrier.”104 Similarly, a common type of claim to a vaccine is one such as the following: “A pharmaceutical composition, comprising: (i) [Peptide Y] having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and (ii) a pharmaceutically acceptable carrier.”105 The patent eligibility of such claims has never been questioned in the past. However, the Guidance would now come into play if Drug X or Peptide Y is a naturally occurring compound isolated from a natural source. In that case, patent eligibility would first turn on how broadly “pharmaceutically acceptable carrier” is defined.

If “pharmaceutically acceptable carrier” encompasses natural products, then the claims would not be eligible under the Guidance, even though the products defined by each claim as a whole are not naturally occurring. This is demonstrated by a comparable example claim from the PTO training slides: “A beverage composition comprising: a) pomelo juice; and b) a preservative.”106 In this example, “preservative” includes naturally occurring preservatives, such as vitamin E.107 Because both the pomelo juice and the preservative are naturally occurring in some embodiments, and neither component is structurally changed by combining them, the combination is not patent-eligible subject matter.108

Even if “pharmaceutically acceptable carrier” encompasses only non-naturally occurring products, the claimed manufacture will not automatically be considered patent-eligible subject matter. In that situation, patent eligibility would turn on factors such as whether the pharmaceutically acceptable carrier imposes meaningful limits on claim scope so that others are not substantially foreclosed from using Drug X/PeptideY, is considered to be more than “nominally, insignificantly, or tangentially related” to Drug X/Peptide Y, or adds a feature that is “more than well-understood, purely conventional or routine” in that field.109 The implication is that patent eligibility could depend on both the state of the art (e.g., whether the pharmaceutically acceptable carrier is well-understood, routine, or conventional) and on potential alternative uses of Drug X/Peptide Y (e.g., whether the only known use of Drug X is for pharmaceutical purposes).110

It is easy to see how harmful this could be in a field such as antibiotic development, where resistance to antibiotics is increasing and development of new antibiotics, many of which are isolated naturally occurring compounds, is decreasing.111 At a time when companies need more incentives to pursue antibiotic development, weakening patent protection by creating uncertainty not only about claims directed to isolated antibiotics but also about claims directed to pharmaceutical compositions comprising antibiotics could have a devastating effect.

A recent case at the U.S. Court of Appeals for the Federal Circuit, Consumer Watchdog v. Wisconsin Alumni Research Foundation,112 could have provided some additional guidance for manufacture claims comprising natural products. The issue in Consumer Watchdog that would have been addressed is whether the in vitro embryonic stem cell cultures claimed in U.S. Patent No. 7,029,913 are patent eligible. The broadest claim is claim 1:

A replicating in vitro cell culture of human embryonic stem cells comprising cells which (i) are capable of proliferation in in vitro culture for over one year without the application of exogenous leukemia inhibitory factor, (ii) maintain a karyotype in which the chromosomes are euploid through prolonged culture, (iii) maintain the potential to differentiate to derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and (iv) are inhibited from differentiation when cultured on a fibroblast feeder layer.113

The appellants were arguing that the claimed stem cell cultures are not patent eligible in light of Myriad because of certain parallels between isolated DNA and in vitro stem cell cultures. For example, the appellants argued that the claim limitation that the stem cell culture be in vitro is analogous to the claim limitation in Myriad that the DNA be isolated.114 Similarly, they argued that the properties inherent in the claimed stem cells were not created or altered, just as the genetic information encoded in the DNA was not created or altered in Myriad.115 The other limitations in claim 1, they argued, are “merely…properties that are inherent in all [embryonic stem] cells, including those that exist naturally.”116

The appellees were instead arguing that a replicating culture of embryonic stem cells is a distinct population of cells with unique properties different from those of embryonic stem cells found in an embryo.117 Moreover, they argued that the claims are directed not only to cells, but also to cell cultures, which are cells grown in a culture medium containing nutrients and other processed ingredients necessary to keep the cells viable outside the body.118 These issues were never addressed, however, because the Federal Circuit held that Consumer Watchdog lacked standing to appeal.118a Because the appeal was dismissed, we will likely have to wait for another case to arise before we will get further clarity on the patent eligibility of manufactures comprising natural products.