If At First You Don’t Succeed, (Don’t) Try, Try Again?: Myriad Genetics Lost More Claims To 35 U.S.C. §101.

Cindy Chen | January 29, 2015

In re BRCA1- and BRCA2-Based Hereditary Cancer Test Patent Litigation, also known as University of Utah Research v. Ambry Genetics Corp.

December 17, 2014

Panel: Prost, Clevenger, and Dyk. Opinion by Prost.

Summary

A year after Association For Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107 (2013), in which Myriad saw its isolated DNA claims being invalidated by the Supreme Court for patent ineligibility, Myriad found itself once again trying to defend the patent eligibility of its patent claims. This time, the claims were directed to isolated single-stranded polynucleotides and the use of those polynucleotides to detect the presence of genetic mutations. Different claims, but the outcome was the same as the Federal Circuit, following the Supreme Court and its own precedents, invalidated Myriad’s claims as being directed to patent ineligible subject matter under  35 U.S.C. §101.

Details

BRCA1 and BRCA2 genes are human breast and ovarian cancer predisposing genes. Mutations in those genes, whether hereditary or environmentally induced, could dramatically increase a carrier’s susceptibility to cancers. Myriad Genetics, Inc. (“Myriad”) owns U.S. Patent Nos. 5,753,441 (the “441 patent”); 5,747,282 (the “282 patent”); and 5,837,492 (the “492 patent”), all of which relate to materials and methods for isolating the BRCA genes for use in screening for mutations.

Myriad sought preliminary injunction against Ambry Genetics Corporation (“Ambry”) to enjoin Ambry’s sale of testing kits for susceptibility to certain cancers. Myriad alleged that Ambry’s kits infringed various claims of the asserted patents. The district court denied Myriad’s request for preliminary injunction. To be entitled to preliminary injunction, Myriad needed to show that it was likely to prevail on the issues of patent validity and infringement. Unfortunately, the odds were not on Myriad’s side, because the district court found instead that Myriad’s asserted claims were directed to patent ineligible subject matter under 35 U.S.C. §101. Myriad appealed.

Two sets of specific claims were at issue. The first set included the composition of matter claims, or “primer” claims, which relate to isolated polynucleotide sequences (i.e., DNA primers) that are complementary to certain portions of the BRCA genes. The second set of claims related to methods of screening BRCA genes for mutations using the specific polynucleotide sequences.

(1)        The primer claims

The Federal Circuit began its discussion with the primer claims, a representative of which is claim 16 of the 282 patent:

16.  A pair of single-stranded DNA primers for determination of a nuycleotide [sic] sequence of a BRCA1 gene by a polymerase chin [sic] reaction, the sequence of said primers being derived from human chromosomne [sic] 17q, wherein the use of said primers in a polymerase chain reaction results in the synthesis of DNA having all or part of the sequence of the BRCA1 gene.

Myriad’s arguments for the patent eligibility of the primer claims are threefold. One, the primers are synthetically replicated. Two, the single-stranded primers are not naturally occurring, as they cannot be found in human bodies. And three, the primers in isolated form are functionally distinct from those existing as a part of a DNA molecule.

The Federal Circuit rejected each of those arguments. On synthetic replication, the Federal Circuit followed the Supreme Court’s decision in Association for Molecular Pathology v. Myriad, 133 S. Ct. 2107 (2013):

As the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible.

(emphasis added). Id., at 2117.

The Federal Circuit found structural identity in this case. Two complementary strands of DNA bond to form a naturally occurring double-stranded DNA encoding the BRCA genes. In order for the primers to bind to the BRCA genes, the primers must therefore be “structurally identical” to the nucleotide sequence on one or the other of the two strands making up the native double-stranded DNA.

The Federal Circuit was likewise unconcerned that Myriad’s single-stranded DNA primers are not found in human bodies, because Myriad’s isolation of those primers merely involves the uninventive act of “separating [DNA] from its surrounding genetic material”. Myriad, 133 S. Ct. at 2117.

Moreover, citing In re Roslin Institute (Edinburgh), 750 F.3d 1333 (Fed. Cir. 2014), the Federal Circuit found that, much like Dolly the sheep in Roslin, Myriad’s primers possess no “markedly different characteristics” from what is found in nature, and are in fact “an exact genetic replica” of the naturally occurring BRCA genes.

This brings us to Myriad’s third argument based on functional distinctness. Myriad argued that when isolated, its DNA primers are fragments that “serve as a starting material for a DNA polymerization process”. This, according to Myriad, is a “fundamentally different function” than when those sequences are a part of a native double-stranded DNA to “store[] biological information used in the development and functioning of all known living organisms.”

The Federal Circuit disagreed:

One of the primary functions of DNA’s structure in nature is that complementary nucleotide sequences bind to each other. It is this function that is exploited here—the primer binds to its complementary nucleotide sequence. Thus, just as in nature, primers utilize the innate ability of DNA to bind to itself.

(emphasis added).

From a technical perspective, the Federal Circuit’s reasoning on this point was curious. That a strand of DNA binds to a complementary strand is the structure of DNA. This structural complementarity underlies the functions and utility of DNA. For example, complementarity imparts DNA strands with their utility in recombinant DNA technology. In the Federal Circuit’s own words, complementarity is an “innate ability of DNA”, which does more to imply that complementary binding is an inherent property, rather than a function, of DNA. Rarely has it been said that complementarity is itself a function of DNA.

Assuming that the Federal Circuit had confused the structure of DNA with its functions, then it would seem possible that Myriad would have prevailed on its “fundamentally different function” argument. The best support for this would probably come from Diamond v. Chakrabarty, 447 U.S. 303 (1980), in which the Supreme Court found that a claimed bacterium was patent eligible for having a different functional characteristic from its naturally occurring counterpart, i.e., it was able to degrade more different hydrocarbons this its counterpart in nature.

On December 16, 2014, the Patent Office published its “2014 Interim Guidance on Patent Subject Matter Eligibility”. The guidance provides that a nature-based product could be patent eligible if it exhibits “markedly different characteristics from its naturally occurring counterpart in its natural state.” Furthermore, “[m]arkedly different characteristics can be expressed as the product’s structure, function, and/or other properties” (emphasis added), including as “biological or pharmacological functions or activities”. Based on this guidance, the fact that human bodies do not use DNA primers (but rather, RNA primers) in DNA replication would seem to impart patent eligibility to Myriad’s claimed DNA primer.

(2)        The method claims

Next came the method claims. Claim 8 of the 441 patent is representative:

8.   A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequences of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject[,]

wherein a germline nucleic acid sequence is compared by amplifying all or part of a BRCA1 gene from said sample using a set of primers to produce amplified nucleic acid and sequencing the amplified nucleic acids.

(emphasis added).

In determining that Myriad’s method claims were patent ineligible, the Federal Circuit did not find it necessary to consider the Supreme Court’s decision in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 132 S. Ct. 1289 (2012). In Mayo, the Supreme Court held that, without “significantly more”, “a bare recitation of the natural law” (e.g., a difference between a normal BRCA1 gene and a test sequence being indicative of mutations) is not patent eligible.

Instead, the Federal Circuit directly applied Alice Corp. v. CLS Bank Int’l, 134 S. Ct. 2347 (2014):

We need not decide if Mayo is directly on point here because the method claims before us suffer from a separate infirmity: they recite abstract ideas.

(emphasis added).

The Federal Circuit reiterated Alice’s two-step test for patent eligibility:

First, “we determine whether the claims at issue are directed to [a] patent-ineligible concept[]. If so, we then ask, ‘what else is there in the claims before us?’” That is, we next ask whether the remaining elements . . . are sufficient to “‘transform the nature of the claim’ into a patent-eligible application.”

Then, the Federal Circuit separated Myriad’s method claims into two parts, each corresponding to one of the steps in Alice:

[T]he comparison of wild-type genetic sequences with the subject’s genetic sequence [] correspond[s] to the first step of Alice, and . . . the techniques to be used in making the comparison [] correspond[s] to the second step of Alice.

The comparison of two gene sequences to determine the existence of mutations was an abstract mental process, while the mechanism for making the comparison (i.e., the amplifying and sequencing of the genetic sequences in the above claim 8) was a “well-understood, routine and conventional activity engaged in by scientists”. Thus, Myriad’s method claims as a whole were patent ineligible.

However, all is not lost. The Federal Circuit did provide some instructions on how Myriad’s method claims could be drafted so as to be patent eligible. The key would be to avoid preemption, as the Federal Circuit’s determination that Myriad’s method claims were patent ineligible was motivated in part by the sheer breadth of those claims:

The covered comparisons are not restricted by the purpose of the comparison or the alteration being detected. Because of its breadth, the comparison step covers detection of yet-undiscovered alterations, as well as comparisons for purposes other than detection of cancer.

Takeaway

It should be noted that the Myriad claims being invalidated were very broad. Their invalidation therefore does not necessarily endanger all claims directed to diagnostic methods and materials. Rather, as many have said before, a claim directed to a nature-based product or a diagnostic method could very well survive scrutiny for patent eligibility if drafted creatively to highlight structural or functional differences over what is found in nature, or more specifically.

Perhaps Myriad would have fared better if its claims specify the homology of the primers to the natural or mutated BRCA genes, or define that the purpose or utility of the claimed methods is to determine the subject’s predisposition to breast and ovarian cancers.

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