Now that the Supreme Court has issued its decision in the “ACLU/Myriad” gene patents case (Association For Molecular Pathology v. Myriad Genetics, Inc.), people are wondering what the decision means for the Myriad patents and BRCA1/BRCA2 genetic testing. If you missed it, this article provides an overview of the Supreme Court Myriad decision. Here, I review the claims of the seven patents that were at issue, and highlight how they may or may not be affected by the Supreme Court decision. My comments are provided for discussion purposes only, and do not constitute any legal determinations of validity, invalidity, or freedom to operate.

The Myriad Patents

In a statement released on June 13, 2013, Myriad said that it “has more than 500 valid and enforceable claims in 24 different patents conferring strong patent protection for its BRACAnalysis® test.” I am confining my review to the seven patents that were involved in the litigation, and make no comment regarding which claims may or may not cover Myriad’s test.

The following seven patents were at issue:

• U.S. Patent No. 5,747,282
• U.S. Patent No. 5,837,492
• U.S. Patent No. 5,693,473
• U.S. Patent No. 5,709,999
• U.S. Patent No. 5,710,001
• U.S. Patent No. 5,753,441
• U.S. Patent No. 6,033,857

Only a few claims of each patent were challenged, but the Supreme Court decision may impact the validity of claims that were not directly at issue. On the other hand, at least some of the patents include at least some claims that may have survived intact.

U.S. Patent No. 5,747,282

Challenged claims: 1, 2, 5, 6, 7, and 20.

The Supreme Court discussed claims 1, 2, 5 and 6 of the ’282 patent as representative of the Myriad claims at issue.

1. An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2.

This claim encompasses isolated naturally occurring DNA, and so is invalid in view of the Supreme Court decision.

2. The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1.

This claim recites an isolated full-length cDNA sequence, and so is not invalid in view of the Supreme Court decision.

5. An isolated DNA having at least 15 nucleotides of the DNA of claim 1.

This claim encompasses isolated naturally occurring DNA, and so is invalid in view of the Supreme Court decision.

6. An isolated DNA having at least 15 nucleotides of the DNA of claim 2.

This claim likely encompasses isolated fragments of naturally occurring DNA, and so is likely invalid in view of the Supreme Court decision, and its discussion of short strands of cDNA that “may be indistinguishable from natural DNA.”

7. An isolated DNA selected from the group consisting of:
(a) a DNA having the nucleotide sequence set forth in SEQ ID NO:1 having T at nucleotide position 4056;
(b) a DNA having the nucleotide sequence set forth in SEQ ID NO:1 having an extra C at nucleotide position 5385;
(c) a DNA having the nucleotide sequence set forth in SEQ ID NO: 1 having G at nucleotide position 5443; and,
(d) a DNA having the nucleotide sequence set forth in SEQ ID NO:1 having 11 base pairs at nucleotide positions 189-199 deleted.

This claim recite specific variants of the full-length cDNA sequence, and so is not invalid in view of the Supreme Court decision.

20. A method for screening potential cancer therapeutics which comprises: growing a transformed eukaryotic host cell containing an altered BRCA1 gene causing cancer in the presence of a compound suspected of being a cancer therapeutic, growing said transformed eukaryotic host cell in the absence of said compound, determining the rate of growth of said host cell in the presence of said compound and the rate of growth of said host cell in the absence of said compound and comparing the growth rate of said host cells, wherein a slower rate of growth of said host cell in the presence of said compound is indicative of a cancer therapeutic.

The Federal Circuit upheld the validity of claim 20, and this claim was not at issue before the Supreme Court; thus, this claim is not invalid.

Other claims:

3. The isolated DNA of claim 1 which contains BRCA1 regulatory sequences.

Likely invalid.

4. The isolated DNA of claim 2 which contains BRCA1 regulatory sequences.

Likely not invalid.

8. A replicative cloning vector which comprises the isolated DNA of claim 1 or parts thereof and a replicon operative in a host cell.

Likely not invalid, assuming the replicative cloning vector necessarily is something “created by man.”

9. A replicative cloning vector which comprises the isolated DNA of claim 2 or parts thereof and a replicon operative in a host cell.

Likely not invalid.

10. An expression system which comprises the isolated DNA of claim 1 or parts thereof operably linked to suitable control sequences.

Likely not invalid, assuming the expression system necessarily is something “created by man.” But, is a naturally occurring human cell an expression system?

11. An expression system which comprises the isolated DNA of claim 2 or parts thereof operably linked to suitable control sequences.

Likely not invalid.

12. Host cells transformed with the expression system of claim 10.

Likely not invalid, assuming the “transformed with” implies human intervention.

13. Host cells transformed with the expression system of claim 11.

Likely not invalid.

14. A method of producing BRCA1 polypeptide which comprises culturing the cells of claim 12 under conditions effective for the production of saod [sic] BRCA1 polypeptide and harvesting the BRCA1 polypeptide.

Likely not invalid.

15. A method of producing BRCA1 polypeptide which comprises culturing the cells of claim 13 under conditions effective for the producton [sic] of said BRCA1 polypeptide and harvesting the BRCA1 polypeptide.

Likely not invalid.

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.

????? Does the “pair” of primers distinguish this claim from claims to a single fragment? Can this claim be distinguished from the Funk Brothers case?

17. The pair of primers of claim 16 wherin [sic] said BRCA1 gene has the nucleotide sequence set forth in SEQ ID NO:1.

????? (see above)

18. A kit for detecting mutations in the BRCA1 gene resulting in a susceptibility to breast and ovariann [sic] cancers comprising at least one oligonucleotide prime [sic] specific for a BRCA1 gene mutation and instructions relatiing [sic] to detectiong [sic] mutations in the BRCA1 gene.

Likely not invalid, at least not for any reasons specific addressed by the Supreme Court.

19. A kit for detecting mutations in the BRCA1 gene resulting in a sisceptibility [sic] to breast and ovarian cancers comprising at least one allele-specific oligimucleotide [sic] probe for a BRCA1 gene mutation and instructions relating to detecting mutations in the BRCA1 gene.

Likely not invalid, at least not for any reasons specific addressed by the Supreme Court.

U.S. Patent No. 5,837,492

This patent is similar to the ’282 patent, but related to BRCA2 instead of BRCA1.

Challenged claims: 1, 6, and 7.

1. An isolated DNA molecule coding for a BRCA2 polypeptide, said DNA molecule comprising a nucleic acid sequence encoding the amino acid sequence set forth in SEQ ID NO:2.

This claim encompasses isolated naturally occurring DNA, and so is invalid in view of the Supreme Court decision.

6. An isolated DNA molecule coding for a mutated form of the BRCA2 polypeptide set forth in SEQ ID NO:2, wherein said mutated form of the BRCA2 polypeptide is associated with susceptibility to cancer.

This claim encompasses isolated naturally occurring DNA, and so is invalid in view of the Supreme Court decision.

7. The isolated DNA molecule of claim 6, wherein the DNA molecule comprises a mutated nucleotide sequence set forth in SEQ ID NO:1.

This claim recites an isolated full-length cDNA sequence, and so is not invalid in view of the Supreme Court decision.

Other claims:

The other claims of the ’492 patent are similar to the claims of the ’282 patent, and include claims to “isolated DNA molecule[s],” “replicative cloning vector[s],” “expression vector[s],” “isolated [transformed] host cell[s],” “methods of producing recombinant BRCA2 polypeptide[s],” and “pair[s] of single-stranded DNA primers of at least 15 nucleotides in length.” To the extent a claim reads on isolated naturally occurring DNA (or fragment of naturally occurring DNA), it is invalid in view of the Supreme Court decision. To the extent a claim only reads on a full-length cDNA sequence, or other man-made sequence or construct, it is not invalid in view of the Supreme Court decision.

U.S.Patent No. 5,693,473;

Challenged claim: Claim 1

1. An isolated DNA comprising an altered BRCA1 DNA having at least one of the alterations set forth in Tables 12A, 14, 18 or 19 with the proviso that the alteration is not a deletion of four nucleotides corresponding to base numbers 4184-4187 in SEQ. ID. NO:1.

This claim appears to encompass isolated naturally occurring DNA, and so is likely invalid in view of the Supreme Court decision.

Other claims:

The other claims of the ’473 patent recite “isolated DNA comprising an altered BRCA1 DNA,” or “[a] nucleic acid probe specifically hybridizable to a human altered BRCA1 DNA and not to wild-type BRCA1 DNA.” These claims appear to read on isolated naturally occurring DNA (or fragments of naturally occurring DNA), are so are likely invalid in view of the Supreme Court decision.

U.S.Patent No. 5,709,999; U.S.Patent No. 5,753,441;
U.S.Patent No. 5,710,001; U.S. Patent No. 6,033,857

Challenged claims: Claim 1 of each of these patent was challenged, as was claim 2 of the ’857 patent.

Claim 1 of the ’999 patent is representative:

1. A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1.

The Federal Circuit first held these claims invalid “on the ground that they claim only abstract mental processes,” and then “reaffirm[ed] that prior holding,” in view of Mayo v. Prometheus, where the Supreme Court held that “such diagnostic methods in that case essentially claim natural laws that are not eligible for patent.”

Other claims:

These patents include a number of dependent claims that recite specific embodiments of the “detecting” methods. For example, claim 2 of the ’857 patent recites:

4. The method of claim 2 wherein the detection in the alteration in the germline sequence is determined by an assay selected from the group consisting of (a) observing shifts in electrophoretic mobility of single-stranded DNA on non-denaturing polyacrylamide gels, (b) hybridizing a BRCA2 gene probe to genomic DNA isolated from said tissue sample, (c) hybridizing an allele-specific probe to genomic DNA of the tissue sample, (d) amplifying all or part of the BRCA2 gene from said tissue sample to produce an amplified sequence and sequencing the amplified sequence, (e) amplifying all or part of the BRCA2 gene from said tissue sample using primers for a specific BRCA2 mutant allele, (f) molecularly cloning all or part of the BRCA2 gene from said tissue sample to produce a cloned sequence and sequencing the cloned sequence, (g) identifying a mismatch between (1) a BRCA2 gene or a BRCA2 mRNA isolated from said tissue sample, and (2) a nucleic acid probe complementary to the human wild-type BRCA2 gene sequence, when molecules (1) and (2) are hybridized to each other to form a duplex, (h) amplification of BRCA2 gene sequences in said tissue sample and hybridization of the amplified sequences to nucleic acid probes which comprise wild-type BRCA2 gene sequences, (i) amplification of BRCA2 gene sequences in said tissue sample and hybridization of the amplified sequences to nucleic acid probes which comprise mutant BRCA2 gene sequences, (j) screening for a deletion mutation in said tissue sample, (k) screening for a point mutation in said tissue sample, (l) screening for an insertion mutation in said tissue sample, (m) in situ hybridization of the BRCA2 gene of said tissue sample with nucleic acid probes which comprise the BRCA2 gene.

It seems likely that at least some of these dependent claims would not be held invalid as claiming “only abstract mental processes,” but do they recite “significantly more than the natural phenomenon itself,” e.g., are the additional steps more than “well-understood, routine, conventional activity,” as may be required to survive scrutiny under Mayo v. Prometheus?

It will be interesting to see whether any competitors start offering BRCA1/BRCA2 genetic testing, and, if so, if Myriad asserts any of its other claims against them.

USPTO Memo to Examiners

By the end of the day on June 13, 2013, the USPTO had issued a memo to the Examining Corps, advising examiners of the Supreme Court decision. As noted in the memo:

Myriad significantly changes the Office’s examination policy regarding nucleic acid-related technology.

The memo provides this ”preliminary guidance”:

As of today, naturally occurring nucleic acids are not patent eligible merely because they have been isolated. Examiners should now reject product claims drawn solely to naturally occurring nucleic acids or fragments thereof, whether isolated or not, as being ineligible subject matter under 35 U.S.C. § 101. Claims clearly limited to non-naturally-occurring nucleic acids, such as a cDNA or a nucleic acid in which the order of the naturally occurring nucleotides has been altered (e.g., a man-made variant sequence), remain eligible. Other claims, including method claims, that involve naturally occurring nucleic acids may give rise to eligibility issues and should be examined under the existing guidance in MPEP 2106, Patent Subject Matter Eligibility.

I am pleased to be moderating a Foley & Lardner LLP Patent Nation Web Conference on the Myriad decision on Wednesday, June 26, 2013, at 12:00 noon eastern. Our panelists, the Honorable Paul R. Michel (ret.), United States Court of Appeals for the Federal Circuit, Hans Sauer, Ph.D., Associate General Counsel for Intellectual Property, Biotechnology Industry Organization, and Kevin Noonan, Ph.D., Partner, McDonnell Boehnen Hulbert & Berghoff LLP, and co-founder, Patent Docs, will discuss the intricacies and likely impact of the Myriad decision and discuss what it means for the life sciences industry and the evolving area of patent-eligibility jurisprudence as a whole. The program is free but requires preregistration.