Myriad Sues GeneDx on BRCA and Other Genetic Diagnostic Patents

MyriadAfter a brief hiatus that saw Counsyl and Quest Diagnostics file declaratory judgment actions in alternate venues, Myriad has filed yet another lawsuit against a genetic diagnostics company that brought its own BRCA gene testing to market after the Supreme Court's decision in AMP v. Myriad Genetics.  Last Wednesday, Myriad filed suit against this company, GeneDx of Gaithersburg, in the District of Utah, Central Divisions (Case No. 2:13-CV-00954-TS; complaint).  The complaint is similar to Myriad's complaints against Ambry Genetics and Gene-by-Gene, but this time Myriad has added infringement allegations relating to its mutY homolog (MUTYH) test for hereditary colon cancer.  Once again, Myriad is joined by the University of Utah Research Foundation, the Trustees of the University of Pennsylvania, HSC Research and Development Limited Partnership, and Endorecherche Inc.

This Complaint alleges that:

With knowledge of Plaintiffs' patents, Defendant began offering its BRCA1 and BRCA2 analysis as part of its cancer-testing menu on or about August 26, 2013.  On information and belief, Defendant offers stand-alone tests comprising full gene sequencing and deletion/duplication analyses for the BRCA 1 and BRCA 2 genes.  On information and belief, Defendant also offers full gene sequencing and deletion/duplication analyses for the BRCA 1, BRCA 2, and MUTYH genes as part of multiple hereditary cancer panels that test cancer susceptibility using next-generation and Sanger sequencing technology.

GeneDxMyriad alleges infringement by GeneDx's "making, manufacturing, promoting, marketing, advertising, distributing, offering for sale and selling and/or causing to be offered or sold certain BRCA1 and BRCA2 Sequencing, BRCA1 and BRCA2 Deletion/Duplication Analysis, BRCA1 and BRCA2 Sequencing and Deletion/Duplication Analysis, BRCA1 and BRCA2 Ashkenazi Founder Mutation Panel, Comprehensive Cancer Panel, Breast/Ovarian Cancer Panel, Pancreatic Cancer Panel, Endometrial Cancer Panel, and Breast Cancer High Risk Panel products."  The specific claims Myriad alleges are infringed include the following:  claim 6 of U.S. Patent No. 5,709,999; claims 6, 16 and 17 of  U.S. Patent No. 5,747,282; claims 7, 8, 12, 23, and 26 of U.S. Patent No. 5,753,441; claims 29 and 30 of U.S. Patent No. 5,837,492; claim 4 of U.S. Patent No. 6,033,857; claims 2, 3 and 4 of U.S. Patent No. 5,654,155; claims 2, 3, 4, 5, 6, and 7 of U.S. Patent No. 5,750,400; claims 32 and 33 of U.S. Patent No. 6,051,379; claim 5 of U.S. Patent No. 6,951,721; claims 3, 4, 5, 6, 7, 8, 11, 14, 17, 18, 19 of U.S. Patent No. 7,250,497; claims 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18 of U.S. Patent No. 7,470,510; claims 10, 11, 15, 16, 17 and 19 of U.S. Patent No. 7,622,258; claims 2, 8 and 16 of U.S. Patent No. 7,838,237; claims 2, 3, 5, 9, 10 and 12 of U.S. Patent No. 7,670,776; claims 2 and 7 of U.S. Patent No. 7,563,571; and claim 73 of U.S. Patent No. 6,083,698.

The allegations regarding the '510, '259, '237, '776, '571, and '698 patents relate to GeneDx's colon cancer tests, and the claims at issue are as follows:

The asserted '510 patent claims:

5. A method for determining whether a human subject harbors a mutation in an hMYH gene of the human subject that decreases an activity of the encoded hMYH protein, said method comprising: providing an hMYH-encoding nucleotide sequence of the human subject; and determining the presence or absence of a difference in a coding region in said hMYH-encoding nucleotide sequence, relative to SEQ ID NO:1, which results in decreased binding of the encoded hMYH protein to a substrate containing an A/GO mispair, or decreased glycosylase activity of the encoded hMYH protein on the mispaired adenosine in an A/GO mispair in a substrate containing an A/GO mispair, wherein said hMYH-encoding nucleotide sequence is a complementary DNA sequence, and wherein the step of providing the hMYH-encoding nucleotide sequence comprises: obtaining a sample from said patient; isolating an hMYH-encoding nucleic acid from said sample; and determining the nucleotide sequence of said hMYH-encoding nucleic acid.

6. The method of claim 5, wherein said step of determining the nucleotide sequence of said hMYH-encoding nucleic acid is by DNA sequencing.

7. The method of claim 5, further comprising amplifying a portion of said hMYH-encoding nucleic acid and determining the nucleotide sequence of the amplified nucleic acid.

8. The method of claim 5 wherein said sample is a blood sample, a urine sample, a saliva sample, a tissue biopsy sample, or an autopsy material sample.

9. The method of claim 8 wherein said sample is a blood sample.

10. A method for determining whether a human subject harbors a mutation in an hMYH gene of the human subject that decreases an activity of the encoded hMYH protein, said method comprising: isolating an hMYH-encoding nucleic acid from a sample obtained from the human subject; and determining the presence or absence of a mutation in a coding region in said hMYH-encoding nucleic acid, relative to SEQ ID NO:1, which results in decreased binding of the encoded hMYH protein to a substrate containing an A/GO mispair, or decreased glycosylase activity of the encoded hMYH protein on the mispaired adenosine in an A/GO mispair in a substrate containing an A/GO mispair.

11. The method of claim 10 wherein said mutation is a substitution, a deletion, or an insertion.

12. The method of claim 10 wherein said mutation results in a frame shift in, or a truncation of, the coding region.

13. The method of claim 10 wherein said hMYH-encoding nucleic acid is a complementary DNA.

14. The method of claim 10 wherein said hMYH-encoding nucleic acid is a genomic DNA.

15. The method of claim 10 wherein the step of determining the presence or absence of a mutation comprises amplifying said coding region in said hMYH-encoding nucleic acid.

16. The method of claim 15 wherein the step of determining the presence or absence of a mutation comprises detecting a change in the length of the amplified coding region.

17. The method of claim 15 wherein the step of determining the presence or absence of a mutation comprises nucleic acid hybridization.

18. The method of claim 10 further comprising deducing the amino acid sequence encoded by the isolated hMYH-encoding nucleic acid; and identifying a difference in the deduced amino acid sequence, relative to SEQ ID NO:2.

(where the italicized portion of claim 5 recites limitations from earlier claims incorporated therein by dependency).

The asserted '258 patent claims:

10. A method for predicting in an individual the likelihood of developing colorectal cancer, comprising: determining from a sample obtained from the individual whether the individual has a nucleotide variant in an MYH gene of the individual that results in the amino acid variant G382D, wherein the presence of said nucleotide variant is indicative of an increased likelihood of developing colorectal cancer, wherein if the individual has said nucleotide variant, determining whether the individual is homozygous for said nucleotide variant, wherein said determining step comprises amplifying, from said sample obtained from the individual, the MYH gene, or a portion thereof.

11. The method according to claim 10, further comprising sequencing the amplified MYH gene, or a portion thereof, of the individual.

15. A method of genotyping, comprising: identifying an individual with colorectal adenomas or cancer, having at least one family member diagnosed with colorectal cancer, or with an increased risk for colorectal cancer; and determining subsequently, from a sample obtained from said identified individual, whether said identified individual has a nucleotide variant in an MYH gene of the individual that results in the amino acid variant G382D, wherein said determining step comprises hybridizing the MYH gene, or a portion thereof, obtained from said sample, with an oligonucleotide.

16. The method according to claim 14, wherein said determining step comprises amplifying, from said sample, the MYH gene, or a portion thereof.

17. The method according to claim 16, further comprising sequencing the amplified MYH gene, or a portion thereof, of the individual.

19. A method for predicting in an individual the likelihood of developing colorectal cancer, comprising: determining from a sample obtained from the individual whether the individual has a nucleotide variant in an MYH gene of the individual that results in the amino acid variant G382D, wherein the presence of said nucleotide variant is indicative of an increased likelihood of developing colorectal cancer, wherein if the individual has said nucleotide variant, determining whether the individual is homozygous for said nucleotide variant, wherein said determining step comprises hybridizing the MYH gene, or a portion thereof, obtained from a sample from the individual, with an oligonucleotide.

The asserted '237 patent claims:

2. A method for genotyping an individual comprising: determining the presence or absence of a genetic variant selected from the group consisting of 347-1 G to A corresponding to position 7084 of SEQ ID NO:1, 891+3 A to C corresponding to position 8092 of SEQ ID NO:2, 970 C to T corresponding to position 970 of SEQ ID NO:3 and 349 T to A corresponding to position 349 of SEQ ID NO:4 in the MYH gene of the individual, wherein said determining step comprises sequencing the MYH gene or a portion thereof.

8. A method for genotyping an individual comprising: determining whether the individual has a genetic variant at the position 347-1 G to A corresponding to position 7084 of SEQ ID NO:1, 891+3 A to C corresponding to position 8092 of SEQ ID NO:2, 970 C to T corresponding to position 970 of SEQ ID NO:3 or 349 T to A corresponding to position 349 of SEQ ID NO:4 in the MYH gene of the individual, wherein determining whether the individual has a genetic variant comprises amplifying the MYH gene of the individual, or a portion thereof, and determining if the MYH gene comprises the genetic variant.

16. A method for predicting in an individual the likelihood of developing cancer, comprising: determining whether the individual has a genetic variant at the position 347-1 corresponding to position 7084 of SEQ ID NO:1, 891+3 corresponding to position 8092 of SEQ ID NO:2, 970 corresponding to position 970 of SEQ ID NO:3 or 349 corresponding to position 349 of SEQ ID NO:4 in the MYH gene of the individual, or an amino acid variant of Q324X or W117R of a polypeptide encoded by the MYH gene of the individual, wherein the presence of said genetic variant or the amino acid variant is indicative of an increased likelihood of developing cancer, wherein determining whether the individual has a genetic variant comprises amplifying the MYH gene of the individual, or a portion thereof, and determining if the MYH gene comprises the genetic variant.

The asserted '776 patent claims:

2. A method for genotyping an individual comprising: detecting the 691C ? T nucleotide variant in an MYH gene obtained from said individual, wherein said detecting step comprises sequencing the MYH gene.

3. A method for genotyping an individual comprising: detecting the 691C ? T nucleotide variant in an MYH gene obtained from said individual, wherein a nucleic acid comprising said nucleotide variant is amplified from genomic DNA.

5. A method for genotyping an individual comprising: detecting the 691C ? T nucleotide variant in an MYH gene obtained from said individual, wherein said detecting step comprises amplifying an exon, or fragment thereof, corresponding to the 691C ? T nucleotide variant.

9. A method for determining an increased likelihood for developing colon cancer in an individual, comprising: determining from a sample obtained from said individual whether said individual has the 691C ? T nucleotide variant in an MYH gene of said individual, wherein the presence of said nucleotide variant is indicative of an increased likelihood for developing colon cancer, wherein said determining step comprises sequencing the MYH gene.

10. A method for determining an increased likelihood for developing colon cancer in an individual, comprising: determining from a sample obtained from said individual whether said individual has the 691C ? T nucleotide variant in an MYH gene of said individual, wherein the presence of said nucleotide variant is indicative of an increased likelihood for developing colon cancer, wherein said determining step comprises amplifying the nucleotide variant from genomic DNA.

12. A method for determining an increased likelihood for developing colon cancer in an individual, comprising: determining from a sample obtained from said individual whether said individual has the 691C ? T nucleotide variant in an MYH gene of said individual, wherein the presence of said nucleotide variant is indicative of an increased likelihood for developing colon cancer, wherein said determining step comprises amplifying an exon, or fragment thereof, corresponding to the 691C ? T nucleotide variant.

The asserted '571 patent claims:

2. A method for genotyping an individual comprising: detecting a genetic variant that results in an amino acid variant at position R231H, in reference to SEQ ID NO:2, in the MYH gene of the individual, wherein said detecting step comprises sequencing the MYH gene or a portion thereof.

7. A method comprising: isolating from an individual a genetic variant that corresponds to an amino acid variant at the position R231H, in reference to SEQ ID NO:2, in the MYH gene of the individual; and determining the presence of said genetic variant, wherein said determining step comprises sequencing the MYH gene or a portion thereof.

The asserted '698 patent claims:

73. A chip array having "n" elements for performing allele specific sequence-based techniques comprising:
    a solid phase chip and
    oligonucleotides having "n" different nucleotide sequences,
    wherein "n" is an integer greater than one, p1 wherein said oligonucleotides are bound to said solid phase chip in a manner which permits said oligonucleotides to effectively hybridize to complementary oligonucleotides or polynucleotides,
    wherein oligonucleotides having different nucleotide sequence are bound to said solid phase chip at different locations so that a particular location on said solid phase chip exclusively binds oligonucleotides having a specific nucleotide sequence, and
    wherein at least one oligonucleotide is an oligonucleotide that is an isolated nucleotide that hybridizes to either a normal or a mutant BRCA1 gene selected from the group consisting of:
    a first oligonucleotide for detecting a deletion of a nucleotide in intron 6 at nucleotide number 421-2 of a BRCA1 gene sequence, wherein said first oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 421-2 of the BRCA1 gene,

    a second oligonucleotide for detecting a deletion of two nucleotides at nucleotide number 815 of a BRCA1 gene sequence, wherein said second oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 815 of the BRCA1 gene,
    a third oligonucleotide for detecting an insertion of 10 nucleotides at nucleotide number 926 of a BRCA1 gene sequence, wherein said third oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 926 of the BRCA1 gene,

    a fourth oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 1506 of a BRCA1 gene sequence, wherein said fourth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 1506 of the BRCA1 gene,
    a fifth oligonucleotide for detecting a mutation of one nucleotide at nucleotide number 2034 of a BRCA1 gene sequence, wherein said fifth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 2034 of the BRCA1 gene,

    a sixth oligonucleotide for detecting an amino acid change from serine to a stop codon at codon 770 of a BRCA1 gene sequence, wherein said sixth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 2428 of the BRCA1 gene,
    a seventh oligonucleotide for detecting an amino acid change from tryptophan to a stop codon at codon 1508 of a BRCA1 gene sequence, wherein said seventh oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 4643 of the BRCA1 gene,

    an eighth oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 5053 of a BRCA1 gene sequence, wherein said eighth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5053 of the BRCA1 gene,
    an ninth oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 5210 of a BRCA1 gene sequence, wherein said ninth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5210 of the BRCA1 gene,

    a tenth oligonucleotide for detecting an insertion of 12 nucleotides at nucleotide number 5396+40 in intron 20 of a BRCA1 gene sequence, wherein said tenth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5396+40 of the BRCA1 gene,
    an eleventh oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 5150 of a BRCA1 gene sequence, wherein said eleventh oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5150 of the BRCA1 gene,

    a twelfth oligonucleotide for detecting an amino acid change from serine to a stop codon at codon 1262 of a BRCA1 gene sequence, wherein said twelfth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 3904 of the BRCA1 gene,
    a thirteenth oligonucleotide for detecting an amino acid change from tyrosine to stop at nucleotide number 903 of a BRCA1 gene sequence, wherein said thirteenth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 903 of the BRCA1 gene, and

    a fourteenth oligonucleotide for detecting a detecting an amino acid change from threonine to proline at nucleotide number 4164 of a BRCA1 gene sequence, wherein said fourteenth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 4164 of the BRCA1 gene.

Myriad and its co-plaintiffs demand a jury trial, and request judgment of patent infringement, a preliminary and permanent injunction, an accounting and damages, delivery for destruction of all "products" that infringe any of the asserted claims, a finding of willful infringement, and a request for attorneys' fees, enhanced damages, and costs of suit.

Perhaps Myriad recognized that the genetic diagnostics community would follow the lead of Quest and Counsyl and file defensive declaratory judgment suits in a multiplicity of jurisdictions, and that it could not afford to wait for the Utah court's decision on its preliminary injunction motion.  A positive outcome as to the injunction request could be expected to motivate potential infringers to the negotiating table, for example.  Myriad is serious about protecting its intellectual property, including more than the BRCA tests, and may have decided it has much more to lose than the company's patents scheduled to expire over the next few years.  Sixteen years of patent exclusivity have certainly provided Myriad with the motivation and the economic means to protect its franchise.