IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`GENEDX, INC.
`Petitioner
`v.
`MYRIAD GENETICS, INC.
`Patent Owner
`
`U.S. Patent No. 6,051,379 to Lescallett et al.
`Issue Date: April 18, 2000
`Title: Cancer Susceptibility Mutations of BRCA2
`_____________________
`
`Inter Partes Review No. Unassigned
`_____________________
`
`Petition for Inter Partes Review of U.S. Patent No. 6,051,379 Under 35 U.S.C.
`§§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`

`

`Petition for Inter Partes Review of USPN 6,051,379
`
`TABLE OF CONTENTS
`
`
`
`I.
`
`INTRODUCTION ............................................................................................... 1
`
`II. OVERVIEW ....................................................................................................... 1
`
`III. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS ......... 4
`
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ......................................... 4
`
`V. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`
`REASONS THEREFORE (37 C.F.R. § 42.22(A)) ................................................... 6
`
`VI. CLAIM CONSTRUCTION ................................................................................ 6
`
`VII. PERSON OF ORDINARY SKILL IN THE ART AND STATE OF THE
`
`ART ............................................................................................................................ 8
`
`VIII. IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 42.104(b)) ......111
`
`1. Ground 1: Claims 7, 8, 13, 14, 16, 17, 19, 20, 32, and 33 Would Have
`
`Been Obvious Over Tavtigian in Light of Shattuck-Eidens .............................13
`
`2. Ground 2: Claims 7, 8, 13, 14, 16, 17, 19, 20, 32, and 33 Would Have
`
`Been Obvious Over Wooster in Light of Shattuck-Eidens ...............................38
`
`3. Objective indicia of nonobviousness .........................................................52
`
`IX. CONCLUSION ...............................................................................................587
`
`
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`Petition for Inter Partes Review of USPN 6,051,379
`
`I.
`
`INTRODUCTION
`
`GENEDX, INC. petitions for Inter Partes Review, seeking cancellation of
`
`claims 7, 8, 13, 14, 16, 17, 19, 20, 32, and 33 of U.S. Patent No 6,051,379 to
`
`Lescallett ("the '379 patent") (GDX1001). According to the USPTO assignment
`
`database, the '379 patent is owned by MYRIAD GENETICS, INC.
`
`II. OVERVIEW
`
`The challenged claims of the '379 patent recite oligonucleotides and methods
`
`that are unpatentable over the art identified herein because they are the result of
`
`ordinary skill and common sense, and not innovation. Claims 7, 13, and 16 are
`
`directed to isolated oligonucleotides that are capable of detecting particular
`
`mutations at nucleotide numbers 5193, 6495, and 6909, respectively, of a BRCA2
`
`gene. Claims 19-20 are directed to oligonucleotides with a label bound thereto,
`
`including the oligonucleotides of claims 7, 13, and 16. Claims 8, 14, and 17 are
`
`directed to isolated oligonucleotides having the sequences of SEQ ID NOs:11, 19,
`
`and 23, respectively, or complementary oligonucleotides thereto. And claims 32-33
`
`are directed to methods of detecting a predisposition or higher susceptibility to
`
`cancer in an individual, wherein the presence of a sequence variation at nucleotide
`
`number 2192, 3772, 5193, 5374, 6495, or 6909 indicates a predisposition or higher
`
`susceptibility to cancer.
`
`BRCA2 sequences encompassing nucleotide numbers 5193, 6495, and 6909
`
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`Petition for Inter Partes Review of USPN 6,051,379
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`were known in the prior art. GDX1026, 1:11; GDX1027, 1, 4; GDX1023, 3:FIG. 2,
`
`4:1; GDX1002, ¶¶54, 65, 69, 73, 119. BRCA2 mutations had been identified from
`
`individuals in breast-cancer prone families (i.e., individuals with inherited
`
`mutations) and individuals with pancreatic cancer. GDX1022, 2:3, 2090:1;
`
`GDX1024, 1:Abstract; GDX1023, 1; GDX1026, 2:1; GDX1002, ¶41. Before the
`
`earliest alleged priority date of September 23, 1997, persons of ordinary skill in the
`
`art ("POSAs") would have expected that additional BRCA2 mutations remained to
`
`be identified in association with cancer. GDX1026, 1:1-4:1; GDX1023, 2-4;
`
`GDX1002, ¶41, 57-58, 121. Thus, a POSA would have had a strong motivation to
`
`continue screening BRCA2 sequences from individuals of breast cancer-prone
`
`families and in individuals with suspected BRCA2-associated cancers in order to
`
`identify additional cancer-associated mutations, such as those recited in claims 7,
`
`13, 16, and 32 of the '379 patent. GDX1026, 1:2-4:1; GDX1023, 4:1; GDX1029,
`
`7:24-6:1, 11:23-12:2, 19:6-25; GDX1002, ¶¶58, 121. And, based on routine
`
`screening, a POSA would have had a reasonable expectation of success in
`
`identifying the mutations. GDX1026, 1:2-2:1, 336:1, 337:2; GDX1023, 2;
`
`1 Citations to GDX1001 use the format x:y:z, where x is the exhibit page
`
`number, y is the column number, and z is the line number(s). For GDX1029, x is
`
`the exhibit page number and y is the line number(s). For citations to all other non-
`
`patent publications, x is the exhibit page number and y is the column number.
`
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`Petition for Inter Partes Review of USPN 6,051,379
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`GDX1029, 20:7-24:12; GDX1002, ¶¶42, 59-60, 122-123. After identifying the
`
`mutations, a POSA would have had a reason to combine teachings regarding
`
`known BRCA2 sequences with teachings regarding the well-known and routine
`
`allele-specific hybridization assay to produce oligonucleotides, including labeled
`
`oligonucleotides, capable of detecting the mutations (claims 7, 13, 16, 19, and 20)
`
`and oligonucleotides capable of detecting wild-type (i.e., normal) sequences (such
`
`as the SEQ ID NOs or their complementary sequences of claims 8, 14, and 17).
`
`GDX1026, 1:1; GDX1023, 1-3; GDX1029, 20:25-28, 22:6-8; GDX1002, ¶¶39, 61,
`
`68, 72, 85, 93, 99, 124, 130, 133. And based on well-known methods for designing
`
`oligonucleotides for allele-specific hybridization assays, a POSA would have had a
`
`reasonable expectation of success in producing the claimed oligonucleotides.
`
`GDX1018, 1-5; GDX10212, 1-8; GDX1002, ¶¶64, 68, 72, 88, 95-96, 101-102, 127,
`
`130, 133, 148, 155, 163. A POSA also would have had a reason to combine
`
`teachings regarding known BRCA2 sequences with teachings regarding methods
`
`for determining an individual's predisposition to cancer to develop methods for
`
`2 GDX1021 has an online publication date of May 1, 2001, but corresponds
`
`to the printed publication date of August 1995, as indicated at the bottom of page 1
`
`of the document, which states "Current Protocols in Human Genetics (1995) 9.4.1-
`
`9.4.8." See GDX1021, 1. And, the '379 patent references the 1995 publication. See
`
`GDX1001, 9:15:52-54.
`
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`Petition for Inter Partes Review of USPN 6,051,379
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`determining the presence or absence of identified mutations in an individual's
`
`BRCA2 sequence (claims 32-33). GDX1026, 1:1; GDX1023, 1-3; GDX1029, 7:27-
`
`8:1, 41:14-18, 21:12-13, 26, 20:7-9, 40:25-27; GDX1002, ¶¶107, 115, 167, 174.
`
`Based on conventional methods in the art for detecting mutations in other genes, a
`
`POSA would have had a reasonable expectation of success in developing the
`
`methods. GDX1002, ¶¶111, 115, 170, 174.
`
`III. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
`Petitioner certifies that (1) the '379 patent is available for IPR and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the ‘379
`
`patent. This Petition is filed in accordance with 37 CFR § 42.106(a). A Power of
`
`Attorney and an Exhibit List are filed concurrently herewith. The required fee is
`
`paid online via credit card. The Office is authorized to charge fee deficiencies and
`
`credit overpayments to Deposit Acct. No. 19-0036 (Customer ID No. 45324).
`
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
`Real Parties-In-Interest (37 C.F.R. § 42.8(b)(1)) is: GENEDX, INC. and
`
`BIOREFERENCE LABORATORIES, INC.
`
`Related Matters (37 C.F.R. § 42.8(b)(2)): Judicial matters: The '379 patent
`
`has been asserted against GENEDX in Univ. of Utah Research Foundation et al. v.
`
`GeneDx, No. 2-13-cv-00954 (D. Utah Oct. 16, 2013) and against others in cases
`
`consolidated into: In Re: BRCA1- and BRCA2- Based Hereditary Cancer Test
`
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`Petition for Inter Partes Review of USPN 6,051,379
`
`Patent Litigation, No. 2-14-md-02510 (D. Utah Feb. 25, 2014); Invitae
`
`Corporation v. Myriad Genetics, Inc., No. 3-13-cv-05495 (N. D. Cal. Nov. 26,
`
`2013); Quest Diagnostics Inc. et al. v. Myriad Genetics, Inc., No. 8-13-cv-01587
`
`(C. D. Cal. Oct. 10, 2013); Counsyl, Inc v. Myriad Genetics, Inc., 5-13-cv-04391
`
`(N. D. Cal. Sep. 20, 2013); Univ. of Utah Research Foundation et al v. Gene by
`
`Gene, Ltd., No. 2-13-cv-00643 (D. Utah Jul. 10, 2013). GDX1030. Administrative
`
`matters: Petitions for IPR of U.S. Patent Nos. 5,654,155; 5,753,441; 6,033,857;
`
`6,083,698; and 6,951,721 are filed concurrently with the instant petition.
`
`Designation of Counsel (37 C.F.R. § 42.8(b)(3)):
`
`Lead Counsel
`Eldora L. Ellison (Reg. No. 39,967)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8508 (telephone)
`202.371.2540 (facsimile)
`eellison-PTAB@skgf.com
`
`
`
`
`
`Back-Up Counsel
`Deborah A. Sterling (Reg. No. 62,732)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8501 (telephone)
`202.371.2540 (facsimile)
`dsterlin-PTAB@skgf.com
`Ralph W. Powers III (Reg. No. 63,504 )
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8876 (telephone)
`202.371.2540 (facsimile)
`tpowers-PTAB@skgf.com
`
`Notice of Service Information (37 C.F.R. § 42.8(b)(4)): Please direct all
`
`correspondence regarding this Petition to lead counsel at the above address.
`
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`Petition for Inter Partes Review of USPN 6,051,379
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`Petitioner consents to service by email at: eellison-PTAB@skgf.com,
`
`dsterlin-PTAB@skgf.com, and tpowers-PTAB@skgf.com.
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(A))
`
`
`
`Petitioner requests IPR and cancellation of claims 7, 8, 13, 14, 16, 17, 19,
`
`20, 32, and 33. Petitioner's full statement of the reasons for the relief requested is
`
`set forth in detail in the § VIII.
`
`VI. CLAIM CONSTRUCTION
`
`In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be
`
`given their broadest reasonable interpretations in light of the specification of the
`
`'379 patent. Terms not explicitly discussed below are plain on their face and should
`
`be construed to have their ordinary and customary meanings.
`
`The term "isolated" in claims 7-8, 13-14, 16-17, and 19-20 is explicitly
`
`defined in the patent as "being substantially free of other polynucleic acids,
`
`proteins, lipids, carbohydrates or other materials with which they may be
`
`associated. Such association being either in cellular material or in a synthesis
`
`medium." GDX1001, 7:11:27-31. Accordingly, a POSA would construe the term
`
`"isolated" consistent with its definition in the '379 patent. GDX1002, ¶22.
`
`The term "region" in claims 7, 13, and 16 is explicitly defined in the patent
`
`as "an area from several nucleotides upstream to several nucleotides downstream
`
`from the specific nucleotide mentioned. 'Region' also includes the complementary
`
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`Petition for Inter Partes Review of USPN 6,051,379
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`nucleotides on the antisense strand of sample DNA." GDX1001, 7:12:36-40.
`
`Accordingly, a POSA would construe the term "region" consistent with its
`
`definition in the '379 patent. GDX1002, ¶23.
`
`The term "BRCA2 gene" in claims 7, 13, 16, and 32 is explicitly defined in
`
`the patent as:
`
`a group of compounds and refers to the published gene sequences,
`those appearing in the GENBANK database and the BIC database.
`Other different sequences
`include polymorphisms and genetic
`alterations, especially those which define other haplotypes for the
`BRCA2 gene. Generally polymorphisms which don't cause an amino
`acid change or which are naturally occurring (wild types), which are
`not associated with pathology are also considered the BRCA2 gene.
`The corresponding nucleotides would then be used even if the
`nucleotide number differs. While the BRCA2 gene discussed herein is
`the human BRCA2 gene, the corresponding assays and reagents for
`the gene in other animals may also be used. The BRCA2 gene
`includes the coding sequences, non-coding sequences (e.g. introns)
`and regulatory regions affecting gene expression.
`
`GDX1001, 7:12:9-22. Accordingly, a POSA would construe the term "BRCA2
`
`gene" consistent with its definition in the '379 patent. GDX1002, ¶24.
`
`The term "higher susceptibility to" in claim 32 is explicitly defined in the
`
`patent to mean "at risk of." GDX1001, 6:9:29. Accordingly, a POSA would
`
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`Petition for Inter Partes Review of USPN 6,051,379
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`construe the term "higher susceptibility to" consistent with its definition in the '379
`
`patent. GDX1002, ¶25.
`
`The remaining terms in claims 7, 8, 13, 14, 16, 17, 19, 20, 32, and 33 are
`
`plain on their face and should be construed to have their ordinary and customary
`
`meanings. GDX1002, ¶26.
`
`VII. PERSON OF ORDINARY SKILL IN THE ART AND STATE OF THE
`ART
`
`A person of ordinary skill in the art ("POSA") is a hypothetical person who
`
`is presumed to be aware of all the pertinent art, thinks along conventional wisdom
`
`in the art, and is a person of ordinary creativity. With respect to the subject matter
`
`of the '379 patent, a POSA would typically have had (i) a Ph.D. in genetics,
`
`molecular genetics, or molecular biology, or in a related field in the biological
`
`sciences, and have experience in recombinant DNA technology, medical genetics,
`
`or genetic diagnostics, or (ii) a Master's degree in genetics, molecular genetics, or
`
`molecular biology, or a related field in the biological sciences, and have at least 2
`
`years of experience in recombinant DNA technology, medical genetics, or genetic
`
`diagnostics. GDX1002, ¶10. A POSA would have known how to research the
`
`scientific literature regarding recombinant DNA technology, medical genetics, or
`
`genetic diagnostics. Id., ¶11. Also, a POSA may be comprised of a
`
`multidisciplinary team with each member drawing upon not only his or her own
`
`skills, but also taking advantage of certain specialized skills of others in the team,
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`e.g., to solve a given problem. Id. For example, a molecular biologist and a
`
`physician may have been part of the team. Id. As of September 23, 1997, a POSA
`
`of recombinant DNA technology, medical genetics, or genetic diagnostics would
`
`have had knowledge of scientific literature concerning methods for identifying and
`
`cloning genes or gene sequences and methods for screening or detecting alterations
`
`in genes. Id., ¶12. Such a POSA would have had knowledge of strategies for
`
`identifying and cloning genes or gene sequences and for screening or detecting
`
`alterations in genes. Id.
`
`As of September 23, 1997, the state of the art included the teachings
`
`provided by each of the references discussed in each of the unpatentability grounds
`
`set forth below. Additionally, a POSA would have been aware of other important
`
`references and techniques relating to methods for identifying and screening
`
`mutations of genes or gene sequences.
`
`Prior to September 23, 1997, genes and gene sequences were routinely
`
`analyzed for the presence of mutations that cosegregate with disease, for example,
`
`by detecting whether any sequence variation was present in the gene of individuals
`
`with disease as compared to individuals without disease in the same family.
`
`GDX1006, 11:1-12:2; GDX1002, ¶38. And various methods for screening genes
`
`for sequence variations were well-known and routinely used. GDX1026, 1:2-2:1,
`
`336:1, 337:2; GDX1023, 2; GDX1029, 20:7-24:12; GDX1002, ¶¶38, 42, 59, 122.
`
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`Such
`
`routine methods also
`
`included hybridization
`
`(e.g., allele-specific
`
`hybridization using ASO probes) and DNA sequencing. GDX1006, 11:1-12:2;
`
`GDX1020, 11-12; GDX1029, 20:25-28; GDX1018, 1-5; GDX1021, 1-8;
`
`GDX1026, 1:2, 4:1, 5:2; GDX1023, 2-3;GDX1002, ¶38.
`
`BRCA2 wild-type sequences encompassing nucleotide numbers 5193, 6495,
`
`and 6909 were known prior to September 23, 1997. GDX1026, 1:1; GDX1027, 1,
`
`4; GDX1023, 3-4; GDX1002, ¶¶41, 44-45, 54, 68, 72, 119, 146, 153, 161. And
`
`screening of the BRCA2 gene and gene sequences before September 23, 1997 had
`
`identified several cancer-associated mutations. See, e.g., GDX1022, 2:3-3:1;
`
`GDX1023, 1; GDX1026, 2:1; GDX1011, 1:2; GDX1002, ¶41. A person of
`
`ordinary skill in the art ("POSA") also expected that additional BRCA2 mutations
`
`associated with cancer remained to be identified. GDX1026, 1:1-4:1; GDX1023,
`
`2-4; GDX1002, ¶¶41, 57, 121. Thus, there was a strong motivation in the art for a
`
`POSA to screen BRCA2 sequences from individuals to identify additional
`
`mutations associated with cancer. GDX1002, ¶¶41, 58, 121. And, several methods
`
`were well-known in the art for routinely detecting and characterizing mutations.
`
`GDX1026, 1:2-2:1, 4:1, 5:2; GDX1023, 2; GDX1029, 20:7-24:12; GDX1002,
`
`¶¶38, 42, 59, 122.
`
`Prior to September 23, 1997, routine methods existed for detecting the
`
`presence or absence of a mutation in an individual's DNA. GDX1002, ¶¶38, 42.
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`Petition for Inter Partes Review of USPN 6,051,379
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`The allele-specific hybridization assay was one such well-known method.
`
`GDX1001, 8:13:5-10, 9:15:34-9:16:5; GDX1018, 1-5; GDX1021, 1-8; GDX1002,
`
`¶¶38-39. In the allele-specific hybridization assay, a target sequence, such as a
`
`gene or gene fragment from an individual, is probed with isolated oligonucleotides
`
`that can distinguish even single-base changes in a DNA sequence by specific
`
`hybridization. GDX1018, 1:1; GDX1029, 20:25-28; GDX1021, 1, 6:2; GDX1002,
`
`¶39. The assay was known to include an oligonucleotide designed to detect a
`
`mutant sequence by specifically hybridizing to the mutant sequence and an
`
`oligonucleotide designed to detect the corresponding wild-type sequence by
`
`specifically hybridizing to the wild-type sequence. GDX1018, 1-2; GDX1021, 8;
`
`GDX1002, ¶¶39, 63, 87, 126, 147. And the design of oligonucleotides for allele-
`
`specific hybridization assays was well-known and routine in the art. GDX1001,
`
`9:15:34 to 9:16:5; GDX1021, 1-8; GDX1002, ¶39.
`
`Methods were also known in the art prior to September 23, 1997 for
`
`detecting the presence or absence of a mutation in genes or gene sequences from
`
`an individual in order to determine the individual's predisposition to cancer.
`
`GDX1029, 7:24-8:1, 19:30-25:31, 40:25-43:24; GDX 1002, ¶¶109-110, 123.
`
`VIII. IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 42.104(b))
`Petitioner requests inter partes review of the challenged claims of the '379
`
`patent on the grounds for unpatentability listed in the index below. Per 37 C.F.R.
`
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`Petition for Inter Partes Review of USPN 6,051,379
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`§ 42.6(d), copies of the exhibits relied on are filed herewith. In support of the
`
`proposed grounds for unpatentability, this Petition is accompanied by a declaration
`
`of expert Dr. Madhuri Hegde (GDX1002), which explains what the art would have
`
`conveyed to a POSA.
`
`Ground 35 U.S.C. Section
`(pre-3/16/2013)
`
`1
`
`2
`
`§ 103
`
`§ 103
`
`Index of References
`
`‘379 Patent Claims
`
`Tavtigian and Shattuck-
`Eidens
`Wooster and Shattuck-
`Eidens
`
`7, 8, 13, 14, 16, 17,
`19, 20, 32, and 33
`7, 8, 13, 14, 16, 17,
`19, 20, 32, and 33
`
`Grounds 1 and 2 are not redundant. Tavtigian discloses the complete
`
`nucleotide coding sequence of BRCA2 as GenBank Accession No. U43746 and
`
`provides methods for screening the entire BRCA2 gene for germline mutations
`
`using polymerase chain reaction ("PCR") and DNA sequencing. GDX1026, 1;
`
`GDX1002, ¶45. And, Tavtigian discloses that its insight into germline mutations is
`
`preliminary and that there may be an even greater number of BRCA2 mutations in
`
`the population than BRCA1 mutations. GDX1026, 1:1, 3:2; GDX1002, ¶45.
`
`Tavtigian in combination with Shattuck-Eidens provide a reason to combine the art
`
`to arrive at the subject matter of claims 7, 8, 13, 14, 16, 17, 19, 20, 32, and 33 and
`
`provide a reasonable expectation of success. GDX1002, ¶¶45, 54-66, 68-70, 72-74,
`
`80-81, 85-90, 93-97, 99-103, 105-112, 114-115. Wooster includes distinct reasons
`
`in combination with Shattuck-Eidens to combine the art to arrive at the claimed
`
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`subject matter with a reasonable expectation of success. GDX1002, ¶¶44, 118-128,
`
`130-131, 133-134, 137-138, 140-141, 144-149, 152-156, 159-163, 165-171, 173-
`
`174. Wooster discloses isolation of 7300 base pairs of the BRCA2 gene and a
`
`partial, predicted protein sequence of 2329 amino acids. GDX1023, 3-4;
`
`GDX1002, ¶44. And Wooster provides methods for analyzing BRCA2 germline
`
`mutations by migration shift assays and DNA sequencing. GDX1023, 2-3;
`
`GDX1002, ¶44. Wooster also discloses that BRCA2 is a strong candidate for
`
`somatic mutations leading to breast and other cancers. GDX1023, 4; GDX1002,
`
`¶120. Petitioner is at least reasonably likely to prevail in challenging the
`
`patentability of claims 7, 8, 13, 14, 16, 17, 19, 20, 32, and 33 on the basis of each
`
`ground herein.
`
`1. Ground 1: Claims 7, 8, 13, 14, 16, 17, 19, 20, 32, and 33
`Would Have Been Obvious Over Tavtigian in Light of
`Shattuck-Eidens
`An article by Tavtigian et al. entitled "The complete BRCA2 gene and
`
`mutations in chromosome 13q-linked kindreds" was published on March 12, 1996
`
`in the journal Nature Genetics ("Tavtigian"; GDX1026). Tavtigian qualifies as
`
`prior art to the '379 patent under 35 U.S.C. § 102(b) because it published more than
`
`one year prior to the earliest alleged U.S. priority date of September 23, 1997.
`
`While Tavtigian was cited by the Examiner during prosecution of the '379 patent, it
`
`was not considered in combination with Shattuck-Eidens. GDX1004, 124-126,
`
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`Petition for Inter Partes Review of USPN 6,051,379
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`139-143. And, the Examiner's reason for finding claims allowable based on the
`
`lack of a literal teaching in the art of the specifically claimed mutations is not
`
`congruent with subsequent decisions in KSR v. Teleflex, Inc., 550 U.S. 398 (2007)
`
`and In re Kubin, 561 F.3d 1351 (Fed. Cir. 2009). GDX1044, 143.
`
`Prior art references must be "considered together with the knowledge of one
`
`of ordinary skill in the pertinent art." In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
`
`1994). In that regard, "it is proper to take into account not only specific teachings
`
`of the reference but also the inferences which one skilled in the art would
`
`reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826 (CCPA
`
`1968). That is because an obviousness analysis "need not seek out precise
`
`teachings directed to the specific subject matter of the challenged claim, for a court
`
`can take account of the inferences and creative steps that a person of ordinary skill
`
`in the art would employ." KSR at 418. And, "where a skilled artisan merely pursues
`
`'known options' from a 'finite number of identified, predictable solutions,'
`
`obviousness under § 103 arises." In re Kubin at 1359, citing KSR at 421.
`
`Tavtigian teaches that "[b]ecause family history remains the strongest single
`
`predictor of breast cancer risk, attention has focused on the role of highly
`
`penetrant, dominantly inherited genes in cancer-prone kindreds" such as the
`
`BRCA1 and BRCA2 genes. GDX1026, 1:1; GDX1002, ¶45. Tavtigian teaches the
`
`determination of "the complete coding sequence and exonic structure of BRCA2"
`
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`Petition for Inter Partes Review of USPN 6,051,379
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`and identifies the sequence as GenBank Accession No. U43746. GDX1026, 1:1;
`
`GDX1027, 1; GDX1002, ¶45. Tavtigian also teaches that its data provide a
`
`"preliminary insight into the BRCA2 mutation profile" and that the entire coding
`
`sequence of BRCA2 can be screened for mutations. GDX1026, 1-2; GDX1002,
`
`¶45, emphasis added. And, Tavtigian teaches that "the number of BRCA2
`
`mutations in the population may be even greater than the number of BRCA1
`
`mutations." GDX1026, 3:2; GDX1002, ¶57. Thus, a POSA would have understood
`
`that additional BRCA2 mutations remained to be identified. GDX1002, ¶57. And,
`
`Tavtigian discloses that "[o]ne of the significant goals ahead is the development of
`
`reliable diagnostic tests for BRCA1 and BRCA2." GDX1026, 4:1; GDX1002, ¶108.
`
`International Publication No. WO 96/05306 was published on February 22,
`
`1996, naming Shattuck-Eidens et al. as inventors and entitled "In vivo mutations
`
`and polymorphisms in the 17q-linked breast and ovarian cancer susceptibility
`
`gene" ("Shattuck-Eidens"; GDX1029). Shattuck-Eidens qualifies as prior art to
`
`the '379 patent under 35 U.S.C. § 102(b) because it published more than one year
`
`prior to the earliest alleged U.S. priority date of September 23, 1997.
`
`Shattuck-Eidens
`
`teaches
`
`that "[i]dentification of a breast cancer
`
`susceptibility locus would permit the early detection of susceptible individuals and
`
`greatly increase our ability to understand the initial steps which lead to cancer."
`
`GDX1029, 7:16-20; GDX1002, ¶46. Specifically, Shattuck-Eidens teaches the
`
`
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`Petition for Inter Partes Review of USPN 6,051,379
`
`coding sequence and exonic structure of the BRCA1 gene and "the screening of the
`
`BRCA1 gene for mutations, which are useful for diagnosing the predisposition to
`
`breast and ovarian cancer." GDX1029, 10:3-15; GDX1002, ¶46. Shattuck-Eidens
`
`teaches that its diagnostic methods can detect alteration of the wild-type BRCA1
`
`locus, encompassing "all forms of mutations including deletions, insertions and
`
`point mutations." GDX1029, 19:6-25; GDX1002, ¶46. And, Shattuck-Eidens
`
`teaches that that "[o]nce a mutation is known, an allele specific detection approach
`
`such as allele specific oligonucleotide (ASO) hybridization can be utilized to
`
`rapidly screen large numbers of other samples for that same mutation." GDX1029,
`
`20:25-28; GDX1002, ¶46. Shattuck-Eidens also teaches that it methods "can be
`
`performed by detecting the wild-type BRCA1 locus and confirming the lack of a
`
`predisposition to cancer at the BRCA1 locus." GDX1029, 19:7-8; GDX1002, ¶46.
`
`Additionally, Shattuck-Eidens teaches that "[p]robes for BRCA1 alleles may be
`
`derived from the sequences of the BRCA1 region or its cDNAs" and can be of any
`
`suitable length to allow specific hybridization to the BRCA1 region. GDX1029,
`
`31:26-28; GDX1002, ¶46. Thus, Shattuck-Eidens teaches that, after the coding
`
`sequence of a breast cancer gene is determined, mutations can be readily screened
`
`and sequenced, and oligonucleotides can be readily developed to detect the
`
`presence or absence of the mutations.
`
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`Petition for Inter Partes Review of USPN 6,051,379
`
`Claims 7, 13, and 16. Claims 7, 13, and 16 are independent claims that
`
`recite isolated oligonucleotides capable of detecting specific mutations at
`
`nucleotide numbers 5193, 6495, and 6909, respectively, of a BRCA2 gene by
`
`specifically hybridizing to the region of the gene containing the nucleotide number.
`
`The '379 patent discloses that the oligonucleotides of claims 7, 13, and 16 are
`
`allele-specific oligonucleotide probes (ASO probes). GDX1001, 3:4:58 to 4:5:3,
`
`4:5:40-52, and 4:5:66 to 4:6:10; GDX1002, ¶52. The numbering of the nucleotides
`
`recited in the claims corresponds to the numbering of the BRCA2 sequence in
`
`GenBank Accession No. U43746. GDX1001, 2:1:26-28; GDX1002, ¶52.
`
`Claim 7
`An isolated
`oligonucleotide
`
`wherein the
`oligonucleotide
`is capable of
`detecting a
`
`Disclosure of Tavtigian (GDX1026) and
`Shattuck-Eidens (GDX1029)
`Shattuck-Eidens: "The present invention provides an isolated
`polynucleotide comprising all, or a portion of the BRCA1
`locus or of a mutated BRCA1 locus, preferably at least eight
`bases and not more than about 100 kb in length." (GDX1029,
`10:16-18) (emphasis added)
`Shattuck-Eidens: "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." (GDX1029, 28:12-18) (emphasis added)
`
`Shattuck-Eidens: "An allele-specific oligonucleotide (ASO)
`was designed to detect the presence of the sequence variant in
`Kindred 2099." (GDX1029, 88:1-2) (emphasis added)
`Tavtigian: "We have now determined the complete coding
`sequence and exonic structure of BRCA2 (GenBank
`accession #U43746), and examined its pattern of expression.
`Here, we provide sequences for a set of PCR primers sufficient
`
`
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`Petition for Inter Partes Review of USPN 6,051,379
`
`Disclosure of Tavtigian (GDX1026) and
`Shattuck-Eidens (GDX1029)
`to screen the entire coding sequence of BRCA2 using
`genomic DNA." (GDX1026, 1:1) (emphasis added)
`
`Tavtigian: "Individuals from 18 putative BRCA2 kindreds
`were screened for BRCA2 germline mutations by DNA
`sequence analysis." (GDX1026, 1:2) (emphasis added)
`
`Tavtigian: "Table 2 Primers used to amplify and mutation
`screen BRCA2 from genomic DNA" (GDX1026, 4:Table 2)
`(emphasis added)
`
`Shattuck-Eidens: "According to the diagnostic and prognostic
`method of the present invention, alteration of the wild-type
`BRCA1 locus is detected. In addition, the method can be
`performed by detecting the wild-type BRCA1 locus and
`confirming the lack of a predisposition to cancer at the BRCA1
`locus. "Alteration of a wild-type gene" encompasses all
`forms of mutations including deletions, insertions and point
`mutations in the coding and noncoding regions." (GDX1029,
`19:6-10) (emphasis added)
`
`Shattuck-Eidens: "Once a mutation is known, an allele
`as allele
`specific
`specific detection
`approach
`such
`oligonucleotide (ASO) hybridization can be utilized to
`rapidly screen large numbers of other samples for that
`same mutation." (GDX1029, 20:25-28) (emphasis added)
`
`Shattuck-Eidens: "In an allele-specific oligonucleotide
`assay, an oligonucleotide is designed which detects a specific
`sequence, and the assay is performed by detecting the presence
`or absence of a hybridization signal." (GDX1029, 22:6-8)
`(emphasis added)
`Shattuck-Eidens: "DNA sequences of the BRCA1 gene which
`have been amplified by use of PCR may also be screened using
`allele-specific probes. These probes are nucleic acid
`oligomers, each of which contains a region of the BRCA1 gene
`sequence harboring a known mutation. . . . Hybridization to a
`particular probe under stringent hybridization conditions
`indicates the presence of the same mutation in the tumor
`
`Claim 7
`substitution of
`G for C at
`nucleotide
`number 5193 of
`a BRCA2 gene
`
`by specifically
`hybridizing to
`the region
`containing
`nucleotide
`number 5193 of
`the BRCA2
`
`
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`

`Claim 7
`gene.
`
`
`
`
`
`Petition for Inter Partes Review of USPN 6,051,379
`
`Disclosure of Tavtigian (GDX1026) and
`Shattuck-Eidens (GDX1029)
`tissue as in the allele-specific probe." (GDX1029, 23:4-13)
`(emphasis added)
`
`Shattuck-Eidens: "Probes for BRCA1 alleles may be derived
`from the sequences of the BRCA1 region or its cDNAs. The
`probes may be of any suitable length, which span all or a
`portion of the BRCA1 region, and which allow specific
`hybridization to the BRCA1 region." (GDX1029, 31:26-28)
`(emphasis added)
`
`
`Note: The substitution of G for C at nucleotide number 5193 is a mutation in
`
`the BRCA2 gene. GDX1001, 2:1:65-67, 3:3:26-43, 3:4:58-4:5:3; GDX1002, ¶65.
`
`Tavtigian teaches the complete coding sequence and exonic structure of the
`
`BRCA2 gene and identifies the sequence as being publically available under
`
`GenBank Accession No. U43746, which is the accession number referenced in the
`
`'379 patent. GDX1001, 2:1:26-28; GDX1026, 1:1; GDX1027, 1; GDX1002, ¶54.
`
`Nucleotide numbe