Patenting Human Genes and Genetic Tests: Recent Developments

Patenting Human Genes Patenting Human Genes and Genetic Tests:and Genetic Tests:

Recent DevelopmentsRecent DevelopmentsNational Advisory Council on Human National Advisory Council on Human

Genome ResearchGenome Research

May 17, 2010May 17, 2010

Jorge L. ContrerasJorge L. ContrerasWashington University in St. LouisWashington University in St. Louis

School of LawSchool of LawPilar N. OssorioPilar N. Ossorio

University of WisconsinUniversity of Wisconsin

Requirements for PatentabilityRequirements for Patentability

Patentable subject matter Patentable subject matter (§101)(§101)

Utility (§101, 112)Utility (§101, 112)

Novelty (§102)Novelty (§102)

Non-obviousness (§103)Non-obviousness (§103)

TopicsTopics Patentable subject matterPatentable subject matter

Association for Molecular Pathology v. USPTOAssociation for Molecular Pathology v. USPTO

(a/k/a (a/k/a ACLU v. MyriadACLU v. Myriad) (S.D.N.Y. Mar. 2010)) (S.D.N.Y. Mar. 2010)

UtilityUtility Eli Lilly v. Human Genome SciencesEli Lilly v. Human Genome Sciences (UK Ct. (UK Ct. Appeal, Feb. 2010)Appeal, Feb. 2010)

Non-obviousnessNon-obviousness KSR v. Teleflex, US Supreme Ct. (2007)KSR v. Teleflex, US Supreme Ct. (2007) In re Kubin, Fed. Cir. (2009)In re Kubin, Fed. Cir. (2009)

SACGHS SACGHS Report on Gene Patents Report on Gene Patents (Feb. (Feb. 2010)2010)

Patent LawPatent Law

The intellectual property right The intellectual property right is defined by a is defined by a claimclaim. Claims . Claims come at the end of a narrative come at the end of a narrative description of the invention and description of the invention and the problem the invention is the problem the invention is intended to solve. E.g.,intended to solve. E.g.,• I claim an isolated nucleic acid I claim an isolated nucleic acid molecule comprising a polypeptide molecule comprising a polypeptide at least 80% identical to amino at least 80% identical to amino acids 22 - 221 of SEQ ID No. 2, acids 22 - 221 of SEQ ID No. 2, wherein the polypeptide binds CD48.wherein the polypeptide binds CD48.

Patent LitigationPatent Litigation

Patent Office Determination Trial in District Court

Court of Appeals for the Federal Circuit (CAFC)

United States Supreme Court

Patentable Subject MatterPatentable Subject Matter

Patentable Subject MatterPatentable Subject Matter

35 USC §10135 USC §101: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.

Association for Molecular Association for Molecular Pathology v. USPTOPathology v. USPTO (S.D.N.Y. Mar. 2010)(S.D.N.Y. Mar. 2010)

BRCA1 and Myriad Background BRCA1 and Myriad Background Early 1980s: various groups (incl. Collins) Early 1980s: various groups (incl. Collins) begin to seek DNA sequences associated with begin to seek DNA sequences associated with breast cancerbreast cancer

1988/89: Intl. Breast Cancer Linkage 1988/89: Intl. Breast Cancer Linkage Consortium establishedConsortium established

1990: Mary-Claire King (Berkeley) linkage 1990: Mary-Claire King (Berkeley) linkage analysis paper locating BRCA1 on long arm analysis paper locating BRCA1 on long arm of chromosome 17of chromosome 17

1991: Mark Skolnick (w/ W. Gilbert and P. 1991: Mark Skolnick (w/ W. Gilbert and P. Meldrum) founds Myriad to search for breast Meldrum) founds Myriad to search for breast cancer genescancer genes• Funding: VC, Lilly, NIH ($5M to Univ. UT)Funding: VC, Lilly, NIH ($5M to Univ. UT)

Aug. 1994: Myriad (w/ NIEHS, Univ. UT, Aug. 1994: Myriad (w/ NIEHS, Univ. UT, McGill & Lilly) clones BRCA1McGill & Lilly) clones BRCA1• Myriad files patent application on BRCA1Myriad files patent application on BRCA1

BRCA2 and MyriadBRCA2 and Myriad Sept. 1994: BRCA2 localized through Sept. 1994: BRCA2 localized through linkage analysis to chromosome 13linkage analysis to chromosome 13

1995: BRCA2 race between Myriad and 1995: BRCA2 race between Myriad and UK team (Michael Stratton at ICR and UK team (Michael Stratton at ICR and Sanger)Sanger)

Dec. 18, 1995: Myriad files US patent Dec. 18, 1995: Myriad files US patent on BRCA2 on BRCA2

Dec. 22, 1995: Stratton announces Dec. 22, 1995: Stratton announces sequencing of BRCA2 and files UK sequencing of BRCA2 and files UK patentpatent

Dec. 23, 1995: Stratton BRCA2 paper Dec. 23, 1995: Stratton BRCA2 paper appears in appears in Nature; Nature; Myriad releases Myriad releases sequence to GenBanksequence to GenBank

Myriad Patent TimelineMyriad Patent Timeline Oct 1991: Univ. UT grants Myriad Oct 1991: Univ. UT grants Myriad exclusive license to BRCA1exclusive license to BRCA1

Aug. 1994: Myriad files BRCA1 Aug. 1994: Myriad files BRCA1 applicationapplication

Nov. 1994: Univ. UT grants Myriad Nov. 1994: Univ. UT grants Myriad exclusive license to BRCA2exclusive license to BRCA2

Dec. 1995: Myriad files BRCA2 Dec. 1995: Myriad files BRCA2 applicationapplication

Dec. 1997: first BRCA1 patent issuesDec. 1997: first BRCA1 patent issues Nov. 1998: first BRCA2 patent issuesNov. 1998: first BRCA2 patent issues

Competing RightsCompeting Rights

NIHNIH• Initial Myriad BRCA1 application omitted Initial Myriad BRCA1 application omitted NIH inventors Wiseman, FutrealNIH inventors Wiseman, Futreal

• 1994: NIH settles dispute with Myriad/Utah 1994: NIH settles dispute with Myriad/Utah and grants Utah exclusive license under and grants Utah exclusive license under BRCA1 rightsBRCA1 rights

OncormedOncormed• 1997: Oncormed sues Myriad 1997: Oncormed sues Myriad

infringement of 1996 consensus wild-type BRCA1 infringement of 1996 consensus wild-type BRCA1 sequence (NIH)sequence (NIH)

incorrect inventorship of 2 Myriad patentsincorrect inventorship of 2 Myriad patents

• 1998: Myriad settles with Oncormed and 1998: Myriad settles with Oncormed and obtains Oncormed patentsobtains Oncormed patents

BRCA1/2 Testing/EnforcementBRCA1/2 Testing/Enforcement 1996: Myriad begins to offer BRCA1/2 1996: Myriad begins to offer BRCA1/2 screening; U. Penn screens 500 screening; U. Penn screens 500 patients/yearpatients/year

1998: Myriad sues U. Penn for patent 1998: Myriad sues U. Penn for patent infringement; Penn ceases testinginfringement; Penn ceases testing

1999: Myriad requests Georgetown to 1999: Myriad requests Georgetown to stop testing for NCI’s Cancer stop testing for NCI’s Cancer Genetics Network Project (CGNP)Genetics Network Project (CGNP)

2000: Myriad cease and desist to Yale2000: Myriad cease and desist to Yale Today: Myriad is the only U.S. Today: Myriad is the only U.S. provider of commercial BRCA1/2 provider of commercial BRCA1/2 screeningscreening• Myriad permits research, but without Myriad permits research, but without provision of results to patientsprovision of results to patients

Alleged Effects of Myriad’s Gene Alleged Effects of Myriad’s Gene PatentsPatents

Pricing ($3200/test) places testing Pricing ($3200/test) places testing beyond financial means of many patientsbeyond financial means of many patients

Inability for patients to get Inability for patients to get confirmatory testing from second labconfirmatory testing from second lab

Myriad testing is not state-of-the-artMyriad testing is not state-of-the-art Researchers cannot tell patients Researchers cannot tell patients results of testing, conflicting with results of testing, conflicting with ethical obligationsethical obligations

General chilling effect on research General chilling effect on research into genetic testsinto genetic tests

Interference with ability to Interference with ability to investigate complex multi-gene diseasesinvestigate complex multi-gene diseases

The LitigationThe Litigation

On May 12, 2009, a group of On May 12, 2009, a group of plaintiffs represented by the plaintiffs represented by the American Civil Liberties Union American Civil Liberties Union (ACLU) sued Myriad, the Univ. (ACLU) sued Myriad, the Univ. of Utah and the USPTO to of Utah and the USPTO to invalidate 15 claims of 7 invalidate 15 claims of 7 Myriad BRCA1/2 patentsMyriad BRCA1/2 patents

The Litigation: PlaintiffsThe Litigation: Plaintiffs Counsel: ACLU and Public Patent Counsel: ACLU and Public Patent Foundation at Cardozo School of LawFoundation at Cardozo School of Law

Plaintiffs:Plaintiffs:• AssociationsAssociations – Assn. for Molecular – Assn. for Molecular Pathology (AMP), Am. Coll. Of Medical Pathology (AMP), Am. Coll. Of Medical Genetics (AMCG), Am. Soc. For Clin. Genetics (AMCG), Am. Soc. For Clin. Pathology (ASCP), Coll. Of Am. Pathologists Pathology (ASCP), Coll. Of Am. Pathologists (CAP)(CAP)

• ResearchersResearchers – Kazazian, Ganguly (Penn), – Kazazian, Ganguly (Penn), Chung (Columbia), Ostrer, Reich (NYU), Chung (Columbia), Ostrer, Reich (NYU), Ledbetter, Warren (Emory), Matloff (Yale)Ledbetter, Warren (Emory), Matloff (Yale)

• Advocacy GroupsAdvocacy Groups – Breast Cancer Action – Breast Cancer Action (BCA), Our Bodies Ourselves(BCA), Our Bodies Ourselves

• PatientsPatients – Ceriani, Limary, Girard, – Ceriani, Limary, Girard, Fortune, Thomason, RakerFortune, Thomason, Raker

The PatentsThe Patents

7 patents (5 BRCA1, 2 BRCA2)7 patents (5 BRCA1, 2 BRCA2) 15 claims15 claims

• Composition of Matter claimsComposition of Matter claims• Method/Process claimsMethod/Process claims

Terms extend from 2015-2018Terms extend from 2015-2018 Myriad holds 16 other BRCA1/2 Myriad holds 16 other BRCA1/2 patents not in suit (expiring patents not in suit (expiring 2023)2023)

Composition of Matter ClaimsComposition of Matter Claims

““An An isolatedisolated DNA coding for a DNA coding for a BRCA1 polypeptide, said BRCA1 polypeptide, said polypeptide having the amino acid polypeptide having the amino acid sequence set forth in SEQ ID sequence set forth in SEQ ID NO:2” (‘282, cl.1)NO:2” (‘282, cl.1)• ““[Cl. 1]… wherein said DNA has the [Cl. 1]… wherein said DNA has the nucleotide sequence set forth in SEQ nucleotide sequence set forth in SEQ ID NO:1” (‘282, cl. 2)ID NO:1” (‘282, cl. 2)

• ““An isolated DNA having at least 15 An isolated DNA having at least 15 of the nucleotides of the DNA of of the nucleotides of the DNA of claim 1/2” (‘282, cl. 5/6)claim 1/2” (‘282, cl. 5/6)

Patentable Subject Matter:Patentable Subject Matter:Laws of NatureLaws of Nature

““The qualities of these bacteria, like the The qualities of these bacteria, like the heat of the sun, electricity, or the heat of the sun, electricity, or the qualities of metals, are part of the qualities of metals, are part of the storehouse of knowledge of all men. They are storehouse of knowledge of all men. They are manifestations of manifestations of laws of naturelaws of nature, free to all , free to all men and reserved exclusively to none. He who men and reserved exclusively to none. He who discovers a hitherto unknown phenomenon of discovers a hitherto unknown phenomenon of nature has no claim to a monopoly of it which nature has no claim to a monopoly of it which the law recognizes” (the law recognizes” (Funk Bros. Seed Co. Funk Bros. Seed Co. V .Kalo Inoculant CoV .Kalo Inoculant Co. (US 1948). (US 1948)

““Phenomena of naturePhenomena of nature, though just discovered, , though just discovered, mental processes, and abstract intellectual mental processes, and abstract intellectual concepts are not patentable, as they are the concepts are not patentable, as they are the basic tools of scientific and technological basic tools of scientific and technological work.” work.” Gottschalk v. BensonGottschalk v. Benson (US 1972) (US 1972)

Do Myriad’s Composition Patents Do Myriad’s Composition Patents Cover “Products of Nature”?Cover “Products of Nature”?

Myriad’s argumentsMyriad’s arguments• USPTO Utility Examination USPTO Utility Examination Guidelines expressly allow Guidelines expressly allow patenting of isolated genetic patenting of isolated genetic materialmaterial

• Patents claim Patents claim isolatedisolated DNA, which DNA, which does not occur in naturedoes not occur in nature

What is not a Product of Nature?What is not a Product of Nature? To be patentable, a composition must To be patentable, a composition must have “markedly different have “markedly different characteristics” from any occurring characteristics” from any occurring in nature. (in nature. (Diamond v. ChakrabartyDiamond v. Chakrabarty (US 1980))(US 1980))

Mere “purification” of a natural Mere “purification” of a natural compound does not render it compound does not render it patentable. (patentable. (Am Wood-Paper Co. v. Am Wood-Paper Co. v. Fibre Disintegrating CoFibre Disintegrating Co. (US 1874). (US 1874)• Discredits Learned Hand’s 1911 holding in Discredits Learned Hand’s 1911 holding in Parke-Davis v. MulfordParke-Davis v. Mulford, that isolated and , that isolated and purified adrenaline is patentablepurified adrenaline is patentable

Myriad’s Product of Nature Myriad’s Product of Nature ArgumentsArguments

M: Isolated DNA has different M: Isolated DNA has different structural and chemicalstructural and chemical properties properties (chromatin, introns, methylation) than (chromatin, introns, methylation) than native DNAnative DNA• Court: “In light of DNA’s unique qualities Court: “In light of DNA’s unique qualities as a physical embodiment of information, as a physical embodiment of information, none of the structural and functional none of the structural and functional differences cited by Myriad … render the differences cited by Myriad … render the claimed DNA ‘markedly different’.”claimed DNA ‘markedly different’.”

M: Isolated DNA has functional utility M: Isolated DNA has functional utility in probes and primers that native DNA in probes and primers that native DNA does not.does not.• Court: usefulness of isolated DNA in Court: usefulness of isolated DNA in probes/primers exists only because of the probes/primers exists only because of the identity of nucleotide sequence between identity of nucleotide sequence between isolated and native DNA.isolated and native DNA.

Myriad’s Product of Nature Myriad’s Product of Nature Arguments, cont.Arguments, cont.

M: Invention required M: Invention required identification of genes plus identification of genes plus isolation of sequences away from isolation of sequences away from other DNA and cellular materialother DNA and cellular material• Court: Discovery is of the Court: Discovery is of the “handiwork of nature” and not “handiwork of nature” and not patentable;patentable;

Isolation was “simply the Isolation was “simply the application of techniques well-application of techniques well-known to those skilled in the art”known to those skilled in the art”

Holding: Myriad’s BRCA Composition Holding: Myriad’s BRCA Composition of Matter Claims Invalidof Matter Claims Invalid

““Because the claimed isolated Because the claimed isolated DNA is not markedly different DNA is not markedly different from native DNA as it exists in from native DNA as it exists in nature, it constitutes nature, it constitutes unpatentable subject matter …”unpatentable subject matter …”

Claims are thus invalid.Claims are thus invalid.

Method ClaimsMethod Claims

A method for detecting a germline A method for detecting a germline alteration in a BRCA1 gene, said alteration in a BRCA1 gene, said alteration selected from a group alteration selected from a group consisting of the alterations set forth consisting of the alterations set forth in Tables … in a human which comprises in Tables … in a human which comprises analyzinganalyzing a sequence of a BRCA1 gene or a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or BRCA1 RNA from a human sample or analyzinganalyzing a sequence of BRCA1 cDNA made a sequence of BRCA1 cDNA made from mRNA from said human sample with the from mRNA from said human sample with the proviso that said germline alteration is proviso that said germline alteration is not a deletion of 4 nucleotides not a deletion of 4 nucleotides corresponding to base numbers … (‘999, corresponding to base numbers … (‘999, cl. 1)cl. 1)

Method Claims: Unpatentable Method Claims: Unpatentable Subject MatterSubject Matter

““Phenomena of nature, though just Phenomena of nature, though just discovered, discovered, mental processesmental processes, and , and abstract intellectual concepts are abstract intellectual concepts are not patentable, as they are the not patentable, as they are the basic tools of scientific and basic tools of scientific and technological work.” technological work.” Gottschalk v. Gottschalk v. BensonBenson (US 1972) (US 1972)

A claimed process may be patentable A claimed process may be patentable if it “if it “transformstransforms a particular a particular article into a different state or article into a different state or thing” (thing” (In re. BilskiIn re. Bilski (Fed. Cir. (Fed. Cir. en en bancbanc 2008, 2008, cert. granted cert. granted 2009)2009)

Myriad’s Methods Not Myriad’s Methods Not TransformativeTransformative

Simply “analyzing” and “comparing” Simply “analyzing” and “comparing” DNA sequences is an abstract mental DNA sequences is an abstract mental processprocess

The preparatory The preparatory isolation/purification steps are isolation/purification steps are not part of these claimsnot part of these claims

Any “transformations” associated Any “transformations” associated with isolating and sequencing DNA with isolating and sequencing DNA are mere data gathering steps that are mere data gathering steps that are not central to patentability.are not central to patentability.

Holding: method claims are invalidHolding: method claims are invalid

OutcomeOutcome

All 15 of Myriad’s claims-in-suit are All 15 of Myriad’s claims-in-suit are invalidinvalid

Myriad has announced plans to appeal Myriad has announced plans to appeal to the Federal Circuitto the Federal Circuit

At least some justices of the Supreme At least some justices of the Supreme Court (Breyer) have indicated an Court (Breyer) have indicated an interested in patentability issuesinterested in patentability issues

2-4 more years before a final 2-4 more years before a final resolutionresolution

Myriad’s European PatentsMyriad’s European Patents 1998: EPO allows patenting of genes (Council 1998: EPO allows patenting of genes (Council Dir. 98/44)Dir. 98/44)

2001: Myriad’s European patents on BRCA1 2001: Myriad’s European patents on BRCA1 grantedgranted

2002: Institut Curie and other oppose Myriad 2002: Institut Curie and other oppose Myriad patentspatents

Feb. 2004: Cancer Res. UK gets patent on BRCA2Feb. 2004: Cancer Res. UK gets patent on BRCA2 May 2004: EPO revokes first Myriad BRCA1 patentMay 2004: EPO revokes first Myriad BRCA1 patent Jan. 2005: EPO limits claims of 2 remaining Jan. 2005: EPO limits claims of 2 remaining Myriad BRCA1 patentsMyriad BRCA1 patents

Jan. 2005: Myriad gets European patent covering Jan. 2005: Myriad gets European patent covering BRCA2 test for Ashkenazi-Jewish womenBRCA2 test for Ashkenazi-Jewish women

Nov. 2008: EPO limits BRCA1 patent to BRCA1 Nov. 2008: EPO limits BRCA1 patent to BRCA1 frameshift mutations only (not full BRCA1 gene)frameshift mutations only (not full BRCA1 gene)

UtilityUtility

Utility in the U.S.Utility in the U.S.

35 USC §10135 USC §101: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain

a patent therefor...

35 USC §112: §112: The specification shall contain The specification shall contain a written description of the invention, and of the a written description of the invention, and of the manner and process of making and using it…manner and process of making and using it…

Eli Lilly v. Human Genome Eli Lilly v. Human Genome Sciences Sciences (UK Ct. Appeal, (UK Ct. Appeal,

Feb. 2010)Feb. 2010)

HGS’s HGS’s neutrokine-aneutrokine-a Patent Patent

1996: HGS patents sequence for 1996: HGS patents sequence for neutrokine-aneutrokine-a, a protein identified , a protein identified using bioinformatics techniquesusing bioinformatics techniques• Function is unknown, so a list of Function is unknown, so a list of potential uses including therapies for potential uses including therapies for solid tumors, schistosomiasis, and solid tumors, schistosomiasis, and other parasitic diseases is listedother parasitic diseases is listed

Eli Lilly, also developing Eli Lilly, also developing neotrokine-a antibodies, challenges neotrokine-a antibodies, challenges patentpatent

Industrial Application TestIndustrial Application Test

Comparable to U.S. specific and Comparable to U.S. specific and substantial utility testsubstantial utility test

Patent description must disclose a Patent description must disclose a practical way of exploiting the practical way of exploiting the invention in at least one field of invention in at least one field of industrial activityindustrial activity

Requirement is not satisfied by Requirement is not satisfied by claiming an interesting research result claiming an interesting research result without specified applicationwithout specified application

Speculative indication of possible Speculative indication of possible objectives not sufficientobjectives not sufficient

Challenges to PatentChallenges to Patent

Jul 2008: UK Patent Court Jul 2008: UK Patent Court strikes down patentstrikes down patent

2009: EPO Technical Board of 2009: EPO Technical Board of Appeals upholds patentAppeals upholds patent

Feb. 2010: UK Court of Appeal Feb. 2010: UK Court of Appeal strikes down patentstrikes down patent

Possible appeal to UK Supreme Possible appeal to UK Supreme CourtCourt

NOTE: UK decisions not binding NOTE: UK decisions not binding in other EU statesin other EU states

Non-obviousnessNon-obviousness

Non-obviousnessNon-obviousness A patent may not be obtained… if the

differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.

Biotech Non-obviousnessBiotech Non-obviousness

1990s to 2007: 1990s to 2007: • Many scholars and firms believed that the Many scholars and firms believed that the court of national jurisdiction for patent court of national jurisdiction for patent appeals (CAFC) had developed the law in appeals (CAFC) had developed the law in such a way that the non-obviousness such a way that the non-obviousness requirement was too lenient.requirement was too lenient.

• Other requirements of the patent law are Other requirements of the patent law are being applied so as only to uphold being applied so as only to uphold relatively narrow claims to DNA or protein relatively narrow claims to DNA or protein sequences (§ 112 requirements).sequences (§ 112 requirements).

The upshot: many DNA patents, none of The upshot: many DNA patents, none of which are worth much. Patent thicket?which are worth much. Patent thicket?

Biotech Non-obviousnessBiotech Non-obviousness

In re. Bell, 991 F. 2d 781 In re. Bell, 991 F. 2d 781 (CAFC 1993)(CAFC 1993)• DNA seq and cDNA seq for DNA seq and cDNA seq for Insulin-like Growth Factor 1 Insulin-like Growth Factor 1 and 2 (IGF1 & 2) are not and 2 (IGF1 & 2) are not obvious in light of the obvious in light of the completecomplete protein sequences for protein sequences for each and a well-known method each and a well-known method for cloning the DNA.for cloning the DNA.

• CAFC: Not obvious!CAFC: Not obvious!

Biotech Non-obviousnessBiotech Non-obviousness In re Deuel, 51 F. 3d 1552 In re Deuel, 51 F. 3d 1552 (Fed. Cir. 1995)(Fed. Cir. 1995)• Claim for DNA seq and cDNA seq for Claim for DNA seq and cDNA seq for heparin binding growth factor (HBGF) heparin binding growth factor (HBGF) not obvious over method of cloning, not obvious over method of cloning, and a partial protein seq (amino and a partial protein seq (amino terminus.terminus.

PTO argued that when a protein sequence PTO argued that when a protein sequence or part of it was put into the public or part of it was put into the public domain, then so was the DNA sequence domain, then so was the DNA sequence because a person of ordinary skill in the because a person of ordinary skill in the art would be motivated to clone the gene art would be motivated to clone the gene and would know how to do it. and would know how to do it. CAFC CAFC disagreeddisagreed!!

Biotech Non-obviousnessBiotech Non-obviousness Protein seq plus a method of cloning Protein seq plus a method of cloning the gene does not make DNA seq obvious the gene does not make DNA seq obvious because:because:

The relationship between DNA seq and protein seq The relationship between DNA seq and protein seq through the genetic code does not establish a through the genetic code does not establish a prima facie case of obviousness.prima facie case of obviousness.• Redundancy of the genetic code precludes a scientist Redundancy of the genetic code precludes a scientist from formulating an idea of the exact DNA sequence from formulating an idea of the exact DNA sequence just by knowing a protein sequence.just by knowing a protein sequence.

No structural similarity between nucleotides and No structural similarity between nucleotides and amino acids amino acids there is no structurally similar there is no structurally similar compound in the prior art for somebody to modify compound in the prior art for somebody to modify to create the specific, structurally defined DNA to create the specific, structurally defined DNA molecule. molecule.

It is not enough that the general idea of the It is not enough that the general idea of the claimed molecule exists in scientists minds.claimed molecule exists in scientists minds.

Biotech Non-obviousnessBiotech Non-obviousness

From Deuel and Bell: From Deuel and Bell: The existence of a method of cloning is The existence of a method of cloning is “essentially irrelevant” in the absence “essentially irrelevant” in the absence of information in the field suggesting of information in the field suggesting the exact structure of the DNA molecule the exact structure of the DNA molecule (including every base in each codon).(including every base in each codon).

““A general incentive does not make A general incentive does not make obvious a particular result” and obvious a particular result” and ““obvious to try has long been held not obvious to try has long been held not to constitute obviousnessto constitute obviousness.” Deuel at .” Deuel at 1559. 1559.

Biotech non-obviousnessBiotech non-obviousness

Biology as an unpredictable artBiology as an unpredictable art• Analogy to small molecule chemistry Analogy to small molecule chemistry in which a very small change in the in which a very small change in the molecule can substantially alter its molecule can substantially alter its properties.properties.

Contrast to the “predictable arts,” e.g. Contrast to the “predictable arts,” e.g. mechanical and electrical artsmechanical and electrical arts

• DNA is just another chemical, and we DNA is just another chemical, and we have a chemistry jurisprudence have a chemistry jurisprudence already.already.

KSR International Co. KSR International Co.

v. Teleflex Inc., v. Teleflex Inc., 127 S.Ct. 1727 (2007)127 S.Ct. 1727 (2007)

Facts and Case HistoryFacts and Case History

• Teleflex holds an exclusive license Teleflex holds an exclusive license to pt for an adjustable pedal assembly.to pt for an adjustable pedal assembly.

Teleflex sues KSR for infringing claim Teleflex sues KSR for infringing claim 4 of its patent.4 of its patent.

Claim for combining an electronic sensor Claim for combining an electronic sensor with an adjustable automobile pedal so that with an adjustable automobile pedal so that the pedal’s position could be transmitted to the pedal’s position could be transmitted to a computer that controls the automobile’s a computer that controls the automobile’s throttle.throttle.

• Supreme Ct. held that the trial court Supreme Ct. held that the trial court correctly applied the law when it found correctly applied the law when it found

this invention obvious.this invention obvious.

Predictability & Non-obviousnessPredictability & Non-obviousness

After KSR, role of predictability in After KSR, role of predictability in assessing obviousness: assessing obviousness: • An invention is obvious if…An invention is obvious if…

It is a combination of familiar elementsIt is a combination of familiar elements According to known methodsAccording to known methods That does no more than yield predictable That does no more than yield predictable results.results.

• An invention is obvious if…An invention is obvious if… It claims a structure already known in the It claims a structure already known in the field field and does no more than and does no more than

Substitute one material or element for Substitute one material or element for another another known in the fieldknown in the field

And produces a predictable result. And produces a predictable result.

Biotech Non-obviousnessBiotech Non-obviousness

Obvious to try test after KSR? Obvious to try test after KSR? • Obvious to try +Obvious to try +• Motivation to try from design need or Motivation to try from design need or market pressure (or regulatory market pressure (or regulatory pressure, or ???) +pressure, or ???) +

• Finite number of identified, Finite number of identified, predictable solutionspredictable solutions + +

• Likelihood of success.Likelihood of success.

If all of the above apply, then the If all of the above apply, then the invention was obvious. Repudiates invention was obvious. Repudiates Deuel’s formulation of the obvious-Deuel’s formulation of the obvious-to-try doctrine.to-try doctrine.

In re Kubin,In re Kubin, 561 F. 3rd 1561 (Fed Cir 2009)561 F. 3rd 1561 (Fed Cir 2009)

KubinKubin Claim for isolated DNA encoding a Claim for isolated DNA encoding a protein at least 80% identical to protein at least 80% identical to 199 amino acids of the NAIL protein 199 amino acids of the NAIL protein (natural killer cell activation (natural killer cell activation inducing ligand, aka P38), “wherein inducing ligand, aka P38), “wherein the polypeptide binds CD48.”the polypeptide binds CD48.”

Protein had previously been reported, there Protein had previously been reported, there was a commercially available MAb to was a commercially available MAb to NAIL/p38, NAIL/p38, a mouse ortholog had been cloned and had a mouse ortholog had been cloned and had bound to human DNA.bound to human DNA.

Previous patent disclosed p38 receptor/NAIL Previous patent disclosed p38 receptor/NAIL protein and protein and gave explicit instructions on gave explicit instructions on how how to clone the cDNAto clone the cDNA. .

KubinKubin The CAFC upheld the Patent Office’s The CAFC upheld the Patent Office’s finding that the Kubin’s NAIL gene finding that the Kubin’s NAIL gene sequences were obvious.sequences were obvious.

Here, the prior patent and lab manual taught the Here, the prior patent and lab manual taught the existence of the protein, provided motivation to existence of the protein, provided motivation to clone the gene, and provided a step-by-step method clone the gene, and provided a step-by-step method for cloning this particular gene for cloning this particular gene • The prior art provided explicit motivation for The prior art provided explicit motivation for somebody to try cloning the NAIL gene, and a “person somebody to try cloning the NAIL gene, and a “person of ordinary skill in the art” would have had a of ordinary skill in the art” would have had a reasonable expectation of successreasonable expectation of success in doing so given in doing so given what was disclosed in the prior art.what was disclosed in the prior art.

• A person of “skill in this advanced art would find A person of “skill in this advanced art would find these claimed ‘results’ profoundly ‘predictable.’” p. these claimed ‘results’ profoundly ‘predictable.’” p. 1360.1360.

• Granting patent protection to advances that would Granting patent protection to advances that would have occurred in the ordinary course of activities in have occurred in the ordinary course of activities in the field retards innovation rather than advancing the field retards innovation rather than advancing it. it.

Biotech Non-obviousnessBiotech Non-obviousness In the future, it will be at least In the future, it will be at least somewhat more difficult for somewhat more difficult for researchers to obtain patent researchers to obtain patent protection for DNA sequences. protection for DNA sequences. • It remains to be seen how broadly the It remains to be seen how broadly the “obvious to try” doctrine will be applied. “obvious to try” doctrine will be applied.

Will it apply to a DNA sequence when nothing Will it apply to a DNA sequence when nothing about the protein was previously known?about the protein was previously known?

Will it apply to a DNA sequence when there was no Will it apply to a DNA sequence when there was no explicit discussion in the literature of how to explicit discussion in the literature of how to clone that exact protein?clone that exact protein?

At least some existing DNA sequence At least some existing DNA sequence claims likely will be held invalid claims likely will be held invalid under the Kubin standard.under the Kubin standard.

Biotech Non-obviousnessBiotech Non-obviousness

CAFC may be giving up its view CAFC may be giving up its view that for a DNA seq to be that for a DNA seq to be obvious one needs to be able to obvious one needs to be able to predict exactly which predict exactly which nucleotides will be in the nucleotides will be in the sequence!sequence!

SACHGS Report on Gene Patents SACHGS Report on Gene Patents and Licensing (Feb. 2010)and Licensing (Feb. 2010)

Scope of SACGHS ReportScope of SACGHS Report Review of clinical impact of gene Review of clinical impact of gene patents and licensing practices on patents and licensing practices on access to genetic testingaccess to genetic testing

Case studiesCase studies• Breast, ovarian and colon cancerBreast, ovarian and colon cancer• Alzheimer’s DiseaseAlzheimer’s Disease• Cystic FibrosisCystic Fibrosis• Hearing LossHearing Loss• HemochromatosisHemochromatosis• Long QT SyndromeLong QT Syndrome• Spinocerebellar AtaxiaSpinocerebellar Ataxia• Tay-Sachs and Canavan DiseaseTay-Sachs and Canavan Disease

SACGHS RecommendationsSACGHS Recommendations

Exemption from infringement of gene Exemption from infringement of gene patents for patient care and patents for patient care and researchresearch

RequireRequire non-exclusive licensing of non-exclusive licensing of diagnostic genetic technologiesdiagnostic genetic technologies

Ensure that clinically useful Ensure that clinically useful genetic tests are equitably genetic tests are equitably available and accessible to patientsavailable and accessible to patients