Patent Eligibility Under Attack Lab Corp., Myriad, Classen & Prometheus: The New World in U.S. Biotech? Mercedes K. Meyer, Ph.D. March 5, 2013

Disclaimer These materials are public information and have been prepared solely for educational and entertainment purposes to contribute to the understanding of U.S. intellectual property law and practice. These materials reflect only the personal views of the speaker and are not individualized legal advice. It is understood that each case is fact-specific, and that the appropriate solution in any case will vary. Therefore, these materials may or may not be relevant to any particular situation. Thus, Drinker Biddle & Reath LLP and the speaker cannot be bound either philosophically or as representatives of their various present and future clients to the comments expressed in these materials. The presentation of these materials does not establish any form of attorney-client relationship with Drinker Biddle & Reath LLP and the speaker. While every attempt was made to insure that these materials are accurate, errors or omissions may be contained therein, for which any liability is disclaimed. 2

3 Where do we stand? Method claims – Lab Corp., Classen, Prometheus & Myriad Personalized medicine Have Akamai & McKesson helped? Composition claims - Gene claims under fire Gene Claims – Myth v. Fact Politics & Health Care in the U.S.

35 USC 101 § 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. The Exceptions to Eligibility: Law of nature (naturally occurring correlates) MPEP § Algorithm Abstract idea AIA § 33 (a). Notwithstanding any other provision or law, no patent may issue on a claim directed to or encompassing a human organism See also MPEP § 2105 and 1077 Off. Gaz. Pat. Off 24 (1987) – multicellular organisms including animals are patent eligible. 4

Treatment Method Claims Status Check

6 We saw it coming - Lab Corp. Lab Corp.. v. Metabolite Laboratories, Inc., 548 U.S. 124 (2006) Certiorari was dismissed as improvidently granted. Claim 13 (still valid): A method for detecting a deficiency of cobalamin or folate in warm-blooded animals comprising the steps of: assaying a body fluid for an elevated level of total homocysteine; and correlating an elevated level of total homocysteine in said body fluid with a deficiency of cobalamin or folate.

Personalized Medicine Obtain biological sample. Measure biomarker with diagnostic. Metabolites, single & multiple biomarkers, genes, alleles, polymorphisms Correlate biomarker with therapy. Administer therapy. The problem was that no therapy had to be administered in the Prometheus claims. THE DIVIDING LINE 7

Stakeholders & Innovations Ziagen (GSK, Infectious disease) Epito / Tegreto (Novartis, Neuropsychiatric disease) Erbitux (BMS, Cancer) Herceptin (Genentech, Cancer) Tasigna (Novartis, Cancer) Sprycel (BMS, Cancer) Tarceva (Genentech, Cancer) Trisenox (Cephalon, cancer) Vectibex (Amgen, Cancer) Tyverg (GSK, Cancer) Iressa (Astra Zeneca / Teva, Cancer) 8

Prometheus – Claim 1 USPN 6,355, A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising: (a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and (b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder, wherein the level of 6-thioguanine less than about 230 pmol per 8x10 8 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and wherein the level of 6-thioguanine greater than about 400 pmol per 8x10 8 red blood cells indicates a need to decrease the amount of said drug subsequently ad ministered to said subject. INELIGIBLE SUBJECT MATTER 9

Prometheus – Claim 1 USPN 6,680, A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising: (a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and (b) determining a level of 6-thioguanine or 6-methyl- mercaptopurine in said subject having said immune-mediated gastrointestinal disorder, wherein a level of 6-thioguanine less than about 230 pmol per 8x10 8 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and wherein a level of 6-thioguanine greater than about 400 pmol per 8x10 8 red blood cells or a level of 6-methyl-mercaptopurine greater than about 7000 pmol per 8x10 8 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject. INELIGIBLE SUBJECT MATTER 10

Rewriting Claim 1 from the 623 Patent Perhaps a patentable alternative? A method of administering 6-thiopurine to a patient in need thereof for treating an immune-mediated gastrointestinal disorder, comprising the step of administering a therapeutically effective amount of the drug that produces a level of 6-thiopurine no less than 230 pmol and no more than 400 pmol per 8x10 8 red blood cells in blood from the patient. 11

A Look Back to Classen Classen Immunotherapies Inc. v. Biogen IDEC (2011): Remanded from the Supreme Court in light of Bilski. 2 of 3 claims were found patent eligible. 12

USPN 6,638,739 – Classen Immunization Schedule = Patent Eligible 1. A method of immunizing a mammalian subject which comprises: (I) screening a plurality of immunization schedules, by (a) identifying a first group of mammals and at least a second group of mammals, said mammals being of the same species, the first group of mammals having been immunized with one or more doses of one or more infectious disease-causing organism-associated immunogens according to a first screened immunization schedule, and the second group of mammals having been immunized with one or more doses of one or more infectious disease-causing organism-associated immunogens according to a second screened immunization schedule, each group of mammals having been immunized according to a different immunization schedule, and (b) comparing the effectiveness of said first and second screened immunization schedules in protecting against or inducing a chronic immune- mediated disorder in said first and second groups, as a result of which one of said screened immunization schedules may be identified as a lower risk screened immunization schedule and the other of said screened schedules as a higher risk screened immunization schedule with regard to the risk of developing said chronic immune mediated disorder(s), (II) immunizing said subject according to a subject immunization schedule, according to which at least one of said infectious disease- causing organism-associated immunogens of said lower risk schedule is administered in accordance with said lower risk screened immunization schedule, which administration is associated with a lower risk of development of said chronic immune- mediated disorder(s) than when said immunogen was administered according to said higher risk screened immunization schedule. 13

PTO Example – Ineligible 9/5/12 Customer Partnership Meeting 1. A method of determining the increased likelihood of having or developing rheumatoid arthritis in a patient, comprising the steps of: obtaining a serum sample from a patient; contacting the serum sample with an anti-IgM antibody; and determining that the patient has rheumatoid arthritis or an increased likelihood of developing rheumatoid arthritis based upon the increased binding of the anti- IgM antibody to IgM rheumatoid factor in the serum sample. 14

PTO Example – Why Ineligible? Inquiry 1: The claim is a process claim. Inquiry 2: The claim includes the limitation of the correlation between rheumatoid arthritis and the rheumatoid factor IgM, which is a natural principle/law of nature. Inquiry 3: All of the additional steps integrate or relate to the correlation. The additional steps of obtaining and contacting are well understood steps that are routinely conducted to analyze a serum sample. The steps are claimed at a high level of generality. Considered as a whole, the steps taken together amount to no more than recognizing the law of nature itself. 15

But, Claim 3 is eligible! 3. The method of claim 1 or 2, wherein the anti- IgM antibody is antibody XYZ. Inquiry 1: The claim is a process claim. Inquiry 2: The claim includes the limitation of the correlation between rheumatoid arthritis and the rheumatoid factor IgM, which is a natural principle/law of nature. Inquiry 3: The additional step of using a particular anti-IgM antibody (especially one that is not known in the field) integrates the law of nature as it is used to express the principle and is also sufficient to limit the application of the law of nature. The claim does not cover substantially all practical applications of the correlation between IgM and arthritis, because the claim is limited to those applications that use the antibody XYZ. Considered as a whole, the steps taken together amount to a practical application of the law of nature. 16

And finally, Myriad All of the method claims except for claim 20 of the USPN 282 were patent ineligible. 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. …at the heart of claim 20 is a transformed cell, which is made by man, in contrast to a natural material. 17

Claiming Methods – Legal Twister Avoid claims that use comparison or analysis alone. If process is to obtain data, make sure the data is applied. Transform the object. Recast claims into method of treatment claims. Write claims in a kit format if possible. When writing claims, always consider whether a single actor or multiple actors are needed to carry out the method… But what about Akamai and McKesson? 18

Akamai & McKesson Game Changer?

20 The Tension How do you write a claim that is patentable and enforceable? The origin of the claims in Prometheus and Lab Corp. was to claim the essential components of the invention that generally only require one actor in order to practice the process. 35 USC § 271 (b) for induced infringement is difficult to prove. Direct infringement under § 271 (a) is easier to prove. Claims were written for proving direct infringement. 20

Akamai & McKesson (Fed. Cir. 2012) A patent owner claiming induced infringement no longer has to show that a single actor is liable for direct infringement. IMPACT: Huge implications for method claims, medical diagnostics, medical devices, banking, telecommunications and other technologies. BUT, we are awaiting cert from the Supreme Court…..stay tuned 21 STAY TUNED

Myriad – DNA Claims

Myriad The Question: Are human genes patentable? 3 patents, 10 claims left standing Issues unaddressed: Standing Method claim 20 9 DNA claims 23

Prediction Human genes are not patentable! Oral hearing April 15, 2013 But, what are we really claiming? 24

The Problem Claim construction is not an inviolable prerequisite to a validity determination under § 101 Bancorp Services, L.L.C. v. Sun Life Assur. Co. of Canada It is evident from the Myriad CAFC en banc decision, including the dissents and separate concurring opinions, that claim construction did not occur. 25

The Science Eukaryotic Genes

The Science The RNA is spliced to form mRNA For BRCA1 and BRCA2 there are multiple splice forms BRCA1 is 110 kb and BRCA2 is 70 kb BRCA2 has 22 exons / BRCA1 has 27 Only 5,500 and 10,200 bases approximately are claimed Protein

Myriad: USPN 5,747, An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2. Gene? 2. The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1. cDNA? 5. An isolated DNA having at least 15 nucleotides of the DNA of claim 1. Fragment of a gene? 6. An isolated DNA having at least 15 nucleotides of the DNA of claim 2. Fragment of a cDNA? 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 deleted. cDNA variants? 28

Myriad: USPN 5,837, 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 in SEQ. ID. NO:1. Gene variant? 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. Gene variant? 7. The isolated DNA molecule of claim 6, wherein the DNA molecule comprises a mutated nucleotide sequence set forth in SEQ ID NO:1. cDNA variant? 29

Myriad - USPN 5,693, 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 in SEQ. ID. NO:1. Gene variant?

Some Amici Arguments Isolated & Purified USPTO §101 Guidelines (2001) DOJ Infringement of the claims? Yes or No? Whole genome sequencing Damages limitations under 282 Doctors are excused under 35 USC 282(c)(1) Moral and Ethical Considerations Are for Congress, Not the Courts Myriad's Claims Do Not Improperly Preempt The Field 31

32 Is Licensing THE Issue? Single Providers Myriad / BRCA1 & 2 Canavan Disease – Miami Childrens Hospital Multiple Providers Long QT Syndrome has two providers with separate blocking patents Hearing loss – multiple providers for patents and unpatented genes Hereditary hemochromatosis – multiple LDTs; no IP impact Alzheimers Disease Lynch Syndrome (HNPCC) Familial adenomatous polyposis (FAP) Spinocerebellar ataxia

Politics & Health Care in the U.S.

Myriad, Timing and Sec. 27 of AIA SEC. 27. STUDY ON GENETIC TESTING. (a) IN GENERAL.--The Director shall conduct a study on effective ways to provide independent, confirming genetic diagnostic test activity where gene patents and exclusive licensing for primary genetic diagnostic tests exist. (b) ITEMS INCLUDED IN STUDY.--The study shall include an examination of at least the following: (1) The impact that the current lack of independent second opinion testing has had on the ability to provide the highest level of medical care to patients and recipients of genetic diagnostic testing, and on inhibiting innovation to existing testing and diagnoses. (2) The effect that providing independent second opinion genetic diagnostic testing would have on the existing patent and license holders of an exclusive genetic test. (3) The impact that current exclusive licensing and patents on genetic testing activity has on the practice of medicine, including but not limited to: the interpretation of testing results and performance of testing procedures. (4) The role that cost and insurance coverage have on access to and provision of genetic diagnostic tests. Results 9 months after enactment – June 2012 No study results 34

Patents are not the Bogeyman Report alleged that gene patents impeded innovation and increased health care costs. Report was allegedly relied upon by the White House. Fear Mongering - Report could not provide clear evidence of any significant negative implications from patented technology. Relied on the anti-commons (patent thicket) theory of Rebecca Eisenberg, which she now admits is unsupported by facts. Report could only identify a potential for negative impact due to gene patents. J. Breyer: If I am correct in my conclusion in Part III that the patent is invalid, then… we should decide this case. To fail to do so threatens to leave the medical profession subject to the restrictions imposed by this individual patent and others of its kind. Those restrictions may…. force doctors to spend unnecessary time and energy to enter into license agreements. Lab Corp. 35

Questions? Mercedes K. Meyer, Ph.D., J.D. Drinker Biddle & Reath LLP 1500 K Street, NW Suite 1100 Washington, DC

Resources Akamai Technologies Inc. v. Limelight Networks Inc. (Fed. Cir. 2012); McKesson Technologies Inc. v. Epic Systems Corp., 692 F.3d 1301 (Fed. Cir. 2012) Assn for Mol. Path. et al. v. Myriad Genetics, Inc., 689 F.3d 1303 (Fed. Cir. 2012) Bancorp Services, L.L.C. v. Sun Life Assur. Co. of Canada, 687 F.3d 1266 (Fed. Cir. 2012) Coliainni et al., Impact of gene patents and licensing practices on access to genetic testing and carrier screening for Tay-Sachs and Canavan disease. Genet. Med. 12(4 Suppl): S5-S14 (2010) available at: HHS Draft Report on Gene Patents: df df HHS Report on Access to Medical Testing: Laboratory Corp. of America Holdings v. Metabolite Laboratories Inc., 548 U.S. 124 (2006) Classen Immunotherapies Inc. v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011) Mayo Collaborative Services v. Prometheus Laboratories, Inc., 132 S.Ct (2012) MPEP: Public Consultation Draft Report on Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests. 74 F.R Recent Examiner Training and Developments Under 35 USC §101 (Sep. 5, 2012): Smartgene Inc. v. Advanced Biological Lab., SA (D.D.C. Mar. 30, 2012) Case 1:08-cv BAH – claims found ineligible in view of Prometheus. 37

Classen Claim 1 - Ineligible 1. A method of determining whether an immunization schedule affects the incidence or severity of a chronic immune-mediated disorder in a treatment group of mammals, relative to a control group of mammals, which comprises immunizing mammals in the treatment group of mammals with one or more doses of one or more immunogens, according to said immunization schedule, and comparing the incidence, prevalence, frequency or severity of said chronic immune-mediated disorder or the level of a marker of such a disorder, in the treatment group, with that in the control group. 38