AIPLA

1. AIPLA Myriad & Prometheus The Aftermath & Future Concerns Mercedes Meyer, Ph.D.

2. I am NOTYour Lawyer • 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 this 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. • And nothing represents the views Drinker Biddle & Reath, its members, or any sentient life form on the earth or universe, or any parallel universe, alive or dead, fictitious, or real!

3. Myriad Decided • The Court asked: Are human genes patentable? ANSWER: NO cDNAs or complementary DNAs are patentable No decision on method claims in Round 2. • What do these answers mean? CONFUSION • Why? They got the science wrong Nucleotides that do not code for amino acids are introns. Slip. Op. 2 They confused the law

4. 35 USC 101 • § 101: • Whoever invents or discovers any new and usefulprocess, 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 • Algorithm • Abstract idea • AIA § 33. Notwithstanding any other provision or law, no patent may issue on a claim directed to or encompassing a human organism. • Genes

5. Myriad Claims • Claim 1 of the USPN 5,747,282: • 1. An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO: 2. • The Supreme Court found that this claim would include a gene • No claim construction performed • Term “isolated DNA” did not make it patent eligible • This was the USPTO authorized way of claiming all the DNAs that could encode the same protein • A practitioner would not have considered this to include a gene • Claim is PATENT INELIGIBLE

6. Myriad DNA ClaimsUSPN 5,747,282 • 1. An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2. • Ineligible • 2. The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1. • Patent eligible • 5. An isolated DNA having at least 15 nucleotides of the DNA of claim 1. • Ineligible • 6. An isolated DNA having at least 15 nucleotides of the DNA of claim 2. • Valid? Yes, according to Myriad! • 7. An isolated DNA selected from the group consisting of: • (a) a DNA having the nucleotide sequence set forth in SEQ ID NO:1 having T at nucleotide position 4056; • (b) a DNA having the nucleotide sequence set forth in SEQ ID NO:1 having an extra C at nucleotide position 5385; • (c) a DNA having the nucleotide sequence set forth in SEQ ID NO: 1 having G at nucleotide position 5443; and, (d) a DNA having the nucleotide sequence set forth in SEQ ID NO:1 having 11 base pairs at nucleotide positions 189-199 deleted. • Apparently valid

7. The Science - 1 Eukaryotic Genes

8. The Science - 2 Protein • The RNA is spliced to form mRNA • For BRCA1 and BRCA 2 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

9. Good News / Bad News • Gave credence to Funk Brothers • Funk Bros. relates to obviousness – legal confusion • Claim 5 of ‘282 patent ineligible • This style of claim was a problem for freedom to operate opinions – at least in the US, the problem is saved • Still a problem elsewhere globally • How to claim single nucleotide mutations? • “The location and order of the nucleotides existed in nature before Myriad found them. Nor did Myriad create or alter the genetic structure of DNA.” Op. at 12. • Composition may not be patentable unless using “consisting of” language or synthetic language • Use in a method of diagnosis should be patentable

10. Impact on Genes? • First isolated genes / proteins – patents now expired • Human genome project – done in early 2000 • Most of those patent applications stand abandoned • In silico data only • Many of the patents are expired for failure to pay maintenance fees • No real DNA drugs approved yet • Polypeptide drugs are still eligible • Most biologic drugs are modified or non-natural (e.g., antibodies) • BUT….

11. Future Problem in Other Areas?? • DNA from bacteria • Does not contain “introns” – is it patentable just by saying cDNA? • Purified compounds • Allegedly examiners are rejecting naturally occurring polypeptides • What about purified silica? Purified gold? • What about product-by-process claims for natural compositions? • Stem cells? Plant extracts? Taxol? • Enzymes from newly identified organisms that have unusual properties?

12. Claiming Solutions - DNA • Isolated / purified will not work! • How to claim DNA? • cDNA • An isolated cDNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO: 2. [Eligible] • Synthetic DNA • DNA lacking genomic sequences (intronic sequences) • Using “consisting of” v. “comprising” to exclude genomic sequences • Other DNAs – fusion DNA, siRNAs, antisense DNA, DNAs / RNAs modified with a chemical - eligible • DNAs obtained by directed evolution?

13. MORE Claiming Solutions • Proteins – • “Synthetic” polypeptide not produced in its native cell? • Chemical modifications - Unglycosylated or lacking another native modification (fatty acid, unphosphorylated, etc.) • Modified protein – non-naturally occurring variants, non-naturally encoded amino acids, pegylation, fusion proteins, etc. • Product – By – Process • Do we have to demonstrate that the product does not exist in nature? How do we claim purified compositions? • Will product characterization require evidence that it is not naturally-occurring?

14. Myriad – The Fight Continues • Myriad has sued Ambry and Gene-by-Gene for infringement based on their “other” BRCA1/2 patents • Ambry argues that Myriad prohibits enforcing synthesized DNA that mirrors genomic DNA, including probes • Quest Diagnostics has sued Myriad in California on 14 patents, 4 are not part of the other suit

15. Prometheus – What is the PTO Saying? • • Inquiry 1 – Part I: • – Does the claim include additional • elements/steps that integrate the natural • principle into the process? • • It is not necessary that every step show integration. • • If the additional elements/steps do not integrate the • natural principle, there is no practical application. • – If not, the claim fails the analysis and should be • rejected. • See http://www.cabic.com/bcp/090512/BIO_9_2012_101_Train_Update(HANDOUT)_TC1600.pdf

16. Prometheus and the PTO • • Inquiry 2 – Part II: • – Does the claim include additional • elements/steps that amount to significantly • more than the natural principle itself? • • Is the claim as a whole more than a natural • principle plus the general instructions to • simply “apply it”? • – If not, the claim fails the analysis and should be • rejected.

17. Aria Diagnostics, Inc. v. Sequenom, Inc.(Fed. Cir. 2013) • A method for detecting a paternally inherited nucleic acid of fetal origin performed on maternal serum… “detecting the presence of a paternally inherited nucleic acid of fetal origin of the sample.” • Reversed and remanded. Claim construction assessed. • See also Digitech Image Technologies v. Konica Minolta Holdings, Inc. 2013 WL 3947158 (C.D. Cal. July 31, 2013) • Claim construction is going on in these 101 applications!

18. Method Claiming Solutions? • Claim the product or method at least in a picture claim • You will avoid written description and enablement issues in the US and globally • Claim the method where the steps are taken by one actor • McKesson/Akamai issue • Claim the compound to distinguish it over natural compositions • Claim narrowly • Novozymes A/S v. DuPont Nutrition Biosciences APS (Fed. Cir. 2013)

19. Thank You Mercedes Meyer, Ph.D. Drinker Biddle & Reath LLP Washington, DC Mercedes.Meyer@dbr.com 202-842-8821

20. USPTO Example • 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.

21. Example Claim – Not Patent Eligible • 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.

22. USPTO Example 2. The method of claim 1 further comprising: providing a positive control sample; and contacting the positive control sample with an anti-IgM antibody, wherein the step of determining that the patient has rheumatoid arthritis or increased likelihood of developing rheumatoid arthritis comprises a step of comparing the anti-IgM antibody in the serum sample to the positive control sample. NOT ELIGIBLE 3. The method of claim 1 or 2, wherein the anti-IgM antibody is antibody XYZ. ELIGIBLE

23. PTO Guidelines 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.