The Future of Gene Patents: Patenting DNA and Other Biological Molecules and Products Following the Supreme Court’s Decision in AMP v. Myriad Genetics Christopher L. Wight

DNA Primer: What is DNA? The Central Dogma of Molecular Biology:  DNA→RNA→mRNA→Protein (exist in nature)

DNA Primer: What is cDNA? ↓ cDNA (non-naturally occuring) ↓ Recombinant protein

Patent Eligibility Before AMP v. Myriad 35 U.S.C. § 101 – Patent Eligibility 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.

Patent Eligibility Before AMP v. Myriad 35 U.S.C. § 101 – EXCEPTIONS  Laws of nature – E=MC 2  Products of nature – salt  Natural phenomena – gravity  Abstract ideas – calculus  These are the “basic tools of scientific and technological work”

Patent Eligibility Before AMP v. Myriad What makes something patent eligible?  Any non-trivial act of human intervention  Product is distinguishable from anything in nature  Isolation of biomolecule from native source  Example: Protein purified from human tissue, having therapeutic benefits not possessed by native form

Patent Eligibility Before AMP v. Myriad Isolated DNA  Separated from other DNA  Ability to sequence purified/concentrated DNA Isolated proteins  Separated from other biomolecules  Increased specific activity (confers additional utility as a therapeutic)

AMP v. Myriad – Brief History U.S. Patent No. 5,747, An isolated DNA coding for a BRCA1 polypeptide having the amino acid sequence set forth in SEQ ID NO:2 [the BRCA1 protein/amino acid sequence]. Claim defines isolated DNA by its functional ability to encode a BRCA1 protein sequence Both genomic DNA and cDNA encode BRCA1 protein DNA claims held to be ineligible for patent protection

AMP v. Myriad – Brief History U.S. Patent No. 5,747, The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1 [cDNA sequence that encodes BRCA1]. Claim defines isolated DNA by its structural nucleotide sequence cDNA claims held to be eligible for patent protection

AMP v. Myriad – Brief History Majority Opinion (Justice Clarence Thomas) HOLDING: “Myriad did not create anything. To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic materials is not an act of invention” COMPROMISE: “cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments… creation of a cDNA sequence from mRNA results in an exons-only molecule that is not naturally occurring” cDNA is “synthetically created” “…the lab technician unquestionably creates something new when cDNA is made”

AMP v. Myriad – Brief History Only “new” compositions are patent eligible Mere isolation is not enough to render a natural product “new”, absent some other human intervention that goes beyond merely isolating from natural environment

AMP v. Myriad – Brief History What was Supreme Court’s rationale for patent ineligibility of isolated DNA?  Isolated DNA merely “cleaved” from genomic DNA (insufficient physical modification)  Isolated DNA retains the genetic information embodied in cellular DNA

AMP v. Myriad – Brief History What was Supreme Court’s rationale for patent eligibility of cDNA?  cDNA is “synthetically created”  cDNA has a different physical structure than genomic DNA (it omits introns)

AMP v. Myriad – Scope of Holding? Products isolated from natural environment invalid? Isolated proteins from humans, animals, plants? Antibiotics from microbes? Stem cells? Synthetically created versions? DNA having high sequence similarity?

AMP v. Myriad – Ambiguities? Naturally occurring – produced naturally and isolated from its native environment (i.e., isolating DNA from saliva or a blood sample) vs. Synthetically created – made by a non-natural (i.e., human contrived) process (i.e., synthetic DNA produced from PCR process, or DNA made from expression of recombinant DNA molecule)

AMP v. Myriad – Ambiguities? Is ALL synthetically created DNA patent eligible (i.e., synthetically amplified by PCR)? Myriad claims cover “isolated” DNA, but not limited to “synthetic” DNA While “synthetic” DNA may retain genetic information, it is in fact structurally different (i.e., lacks epigenetic modifications, such as methylation of cytosine and adenine DNA molecules, typically found in genomic DNA)

AMP v. Myriad – Ambiguities? cDNA is “synthetic” in the same sense that PCR amplified DNA is “synthetic” Structural difference between cDNA and mRNA (thymine replaced by uracil, differing by only a single methyl group) is comparable to structural differences between genomic DNA and synthetic DNA (addition of methyl group to cytosine or adenine DNA nucleotides)

AMP v. Myriad – Impact on Patenting DNA Isolation of a biomolecule, produced naturally in a biological organism, probably not enough to confer patent eligibility “Synthetic” molecules, having common or similar sequence or structure, probably patent eligible

AMP v. Myriad – Impact on Patenting Protein Therapeutics (or signal interfering DNA) Myriad case held that invalidated claims “are simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA” DNA having similar sequence to genomic DNA may be patent eligible if there are structural differences in the synthetic DNA, and such structural differences are recited in the claim

AMP v. Myriad – Impact on DNA Diagnostics PCR-based amplification Nucleotide probes (short sequences complementary to and capable of hybridizing to template DNA, used to initiate sequencing)

AMP v. Myriad – Impact on Other Biological Discoveries (i.e., Stem Cells) Consumer Watchdog v. Wisconsin Alumni Research Foundation, No (Fed. Cir. 2013). Appeal from holding of USPTO Board of Patent Appeals, which confirmed patentability of claims in U.S. Patent No. 7, Issue of patent eligibility raised for first time on appeal. ISSUE: Are cultured human embryonic stem cells (hESCs) markedly different from naturally-occurring hESCs? Does the process of culturing the cells provide the cells “with markedly different characteristics from any found in nature?” CW asks Fed. Cir. to apply holding of Myriad to in vitro cultured, human embryonic stem cell cultures, and find them ineligible for patent protection under 35 U.S.C. 101.

AMP v. Myriad – Impact on Other Biological Discoveries (i.e., Stem Cells) WARF’s U.S. Patent No. 7,029, A replicating in vitro cell culture of pluripotent human embryonic stem cells derived from a pre-implantation embryo, wherein the stem cells (i) will proliferate in an in vitro culture for over one year in an undifferentiated state without the application of exogenous leukemia inhibitory factor, (ii) maintain a karyotype in which the chromosomes are euploid through prolonged culture, (iii) maintain the potential to differentiate to derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, (iv) are inhibited from differentiation when cultured on a fibroblast feeder layer.

AMP v. Myriad – Impact on Other Biological Discoveries (i.e., Stem Cells) WARF argues that claim recites “in vitro cell culture” – clearly not a “product of nature” Expert witness for WARF further testified that the morphology of the hESCs are different from prior art mouse ES cell colonies (hESC colonies are flatter and more compact) CW argues that the claims “merely identify properties that are inherent in all ES cells, including those that exist naturally” and do not recite either a method of preparation or a scientific application of the claimed composition.

Practical Advice Recite additional limitations beyond mere isolation Significantly altering molecular structure to improve function or biological activity Synthesize biomolecule in such a way as to alter physical properties or biological activity Comparative testing of “isolated” naturally occurring molecule vs. synthetically created molecule Culturing self-replicating organisms (ex vivo) in a manner different from natural environment

Practical Advice Artificially engineer a biomolecule with other biomolecules Example - Amgen’s E NBREL ®, a dimer of two extracellular domains of TNF receptor molecule linked to each arm of an Fc domain of IgG1 antibody (extends half-life and increases biological activity)

Contact Info Christopher L. Wight Bateman IP Law Group 257 East 200 S., Suite 750 Salt Lake City, Utah Web: Phone: (801)