Paper Review• Certiorari: from Latin, means to be informed of gaining appellate review, ordered and examined by superior court.Author: Kevin E. Noonan, Ph.D. • an experienced biotechnology patent lawyer, a partner of a LLP. • more than 10 years as a molecular biologist. • founding author of the Patent Docs weblog. • In 2010, interviewed for a segment that aired on the television program "60 Minutes” addressing the issue of gene patenting.
• In AMP. v. USPTO, Public Patent Foundation (PubPat) and American Civil Liberties Union (ACLU) argued for plaintiffs.The Public Patent Foundation at Benjamin N.Cardozo School of Law (“PUBPAT”) is a not-for-profit legal services organization whose mission isto protect freedom in the patent system. The American Civil Liberties Union (ACLU) is a nonpartisan non-profit organization with mission "to defend and preserve the individual rights and liberties guaranteed to every person in this country by the Constitution and laws of the United States.
Plaintiffs and Defendants• Plaintiffs- appellees • Researchers • Drs. Kazazian, Ganguly (University of Pennsylvania School of medicine, Genetic Diagnostic Lab.), Ostrer (New York University)… • Organizations • AMP (Association for Molecular Pathology), AMCG (American College of Medical Genetics)… • Patients• Defendants- appellants • USPTO • Myriad Genetics, Inc (Salt Lake City) • former co owner and exclusive licensee • UURF (The University of Utah Research Foundation) • an owner or part owner of each patent.• Amici • American Medical Association, American Society of Human Genetics…
Case History Federal District Court of Southern District of New York (S.D.N.Y.) Issued on 3/29.2010 Mayo Collaborative Services v. Prometheus Laboratories, Inc.(C.A.F.C) Federal Court of Appeals, Federal Circuit (C.A.F.C.) Issued on 7/29.2011 PubPat & ACLU Petition for Certiorari near 12/08, 2011 Certiorari granted in light of Mayo Collaborative Services v. Prometheus, on 3/26, 2012, oral Prometheus Laboratories, Inc.(S.C) issued on argument held on 6/20, 2012 3/20,2012
Background• In 1990, one gene that correlated with increased risk of breast and/or ovarian cancer was located in the body on chromosome 17. Some of these researchers formed Myriad in 1991.• In 1994, Myriad, along with researchers from NIEHS, Univ. of Utah, and McGill University, sequenced the cancer gene, and named “BRCA1”.• Later, Myriad found another gene named “BRCA2” in 1995, and obtained series of patents of BRCA1/2.
Background• In 1998~ 2008, Myriad charges about $3000 for BRCA1/2 test. .• In 2008, revenues are $222 million, of which $190 million in profit.• In contrast, the Ontario regional public health plan offering BRCA1/2 testing - in disregard of the Myriad patents –charges about $1000/test.• Through cease and desist letters, communication person in person, licensing and litigations…Myriad‟s act of enforcing its patent right was widely known in the research community.
Isolated DNA Extracted or purified cDNA DNA• Isolated DNA refers to a segment of DNA nucleotides existing separate from other components normally associated with native DNA.• DNA with isolated DNA • Common • same information • Difference • structurally and chemically difference, like introns • usage different as probes or primers
Main Issue• Patent Eligibility • Are human gene patentable?• Standing Requirement • Did the court err in adopting a new and inflexible rule that contradict to MedImmune, Inc. imposing a more rigid requirement for standing?
Category1: Isolated, non- mutated forms,and fragments of BRCA1/2 gene• Claim 1 of the „282 patent • An isolated DNA coding for a BCRA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ. ID. NO: 2.• Claim 2 of the „282 patent • The isolated DNA of claim 1 ,wherein said DNA has the nucleotide sequence set forth in SEQ ID NO: 1.• Claim 5 of the „282 patent • An isolated DNA having at least 15 nucleotides of the DNA of claim1.• Claim 6 of the „282 patent • An isolated DNA having at least 15 nucleotides of the DNA of claim2.• Claim 1 of the „492 patent • An isolated DNA molecule coding for a BRCA2 polypeptide, said DNA molecule comprising a nucleic acid sequence encoding the amino acid sequence set forth in SEQ ID NO: 2.
Category2: BRCA1/2 genes containingmutations• Claim 1 of the „473 patent • 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 4184- 4187 in SEQ. ID . NO:1.• Claim 7 of the „282 patent • 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 position 189-199 deleted.• Claim 6 of the „492 patent • 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.• Claim 7 of the „492 patent • The isolated DNA molecule of claim 6, wherein the DNA molecule comprises a mutated nucleotide sequence set forth in SEQ. ID. NO:1.
Category3: Methods analyzing an individual‟s BRCA 1gene to determine inherited mutations• Claim 1 of the 999‟ patent • A method for detecting a germline alteration in a BRCA1 gene, said alterations set forth in Table 12A, 14, 18 or 19 in a human which comprises • analyzing a sequence of a BRCA 1 gene or BRCA1 RNA from a human sample or • analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID. NO:1.
Category4 : Methods comparing patients‟ BRCA1/2 gene with thenormal, and examination to determine a potential therapeuticcompound• Claim 1 of „001 patent • A method for screening a tumor sample from a human subject for a somatic alteration in a BRCA1 gene in said tumor which comprises • gene comparing a first sequence selected from the group consisting of a BRCA1 from said tumor sample, BRCA1 RNA from said tumor and BRCA 1 cDNA made from mRNA from said tumor sample with • a second sequence selected from the group consisting of BRCA1 gene from a non- tumor sample of said subject, BCRA1 RNA from said non- tumor sample and BRCA1 cDNA made form mRNA from said non-tumor sample, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA from said tumor sample from the sequence of the BRCA1 gene, BRCA1 RNA or cDNA from said non- tumor sample indicates a somatic alteration in the BRCA1 gene in said tumor sample.
• Claim 1 of „441 patent • A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises • comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA rom said sample with • germline sequence of wild- type BRCA1 gene, wild- type BRCA1 RNA or wild- type BRCA 1 cDNA, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA of the subject from wild- type indicates an alteration in the BRCA1 gene in the said subject.
• Claim 1 of „857 patent • A method for identifying a mutant BRCA2 nucleotide sequence in a suspected mutant BRCA2 allele which comprises • comparing the nucleotide sequence of the suspected mutant BRCA2 allele with the wild- type BRCA2 nucleotide sequence, wherein a difference between the suspected mutant and the wild- type sequence identifies a mutant BRCA2 nucleotide sequence.• Claim 2 of „857 patent • A method for diagnosing a predisposition for breast cancer in a human subject which comprises • comparing the germline sequence of the BRCA2 gene or the sequence of its mRNA in a tissue sample from said subject with • the germline sequence of the wild- type BRCA2 gene or the sequence of its mRNA, wherein an alteration in the germline sequence of the BRCA2 gene or the sequence of its mRNA of the subject indicates a predisposition to said cancer.
• Claim 20 of the „282 patent • A method for screening potential cancer therapeutics which comprises • growing a transformed eukaryotic host cell containing an altered BRCA1 gene causing cancer and 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 the said compound and comparing the growth rate of said host cells, wherein a slower rate of said host cell in the presence of said compound is indicative of a cancer therapeutic.
Patents• U.S.C 35, section 101 • Whoever invents or discovers any new and useful process, machine, manufacture, or composition or matter, or any new and useful improvement thereof, may obtain a patent therefore, subject to the conditions and requirements of this title. • Novelty, section 102 • Non- obvious, section 103 • Utility • Utility Examination guidelines • Statutory subject matter
Exceptions of Section 101• from Diamond v. Chakrabarty, • Laws of nature • Natural phenomena • Abstract Idea In General Electronic, a In Funk Brothers, a mixture purified tungsten couldn‟t be of bacteria couldn‟t be patented, since it ”existed in patented, since it “did not nature and doubtless has create a state of inhibition or existed for centuries.” of non- inhibition.” Patentable subject must be markedly different from a product of nature, which means it must possess a new or distinctive from, quality or property.
Judgment of the court - composition matter D.A. C.A.F.C.• What makes DNA unique not • The claim covers molecules that only its chemical structure, but hardly exist in natural status. also the information it conveys. • The isolated DNA is free of some• Isolated DNA may serves as other components in the cell. probes or primer. Why it can • For example, BRCA2 serve so results from the without introns shrink to just sequence it carries. 10,200 nucleotides in• The different chemical structure comparison with those are just the result of purification. normal with introns can have near 80,000 nucleotides. Not Patentable Patentable
Machine and Transformation Test• Use to determine whether a mental process or patentable subject. From Bilski to Prometheus, two prongs: • (1) It is tied to a particular machine or apparatus, or • (2) It transforms a particular article into a different state or thing. In addition, the use of specific machine or transformation must impose meaningful limits on the claim‟s scope, and the involvement of a machine or transformation must not merely insignificant extra- solution activity. (e.g. data gathering)
Example : Prometheus• Claim in Prometheus: • 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 8x108 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 8x108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.
Example : Prometheus• Transformation exist as human body as well as the chemical and physical changes of the drug‟s metabolites.• The “determining” step alone was transformative and central to the claimed method since determining the levels of the metabolites in a subject necessarily involves a transformation, for those levels can‟t be determined by mere inspection.
Example: Grams• The method consisted of two step: • (1) performance of clinical laboratory tests on an individual to obtain data for the parameters, and • (2) analyzing the data to ascertain the existence and identify of an abnormality… • No transformative step on human subject. • Court held that the essence of what was claimed was the mathematical algorithm for analyzing the clinical data, and the sole physical process- laboratory testing was merely data- gathering to obtain clinical data.
Judgment of the court - method D.A.(Category 3,4) (claim 20 of 282‟ patent)• The words “Analyzing and comparing”, in contrast to “determining the metabolite level ”, refers to only abstract mental process. • Viewed in entirety, the• “From a human subject” or “from a non- tumor essence of the claim is sample ” in the claim only serves to identify the that comparing a slower DNA. growth rate to indicates a• The word “analyzing and comparing” even cancer therapeutic. seemed as include “isolating and sequencing Inserting DNA or human DNA”, it won‟t be central to the purpose of compound into host cells claim.• Without specifying how about the words can only be regarded as “analyzing and comparing” impose no meaningful preparatory data limitation on the claim. gathering step. Not Patentable
Judgment of the court - method C.A.F.C(Category 3,4)• Reasoning as D.A. Not Patentable(claim 20 of 282‟ patent)• Tie to specific host cells transformed with BCRA gene.• Satisfying the transformation test, including these transformative steps: • 1. host cells growing with a altered BCRA1 gene • 2. determine growth rate with or without the compound • 3. these steps are central to the claimed process Patentable
Standing requirement• Declaratory Judgment: • Real and substantial, definite and concrete, having adverse legal interests. • Controversy of sufficient immediacy and reality to warrant the issuance of declaratory judgment.• Lujan v. Defenders of Wildlife (Standing) • Suffering some actual or threatened injury as a result • The injury must be fairly traceable to the challenge action • The situation is likely redressed by a favorable decision• MedImmune v. Genentech • From actual infringement to “apprehension of litigation” • All circumstances test: whether the facts alleged, consider all the circumstances, show that there is a substantial controversy…
Standing requirement• Affirmative Act by the defendants • A requirement that there be a specific, affirmative act directed toward the plaintiff to establish standing to seek a declaratory judgment of patent invalidity would be inconsistent with the S.C. mandate that “all facts alleged, under all the circumstances…”• Meaningful preparation • “Ready, willing and able” to infringe and that such expressions of desire and ability are sufficient to establish standing…
Judgment of the court - standing D.A. C.A.F.C.• Myriad constituted a • Only three plaintiffs‟ injury “widespread understanding” that traceable to Myriad, since one may engage BCRA testing affirmative enforcement toward at the risk of being sued for them. infringement liability • Others only took consideration,• Plaintiffs‟ desire and ability to but Dr. Ostrer show unequivocal engage testing is clear. intent to restart testing. (real• The researchers and patients and immediate injury or threat) are deterred from BRCA testing • Plaintiffs failed to show patients because of Myriad. judicially cognizable injury due to denial of health service… Everyone has standing One Dr. Ostrer has standing
Conclusion• C.A.F.C. established a rigid criteria toward standing.• Gene still be regarded as a composition patent subject matter.• Note: In Prometheus, S.C ruled: • The step in claim process involved well- understood, routine, and conventional activity previously engage in the research field. • Upholding the patent would risk disproportionately tying up the use of underlying natural laws.
Feedback ＆ Discussion• The standing requirement? • Better rigid • 節省訴訟資源• Should human gene be patentable? • Criteria: Vague (markedly different? central?) • 考慮分配正義 Thank you for your listening