Understanding Gene Patenting

24th June, 2013 - 6:41 am Categories: Pharma/Biotech Patent Litigations 0 Comments

We are sure that all of you must have learnt about the latest US Supreme Court decision in Association for Molecular Pathology V. Myriad Genetics on June 13, 2013, which has ended the long brawl of 5 years. Yes! the sole provider of BRCA1 and BRCA 2 tests, Myriad Genetics Inc., has lost the battle. Myriad had enjoyed sole monopoly over testing services for BRCA1 and BRCA2 in the United States, since the grant of 2 genes in 1990s.

On May 12, 2009, The American Civil Liberties Union and the Public Patent foundation sued the US Patent and Trademark Office, Myriad Genetics, and the University of Utah Research Foundation, (all holding the patents on the BRCA1 and BRCA2 genes) challenging 15 claims drawn from seven Myriad’s patents owned by, or exclusively licensed to, respondents. The patents violate patent law as genes are “products of nature” and they therefore can’t be patented. Others joining the plaintiffs included several organizations, cancer survivors, physicians, academic researchers and patient advocates, laboratory professionals, pathologists, and represented 150,000 geneticists.

On March 29, 2010, Southern District Federal Court of New York ruled against Myriad, stating that patents on BRCA1 and BRCA2 genes were invalid. Myriad appealed the case, which was heard by the US Court of Appeals for the federal circuit in April 2011. The court ruled in favor of Myriad, finding that patents can be obtained on specific genes.

The US Supreme Court instructed the Appeals court, in March 2012, to reconsider the case after a unanimous ruling invalidated 2 patents on a blood test that determines drug dosages, which had been licensed to Prometheus Laboratories. After 5 months, a divided appeals court (2 to 1) ruled in favor of Myriad. In May 2012, plaintiffs asked the Supreme Court to hear the challenge to Myriad’s patents again. Supreme Court agreed finally to hear the case, in November 2012.

Myriads patents in Challenge:

One of the 7 patents in challenge included US5747282, claim 1 of the patent encompasses any isolated DNA molecule that codes for the natural BRCA1 protein-including an ordinary BRCA gene isolated from a tissue sample taken from any patient. DNA coding is for the polypeptide and not for any specific gene. There are many polypeptides. That would encode the BRCA1 polypeptide. Claim 5, then is a claim on any 15-mer oligonucleotide found in any such sequence. The human genome consists of about one million oligonucleotides covered by this claim. The claim 1 of the patent US6033857 encompasses the comparison of the BRCA gene sequence with a wildtype sequence. The rest were method claims in the patent. Invalidating [it] meant to grant freedom to the plaintiffs to practice diagnostic tests on BRCA gene. Claim 1 of ‘857 is illustrated is one of the invalidated claims:

1. 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 sequences identifies a mutant BRCA2 nucleotide sequence.

The 3, 4, 9, & 10 claims were from U.S Patent 5709999,

3. A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 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, which comprises analyzing BRCA1 RNA from the subject and wherein a germline alteration is detected by hybridizing a BRCA1 gene probe which specifically hybridizes to nucleic acids containing at least one of said alterations and not to wild-type BRCA1 sequences to RNA isolated from said human sample and detecting the presence of a hybridization product, wherein the presence of said product indicates the presence of said alteration in said RNA and thereby the presence of said germline alteration in said sample.

4. A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 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,wherein a germline alteration is detected by obtaining a first BRCA1 gene fragment from a BRCA1 gene isolated from said human sample and a second BRCA1 gene fragment from a wild-type BRCA1 gene, said second fragment corresponding to said first fragment, forming single-stranded DNA from said first BRCA1 gene fragment and from said second BRCA1 gene fragment, electrophoresing said single-stranded DNAs on a non-denaturing polyacrylamide gel, comparing the mobility of said single-stranded DNAs on said gel to determine if said single-stranded DNA from said first BRCA1 gene fragment is shifted relative to said second BRCA1 gene fragment andsequencing said single-stranded DNA from said first BRCA1 gene fragment having a shift in mobility.

9. A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 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, wherein a germline alteration is detected by forming a heteroduplex consisting of a first strand of nucleic acid selected from the group consisting of BRCA1 gene genomic DNA fragment isolated from said sample, BRCA1 RNA fragment isolated from said sample and BRCA1 cDNA fragment made from mRNA from said sample and a second strand of a nucleic acid consisting of a corresponding human wild-type BRCA1 gene fragment, analyzing for the presence of a mismatch in said heteroduplex, and sequencing said first strand of nucleic acid having a mismatch.

Claim 10 from U.S. Patent No. 5,710,001:

10. 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 form the group consisting of a BRCA1 gene from said tumor sample, BRCA1 RNA from said tumor sample andBRCA1 cDNA made from mRNA from said tumor sample with a second sequence selected from the group consisting of BRCA1 gene from a nontumor sample of said subject, BRCA1 RNA from said nontumor sample and BRCA1 cDNA made from mRNA from said nontumor 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 BRCA1 cDNA from said nontumor sample indicates a somatic alteration in the BRCA1 gene in said tumor sample,  wherein the nucleic acid sequence is compared by molecularly cloning all or part of the BRCA1 gene from said tumor sample and from said nontumor sample to produce cloned nucleic acids and sequencing the cloned nucleic acids.

The Supreme Decision made

The Court said that “the Isolated DNA segment is structurally different but both protein coding exons and non-coding sequences is unchanged” hence, are same to native gene. And explained how the differences do not render isolated DNA “markedly different” from native DNA.

The judgement of the supreme court hence concluded that “court  of appeals should be affirmed insofar as it holds that cDNA is patent-eligible, and reversed insofar as it holds that isolated but otherwise unmodified DNA is patient-eligible.

The unchallenged claims implied to methods that are merely applications to the knowledge of the two genes and hence not patent-eligible. On this the Court  had found that however useful these applications may be, they should be treated as insufficient to create patent-eligible subject matter.

Isolated Gene patenting has never been questioned till now!!!!!

The PTO has regularly issued patents directed to isolated genomic DNA, and various government agencies have previously sought and obtained such patents. The patent-eligibility of isolated DNA was never tested in litigation, however, until petitioners filled this suite.Gene patents have been among the most controversial segments of intellectual property. There are up to 3,000-5,000 U.S patents on human genes and 47,000 on inventions involving genetic material. U.S patent Law requires that the “Purified and Isolated” gene fragments have a “specific and substantial utility”. There is much debate regarding gene patens as to whether isolated, purified genes are patentable under Sec. 101 of the U.S Patent Act. A department of health and human services (“HHS”) Advisory Committee studies gene patents and patient access, and found that gene patents can harm genetic research, by hindering faster test development.

Why to patent Human genome for it being our common heritage?? The recent  discussions over the litigation of Association for Molecular Pathology V. Myriad Genetics, involving the validity of Myriad’s BRCA 1 and 2 gene patents, largely overlooked the impact of gene patents on patients. The Fifth Amendment Due process clause protects the right to bodily integrity and its knowledge. The right being a fundamental right of the patients, to which the government cannot intrude upon unless it can show that, the infringement is convincingly in the government’s interest. The patients should have the right to access information and medical treatment for their own body. Patents grant an inventor the right to exclude, but enforce no compulsion on the patent holder to make available the invention to the public.

In 1980, USPTO began issuing patents on three different versions of gene. One being the “cDNA or Complementary DNA  fragments”-  The other two versions of DNA include isolated fragments or the whole of yht raw DNA in a gene. A gene is a double helix structure consisting of base pair sequence, some are expressed and majority of are not. In a cDNA only the expressed base pairs are organized in the same order as the native gene. To make it clear, the other versions are SNP and EST. An EST (Expressed Sequence tag), is a short sequence of the complementary DNA that was expressed by the full length gene. A polymorphism, such as an SNP (Single nucleotide polymorphism), is a variation in gene DNA sequence of some members of a specie. Myriad’s patents extended to all three types of DNA extracted from the two BRCA genes.  It all started in the early 1990s, when a genecist at Berkleley, Mary-Claire King, announced that her laboratory had found probable location of BRCA 1 on Chromosome 17. Then a “transatlantic race” began, where the major competitor was Mark Skolnick, genecist at the university of Utah and cofounder of Myriad Genetics. Mark and his colleagues won the race in 1994; they had found and isolated BRCA1 from the rest of DNA and tangle of protein that forms chromosome 17. In 1995, Myriad had also identified and isolated BRCA2, Which resides on the chromosome 13.

Let’s go through some of the other similar cases which have left a mark:

Diamond V. Chakrabarty: A land mark case, Where the Supreme Court’s ruling in 1980 allowed patents on a genetically modified bacterium, which possessed the capability that no other naturally occurring bacterium did. At first the application was rejected by a patent examiner, because under patent law, at that time, Living things were not patentable subject matter under Sec. 101 of Title 35 U.S.C. However Sidney A. Diamond, Commissioner of patents and Trademarks, appealed to the Supreme Court that the fact that micro-organisms are alive is without legal significance for purpose of the patent law. The Supreme Court case was argued on March 17, 1980 and decided on June 16, 1980. The Patent was granted on March 31, 1981.

Mayo Collaborative Services V. Prometheus Laboratories  was a case decided in 2012, by the Supreme Court of the United States that held that claims directed to a method of giving a drug to patient, measuring metabolites of that drug, and with a known threshold for efficacy in mind, deciding whether to increase or decrease the dosage of the drug, were not patent eligible subject matter. This reversed the decision of Court of Appeals for the Federal Circuit’s holding that the claims were patentable because they included substantial physical limitations.

In June 2004, a case arose in a dispute between Mayo Collaborative Services and Prometheus Laboratories concerning a diagnostic test. Prometheus sued Mayo for infringement in the southern district Court of California and in March 2008, the district court held the patents invalid. The two US patents in the case are 6,355,623 and 6,680,302, which are owned by Hospital Sainte-justine in Montreal.  The invention identifies a relationship between concentration of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm.

On September 2009, The Federal Circuit reversed the District Court, finding that the claims were patentable. Mayo appealed to the Supreme Court and in June 2010 the Court immediately vacated the federal circuit decision and remanded the case back to the Federal Circuit. The Federal Circuit still found that the two steps of the invention were transformative and that the claim as a whole was patentable. The Federal Circuit went into more depth on the third step, the “mental step”, noting that “a subsequent mental step does not, by itself, negate the transformative nature of prior steps. Thus, when viewed in the proper context, the final step of providing a warning based on the results of the prior steps does not detract from the patentability of Prometheus’s claimed methods as a whole. On appealing again to the Supreme Court by Mayo, the court gave its “unanimous”  decision on March 20 2012. The court called the correlation between the naturally produced metabolites and therapeutic efficacy and toxicity to be an Unpatentable “natural law” and found the first two steps to be not “genuine applications of the law. And hence concluded that a newly discovered law of nature is itself Unpatentable and the application of that newly discovered law is also Unpatentable if the application merely relates upon elements already known in art.

“The anticommon effect”: Recently the court of Appeals for the Federal Circuit (CAFC) issued a patent law decision, ruling against the applicant in In re Fisher, but maintaining the decision of the USPTO Board of Appeals and Interferences.  The decision bars patent protection for gene fragments that do not have a “specific and substantial” utility.

What Fisher tried to do? There were two researchers at the Monsanto Company Laboratories who harvested and purified DNA from the maize plant during it flowering phase, this research was valuable as would give the researchers an idea of the genes which were expresses and ultimately what proteins were present particularly at the time of development of the maize. The Fisher patent application had used the short nucleic acid sequences thought to be gene fragments or EST, as research tools that could obtain the genetic and protein information.

What is specific and substantial utility? In 2001, the standards of applying “specific and substantial utility” were finalized by the USPTO. This decision is so far the first case of CAFC on this ground.  The guidelines specifically say that: the claimed invention should be useful for any particular practical purpose.”

All seven uses specified in the application of Fisher, none met the standard of the guidelines. All the uses claimed can be applied to any ESTs and not to a particular one. The CAFC further identified that using ESTs as research tools was too insubstantial to meet the standard. The applicant didn’t know that what genes, if any, contained the ESTs, nor what proteins may be involved, and why they were important.

This decision would render hundreds of pending applications worthless and would raise a bar for proving gene and protein related inventions useful.

Conclusion:  Gene Patenting has become a crucial part of medicine. The patenting of gene related inventions not only affect the researchers but also hits the common man. By cDNA being patentable is small compromise the PTO has made. The patenting of gene should be treated in such a way that it facilitates both academic research and commercial testing.  This can be employed by following the similar licensing practices that are being followed by cystic fibrosis Patents, which are nonexclusively licensed for diagnostic use and have been variably licensed for gene transfer and other therapeutic applications. The steps which would hinder the patients to right of information of their own body, due to overpriced testes should be avoided by the Government. Ways like compulsory Licensing for practicing research in development of diagnostic tests can be made permissible.

About the Author: Ms. Shailee Gupta, Woman Scientist, TIFAC Trainee at Khurana & Khurana and can be reached at: shailee@khuranaandkhurana.com

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