2. The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1.

3. The isolated DNA of claim 1 which contains BRCA1 regulatory sequences.

4. The isolated DNA of claim 2 which contains BRCA1 regulatory sequences.

5. An isolated DNA having at least 15 nucleotides of the DNA of claim 1.

6. An isolated DNA having at least 15 nucleotides of the DNA of claim 2.

Yes, they have great claims. An isolated DNA, and a half dozen methods of detecting BRCA mutations.

They also have a plethora of mutations described:
(i) C and T at position 2201,
(ii) T and C at position 2430,
(iii) C and T at position 2731,
(iv) A and G at position 3232,
(v) A and G at position 3667,
(vi) T and C at position 4427, and
(vii) A and G at position 4956;

Isolated genes, i.e. not in a human body, are not found floating around in nature. Yes, they are isolated by the hand of man and fifteen years ago when the genes were isolated, it took a lot of work and investment to identify the genes that correlated to a specific disease. The claims expire in ~5 years and are available without restriction in the public domain.

Others were working on the same or similar problems. I have not reviewed the genes involved or DNA sequences used, but the DNA markers used for detection in “Screening of inherited breast cancer with DNA markers,” Lancet. 1993 May 29;341(8857):1422, may provide some prior art. You would have to do a detailed analysis of the sequences provided, complete alignment, and identify any mutations and/or amplified sequences that are available in the prior art (if Lalle, et al. had the right gene). I do not have a full day to devote to this analysis.

Myriad Genetics currently has 172 assigned patents and applications with the USPTO. I do not have time to review each and every claim of each and every application. IT is clear to me that if someone were to use the Lalle markers to sequence the BRCA gene, they should be in the prior art. It would take much more time and analysis to ensure DNA sequencing using the Lalle markers would be outside each and every one of the Myriad Genetics claims.

Arguing that the excact sequence, SEQ ID NO. 1, would spontaneously end up isolated in a microtube without the hand of man is not a logical argument. That is an emotional statement that you feel Myriad’s work is outside of patent scope because in your professional opinion they don’t deserve a patent. The question of whether or not Myriad deserves a patent is a legal question based on the state of the art at the time the patent was filed, the content of the patent application, and the discussion between the examiner and the patentee. Courts may review the examiner’s decision, especially in light of new prior art. Any sequence existing greater than 1 year prior to the filing of their first application is in the prior art and may be used without fear of infringement.

Claims 5 and 6 should be easy to invalidate because prior art DNA seqeunces of 15 nucleotides are fairly easy to find, if you have the time. Legally, they may already be invalid because they are broader than the claim from which they depend (that’s a “No! No!”). That would have to be flushed out in a legitimate court case.

All of this began through University of Utah and Cancer Institute research. They either are or at one point made money off of this invention and received financial support for their research. The may have some form of licensing agreement to continue research and there may have been US government funding allowing some institutions to research as well.

This is a very long and detailed case, with a lot of patents and pending applications. I cannot review each and every avenue out, but I have shown several paths (prior art, limits on the definition of BRCA gene, and possible licensing) to free up use of the BRCA gene. It would take money and time to clear a path through this patent thicket, a legal, legitimate, fact-based, non-infringing path.

Right now I would use a primer encoding a 20 aa tag sequence to amplify 90% of the BRCA coding region, that would be outside the literal scope of claims 1 – 4. Claims 5 & 6 may be much more difficult to enforce, and more easily invalidated.

Best regards and good luck with your design-around,

Mike

Claims 1, 2, 5, and 6 say nothing about detection… dowload the patent from my blog, or read here verbatim:

1. An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2.

2. The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1.

5. An isolated DNA having at least 15 nucleotides of the DNA of claim 1.

6. An isolated DNA having at least 15 nucleotides of the DNA of claim 2.”

which is why Myriad has enforced their patent against anyone daring to replicate the BRCA1 or 2 genes, no matter what the purpose.

In the Medtronic Bilski amici brief an excellent point was made regarding diagnostic methods and screening predating treatments by years or even decades. It seems incredibly short-sighted to lament the patenting of screening and diagnostics. You have to be able to identify an ailment before you can treat it, so if we give disincentive to screening and diagnostics that will set back treatment advances. I can’t understand how that would be for the greater good or at all help society. This is particularly true here were the testing is to let the individual know whether they are at a higher risk and MAY suffer from cancer later on in life.

-Gene

Whether it’s detecting the genotype, diagnosing a disease, or prescribing a treatment regime, there claims are still hinged on the “method of detecting,” “method of treating a disease,” or “method of identifying a propensity for cancer.” There are some claims directed to the combined detection and subsequent treatment, or selecting a different treatment. Either way, the claims require some physical test, or administration of a product, or the like.

If you have problems with a specific claim, I will analyze it for you and identify the physical aspects of the claim required for patentability. If the claim is directed wholly to a law of nature, physical phenomena, or abstract idea, I will provide support for invalidating that claim.

Best regards,

Mike

These diagnostic patents are predicated purely on the discovered meaning of the test result.

jon

The claims are directed to detecting naturally-occurring mutations of naturally-occurring genes. The operative word is detecting (diagnosing, etc.).

Claims that are directed to naturally-occurring mutations of naturally-occuring genes as they exist in nature are not valid.

The terminology in a claim must be carefully construed because it a very precise excercise to determine exactly what is claimed. The same precision is required when analyzing claim scope as is required when reviewing and analyzing a property survey, title of ownership or other property contract. There is a very big difference between even the simplest of terms (i.e. “hereby” vs “agrees to” assign). Because patents describe complex inventions using the limitations of the written language, each and every word of a claim must be properly construed in light of the claim terms, definitions in the specification, prosecution history, and the meaning of terms as they were used at the time of filing by one of ordinary skill in the art.

Provide any one claim that you feel reads on a naturally-occurring gene and I will provide a detailed analysis of the claim scope. If it does actually read on a naturally-occurring gene, I will provide support for invalidating that claim.

Best regards,

Mike

First, I hate writing blog responses and losing the text when I post.

A technology ban is not the most constructive way to achieve your goals. If patents are the greatest hinderance to academic research, legislation should be put forward to clarify the research exemption that is currently available. The scope of the academic research exemption has not been vetted in court making it difficult to advise universities and foundations regarding the research exemption. It is clear that purely academic research would likely receive a research exemption, unfortunately most universities are business entities with patents and licensing agreements. Thus a university with commercial aspects to their research should respect patent protection and be more patent savvy.

Currently, research scientists and the public in general do not understand patent claims or the true scope of a patent. I have personally designed gene sequences for a variety of pharmaceutical companies that avoid patent claims and allow research to continue. Unfortunately, claim construction is biased – every patent owner thinks they can stop everyone from using their research while each researcher inists they don’t infringe the patented technology. A proper analysis of the claims would clarify what is protected, what is marginally protected, and what is free to use. A good analysis of patent scope would benefit many researchers prior to entering into any agreements or beginning research with patented technology. Ironically, often times people over-pay in licensing agreements for technology they are not using.

Finally, all systems have excesses and poor examples. I do not necessarily agree with Myriad, their licensing decisions, or have a complete understanding of how much patent protection they deserve. They do have very strong patents to a series of different BRCA assays and diagnostics. They have also been very aggressive with enforcing those patents. They are one example of someone who continues to do the speed limit in a blizzard. They are not breaking the law, but the may not be living by the spirit of the law. That said, they have a business that needs to earn money, satisfy investors, and pay off any debt they may have incurred developing the test. That is their business decision.

Changing the laws for each technology area, banning diagnostic assays, would have unintended consequences. It would limit more expensive and complex assays from being commercialized. The patents you are worried about have a 20 year lifetime from the priority date and they will expire in time. Currently, patents are not granted to simple and obvious assays. The entire human genome has been sequenced, simply identifying an ORF and possible function is not sufficient for patent protection today. To revise the entire system, a system that continues to evolve, based on several examples of aging patents would be short sighted and will have unintended consequences.

If you feel that academic research is inexorably hindered by patents, you should first discuss the importance of patents with the university technology transfer office. Next you should investigate the true scope of the patents that hinder research, remember everything available in expired patents is guaranteed free for public use. Finally, you should develop a design around or cross-licensing agreement for each issued patent (published applications pose different problems).

There is a lot of animosity in patent discussions. Some patents are overly enforced, but the overall picture is not the David and Goliath saga you paint. Patents are far more essential to smaller start-up companies than they are to the industrial beasts who own the majority of the patents (IBM uses patents like trading cards, averaging about 10 issued patents a day). Patent practitioners must work to discuss and educate researchers about the value of patents, the true scope of a patent claim, and the overall benefit of a strong patent portfolio to universities and research foundations.

Please advise if there is a more constructive way to explain the benefits of all patents. A way to quantitate commercialization of university research and place value on the end results, a new commercial product with a limited monopoly for innovation.

Thanks for your time,

Mike

First, the labcorp claim at issue was not attacked in the lower courts on the product of nature issue, and the case was essentially dismissed by the supremes because the issue wasn’t preserved below. the issue i raised, whether these sorts of observations comprise patentable subject matter, remains open. Further, the claim at issue cannot be designed around. Sure, there are various assays folks can use to measure homocysteine levels but there’s absolutely no way around the observation claimed.

Second, i’ll just note that the chip manufacturers are almost alone amongst biotechnology companies in not supporting this sort of patenting. imagine a chip that has a million snips, that costs, say $100 for its purchase and use. the marginal cost of looking at any particular snp could be a fraction of a cent. but patentees on these “inventions” may block use, or charge whatever they wish, and experience shows that the royalties demanded (when licensing is used instead of, like myriad, attempted monopolization of the test service itself), have been fixed sums per test. An example for you: one laboratorian we interviewed had developed a jewish panel that tested for a few alleles in CF, Tay Sachs, Gaucher, Neimann Pick, and Canavan disease. his marginal cost of running this assay was under $100. at the time, royalties demanded included $2 for CF, $5 for Gaucher, $12.50 for Canavan, and NP was not being actively enforced. see Merz et al. Nature 2002; 415:577-9. so the royalties stacked on this test accumulated to some 20% of the cost of performing the test. as the marginal cost of performing a test drops to zero, the royalties stay the same. so if everyone held patents on all the known genetic disease assocations out there, the micro chip technology would be simply unaffordable. thankfully, those who hold these patents have largely chosen not to enforce them, and it is the exceptions such as Myriad, Athena Diagnostics, and a handful of others that have driven the discord.

Third, regarding stifling research, Myriad threatened the research community some years ago and did file suit against Penn (which was doing research and maybe some clinical testing), and the NCI negotiated a good deal (sequencing the two genes for somewhere around $800) with the company to do testing for NCI funded projects around the country. The research may take place, but Myriad gets to do the testing and decide what to charge for it. Whether more or less research takes place because of the patents is not, and arguably can not be, known.

jon

take as an example the patents covering diagnostic and prognostic uses of Apo-E. we carry 2 copies of this gene in our body, and it comes most frequently in 3 alleles, E2, E3, and E4. duke researchers recognized that if a person carries at least 1 copy of E4, then s/he is at increased risk for developing late onset alzheimers disease. US Pat. No. 5,508,167 claims characterizing one’s Apo-E status (by one of many methods available to the field, none of which methods are unique or first taught by the patent) and ‘observing’ that the patient is at increased risk because of the presence of at least one copy of E4. now, they also realized that if a patient is homozygous in E4 (carries 2 copies), s/he will be less likely to respond to a certain class of drugs, so they patented the identification of patients likely to be responsive to cholinomimetic drugs by determining how many copies of E4 a person has note that the test is the same test, but the interpretation and use of the test result is different. Another patent (to Pitt if i recall) claims the interpretation of the same test result as relates to the risk of prostate cancer, but that is of questionable scientific validity. Also of note, Apo-E status is a risk factor for cardiovascular disease, so the test may be done for cardiovascular indications and the physician who orders or performs the test is not infringing unless s/he recognizes (i.e., that mental step i mentioned above) that the result may have Alzheimer’s implications.

unlike the bald assertion that it is the “method” that is being patented, the truth is that it is the observation of an association between a genetic difference and a phenotypic difference that is claimed. which leads me to ask Gene (aptly named, BTW): what did you think of Metabolite v. Labcorp, substantively, not procedurally. and, if you think the patent claim there, which claimed the observation that a high homocysteine level meant the patient was suffering a B vitamin deficiency, is valid subject matter. note that there are numerous methods for measuring homocysteine levels in the blood, but only 1 way to observe what that result means.

if you think these are valid, then is the ‘mental step’ proscription dead?

for a somewhat dated exposition of my concerns about these diagnostic patents, see Merz, Clinical Chemistry 1999; 45:324-330. (email me for a copy).

jon

I will have to take another look. I would agree with you though, even if “altered” means mutated there is still isolation that would require some human intervention. The other method claims would also seem to require human intervention as well.

Thanks.

-Gene

For clarity, are you positive that the claim limitation “altered” implies any human intervention? Looking at the specification, it seems like “altered” is used synonymously with “mutated”, and is referencing the naturally occuring mutations of the gene, rather than a manipulated alteration. I only skimmed the patent, so correct me if I’m mistaken. And ultimately, my understanding is that this wouldn’t change anything about the patentabliity because “isolated” still implies human intervention beyond a state that occurs in nature.

To answer your question, the patent may stifle some research and encourage other research.

Investment in biotechnology is required, expensive, and risky. Patents are used to measure the innovation of a company and encourage independent funding. Especially funding for phase I/phase II clinical trials. W/o patents there would be very little investment.

Companies that want to do independent research, especially for FDA approval/submission, have protection under the law allowing them to research. Similar protection is available for BRCA research. There are thousands of research papers on BRCA (the gene in the patent), over 30 published in the last month. University research continues.

What has been stopped by the cease and desist letters are the basement test labs. Labs doing the same diagnostic tests as Myriad. A university lab, without the FDA standards and requirements, could do the same assay for a lot less. Myriad sends them cease and desist letters and is very strict about enforcing their patents.

The ACLU wants the tests to be freely available (Myriad charges ~$3000.00). It is unclear if Myriad has assistance available for those who can’t afford their test. The ACLU also wants to get a “2nd opinion” thus requiring at least one other lab to provide the test other than Myriad. That is currently not available. Part of Myriads costs are ensuring FDA compliance. The tests and equiment must be certified and use certain FDA practices to ensure good protocols are followed. This will always drive up the costs of an assay. Many of the tests must also be managed by skilled labor, especially since PCR tests and binding assays are sensitive to contamination. It would be very hard if 3000 people found out the lab tech was positive for cancer causing BRCA mutations. In conclusion, it is unclear if $3000 is unreasonable for this highly technical, FDA approved assay.

The test is expensive, there is no 2nd opinion available, but research continues and other assays will be available. The test can be conducted in one of the 130+ countries where there is no patent protection, or a new test can be designed “around” the Myriad test. Unfortunately new FDA approval would be required for design around tests.

I hope this helps clarify the research aspect of your question.

Mike

I was arguing from the claims and Table 12a where somatic mutations in the human that occur naturally are associated with patient numbers, confirming their presence in nature. The fact that these gene mutations only predispose an individual to an increased chance of getting breast cancer infers that in others these gene sequences function normally and points to environmental factors or other factors that define the incidence of the disease. This is unlike Sickle Cell Anemia where a single nucleotide change or gene mutation is directly associated with disease incidence. The fact that “something that is isolated and altered by man” is covered by obviousness and infers naturally occuring in the human population. The statement “By definition the steps of isolating and altering are not steps that occur naturally”, are again steps that were derived prior published technologies and supported by public funding. The statement that “Even if the ultimate result is equivalent to nature, the process by which man modifies nature from one form into another form” is not supported by the prior identification of a sequence found naturally occuring in the human population and is only predisposing to an increased incidence in the occurance of the disease. This should not “be patentable under all existing understandings of method patents”.
I was one of the first people to propose, in my postdoctoral grant applications, mismatch hybridization as a method for deducing gene function and correcting gene mutations by replacing, deleting, or inserting nucleotides in any specific area of a gene in 1984. I was awarded funding by the NIH, American Cancer Society, and McKnight Foundation, so the creation of an altered DNA sequence is also obvious. The only bonafide claims should cover a kit for detecting sequences contaning somatic mutations that could predispose an individual to getting breast cancer and not be allowed to prevent further research in an area or extract exorbidant fees from a captive population at risk of death I do not see what you are alluding to, but patent validity is cetainly up for discussion as these gene sequences occur in nature, only predispose an individual to getting a disease, and involves technologies published in the public domain and supported by public funding. The only merit is the kit and this should not prevent anyone from coming up with a better or cheaper version using alternate proceedures.