Author Archives: Nelson R. Capes

Myriad Genetics: Laws of Nature and the Philosophy of Science

In Association for Molecular Pathology vs. Myriad Genetics, the Federal Circuit on August 16, 2012 issued its opinion regarding the patentability of Myriad’s method and composition of matter claims after the case was remanded by the Supreme Court in light of Mayo Collaborative Services v. Prometheus, Inc., 566 U.S. ___, 132 S. Ct. 1289 (2012).  The Federal Circuit upheld the patentability of Myriad’s composition of matter claims to isolated DNA encoding a mutation that is associated with an increased risk of breast cancer in women.  The Federal Circuit also upheld the patentability of Myriad’s therapeutic screening method but affirmed its earlier position that Myriad’s diagnostic methods are invalid under 35 U.S.C. § 101. This article discusses the composition of matter claims only.

 Recall that in this case, the issue (in regard to the composition of matter claims) was whether the cDNAs were or were not patentable as naturally-occurring compositions of matter (products of nature) under the Chakrabarty and Funk Brothers Supreme Court cases. The composition of matter claims were not precisely at issue under the “law of nature” doctrine. Still, a judgment had to be made as to what is “naturally occurring.” And this depends on one’s view of the “laws” of nature involved in gene sequencing and isolation.

 For many philosophers of science, laws of nature are descriptive not prescriptive. If we push a ball bearing off a table, it will fall to the floor. But we don’t imagine that, at the exact instant that the ball bearing ceases to be on the table, it says to itself “Oh my gosh, I’d better hurry up and fall to the floor, or I will be violating a law of nature!” No. What we call a “law” of nature here is that over thousands of years, people have observed that ball bearings or other objects fall to the floor when they are pushed off tables. We describe the result rather than prescribing it. Certainly, we can generalize the “law” well beyond ball bearings and tables. We can say that any macro object in a gravitational field will behave similarly. But our ability to generalize depends upon the lack of observation, in similar circumstances, of any exception to the “law.”

Until relatively modern times, we did not have the testing tools available that would let us modify the “law.” But now we know that in a zero-G environment such as an aircraft following a parabolic arc or in a spacecraft circling the earth, a ball bearing will not always fall to the floor when pushed off a table. Again, though, we don’t imagine the ball bearing saying to itself, “Thank God I don’t have to fall to the floor in this environment.” We can describe what will happen in that particular environment, but we don’t prescribe it.

 Because “laws” of nature are descriptive rather than prescriptive, natural laws can change over time. But we don’t imagine that before a zero-G environment was available for testing, ball bearings would have behaved any differently than they do now that we have the means to vary the testing environment. We just describe the effects of gravity differently, because now we are able to observe instances in which ball bearings don’t fall to the floor.

 The same is true in the wacky worlds of quantum mechanics and particle physics. “Laws” that work at the macro level simply don’t work at the quantum level. Some philosophers believe that fundamental physics is the only science in which it is possible to discover “exceptionless regularities” that can be called “laws.” All other sciences (including genomics) can only specify regularities that are true in a particular context. An interesting discussion of this idea and the idea of laws of nature generally can be found in Carroll, John W., “Laws of Nature”, The Stanford Encyclopedia of Philosophy (Spring 2012 Edition), Edward N. Zalta (ed.), URL = <http://plato.stanford.edu/archives/spr2012/entries/laws-of-nature/&gt;.

 This is why it is difficult to apply Section 101 of the U.S. patent law consistently. The case law around Section 101 states certain inventions are a priori unpatentable, namely, inventions that pre-empt a law of nature or a product of nature. There is a sense that the laws and products of nature should be freely available to anyone. The problem comes in figuring out 1) what law or product of nature is at stake and 2) does the particular invention pre-empt that law. Furthermore, because “laws” of nature are descriptive of the state of scientific knowledge at a given point in time, and scientific knowledge changes as discoveries are made, “laws” of nature (as described by human beings) for many philosophers of science cannot be prescriptive, that is, covering all known instances and unknown future instances. Thus, the really difficult question in cases such as Myriad is whether the issue is one of law or one of philosophy.

 In the August 16 decision, Judge Lourie re-affirmed his earlier holding that the claimed cDNAs were not “naturally occurring” because they do not exist in nature in their exact molecular form. In nature, the cDNAs only exist as a part of genomic DNA. The cDNAs were created by severing covalent chemical bonds, removing the DNA from its natural state where it is bound to histones, and then removing the introns from the genomic DNA. To put his holding into the concepts we are discussing, Judge Lourie was saying, in effect, “genomic scientists have not found any instance of a free standing cDNA with the sequence of nucleotides claimed.”  Thus, the “law” of nature is that living cells do not have such free standing cDNAs (a description). It is conceivably possible that a cell might be found in nature with such cDNAs, so the “law” is not prescribing that such cDNAs cannot be found in nature. It is enough that they are not. Furthermore, Judge Lourie is saying that what makes a cDNA patentable subject matter is not its nucleotide sequence (which is the same in the genomic DNA), but rather the absence of covalent chemical bonds between the cDNA and other entities. Yet this is a challengeable position, and Judge Bryson does challenge it, as we will see below.

 Judge Moore agreed with Judge Lourie that there are chemical differences between the chemical structure of the cDNAs and naturally occurring DNA.  However, for Judge Moore, it is not the absence of chemical bonds alone in the claimed cDNAs that make them patent eligible under Section 101. Rather, it is the different function that cDNAs perform (such as use in primers and probes) that makes them patentable.

 Judge Bryson’s view is that breaking chemical bonds is not patentably different from taking a cutting from a wild plant. For Judge Bryson, “there is no magic in a chemical bond that requires us to recognize a new product when a chemical bond is created or broken, but not when other atomic or molecular forces are altered.” Judge Bryson seems to be saying that different “laws” of nature are not involved in breaking a chemical bond vs. cutting tissue with a scissors.  He is not clear, however, on why breaking a chemical bond does not involve a different “law” than physical cutting. As discussed above, for some philosophers of science, the closer we get to fundamental physics, the more likely the possibility of finding “exceptionless regularities.” Clearly, breaking a chemical bond is much closer to fundamental physics than cutting tissue with a scissors. His other theory is that the inventors in Myriad Genetics were simply isolating the cDNAs “according to nature’s predefined boundaries, i.e., at points that preserve the ability of the gene to express the protein for which it is coded.” This sounds like a prescriptive law, not a descriptive law. Are there “predefined boundaries” in nature?  For example, Judge Bryson says:

 “…the function of the claimed molecule is dictated by the nucleotide sequence of the gene – a sequence that is determined by nature and that appears in nature exactly as it appears in the claimed isolated DNA.”

The continuing discoveries of genomic scientists on the precise inter-working of codons with non-coding portions of DNA makes such a pronouncement risky.

 Judge Lourie stated:

 “The remand of this case for reconsideration in light of Mayo might suggest, as Plaintiffs and certain amici state, that the composition claims are mere reflections of a law of nature. Respectfully, they are not, any more than any product of man reflects and is consistent with a law of nature. Everything and everyone comes from nature, following its laws. But the compositions here are not natural products. They are the products of man, albeit following, as all materials do, laws of nature.” (italics added)

But for many philosophers compositions of matter (whether they be ball bearings or cDNAs) do not “follow” laws of nature (in the sense of obeying them). At any point in time, we only perceive that there are no instances of a particular type of entity not behaving in accordance with observable natural “laws.” Laws of nature describe the way objects in the natural universe behave; they do not prescribe such behavior.

As Judge Lourie further stated:

 Under the statutory rubric of § 101, isolated DNA is a tangible, man-made composition of matter defined and distinguished by its objectively discernible chemical structure. Whether its unusual status as a chemical entity that conveys genetic information warrants singular treatment under the patent laws as the district court did is a policy question that we are not entitled to address. Cf. Nat’l Fed’n of Indep. Bus. v. Sebelius, 132 S. Ct. 2566, slip op. at 6 (2012) (“[W]e possess neither the expertise nor the prerogative to make policy judgments. Those decisions are entrusted to our Nation’s elected leaders, who can be thrown out of office if the people disagree with them.”).

 Ultimately, whether or not isolated cDNAs should be unpatentable because they have the same nucleotide sequence as “naturally occurring” DNA is a philosophical, scientific, and policy question, not purely a legal question.

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Patent trolls and the AIA – a Potential non-Litigation Business Strategy

On March 16, 2013, the United States changes from a “first to invent” country to a “first inventor to file” country for patent applications.

Patent “trolls” or “non-practicing entities” (NPEs) own patents but do not make, use or sell the patented product.  Instead, patent trolls have in the past generally followed a business model in which, under the threat of patent litigation, they demand and receive relatively small amounts of revenue from a large number of targets.  Each of the targets believes that it is in its best interest to pay the troll a relatively small licensing fee for use of the patent rather than face the possibility of huge, uncertain damages in a patent infringement lawsuit. By owning a large number of patents, a patent troll can have a large potential market. However, section 299 of the AIA, effective as of September 15, 2011, limits the ability of patent trolls to join large numbers of accused infringers in a single patent infringement suit. Thus, the AIA section 299 may drastically change the traditional litigation business strategy used by patent trolls.

However, the AIA also opens up a potential new, non-litigation business strategy for patent trolls.

As of March 16, 2013, 35 U.S.C. 102(a)(2) becomes effective. This section of the patent law states “A person shall be entitled to a patent unless…the claimed invention was described in a patent issued…or in an application published…in which the patent or application…names another inventor and was effectively filed before the effective filing date of the claimed invention.” 35 U.S.C. 102(b)(2), however, contains an exception to the above.  It states: “A disclosure shall not be prior art to a claimed invention under subsection (a)(2) if…the subject matter disclosed and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person.”

A picture is worth a thousand words. Take a look at the following example in which B is a patent troll that owns invention B and A is a target company which owns invention A.

Under the AIA, as cited above, if B’s effective filing date is earlier than A’s effective filing date, B will be prior art to A and the disclosure in B may prevent patent A from issuing. However, this result can be avoided if A owns invention B “not later than the effective filing date” of invention A.  On or after March 16, 2013 an issued patent or pending patent application that would be prior art to a new application has potential value to the applicant for a new patent. Thus,  the date of March 16 can be a “bridge” between the troll’s patent or application having no value to target A and a value that may be large, depending on the significance of the target’s new patent application and the presence/absence of other prior art. If company A believes that invention A is key to its business, company A may be willing to buy application B at a significant price. However, if there is other prior art, company A may only be willing to pay the troll less money for application B.

This strategy has the disadvantage that (probably) the patent troll can only use it against one target at a time,  because the troll is selling the leveraging patent, not licensing it to many targets. However, if section 299 of the AIA has the predicted deterrent effect on the joinder of multiple defendants, the strategy may be the only one left to the patent troll.

Note that this strategy will not work before March 16, 2013. Before that date, company A may be able to “swear behind” the filing date of invention B under 37 CFR 1.131 by establishing by oath or declaration that the subject matter of invention A was invented prior to the effective date of invention B.  Therefore, it is prudent for company A to file a patent application for invention A prior to March 16, 2013, particularly if it is aware of invention B. By doing this, company A cuts off the troll’s potential market for invention B.

Gene Patents: The Myriad Genetics Case – Understanding the Science and the Law

This is a series of articles on the Myriad Genetics case (Association for Molecular Pathology v. U.S. Patent and Trademark Office, No. 2010-1406 (Fed. Cir. July 29, 2011). A three-judge panel of the U.S. Court of Appeals for the Federal Circuit reversed a district court decision that Myriad Genetics, Inc. patents to isolated DNA molecules encoding the BRCA1 and BRCA2 genes which control a hereditary predispositon to breast cancer, were patent-ineligible products of nature under 35 USC 101. On March 26, 2012, the U.S. Supreme Court granted a petition for a writ of certiorari and remanded the case to the Federal Circuit for further consideration in light of Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. ___ (2012).

In this series, a biotechnology patent attorney provides a look at the science behind the case, followed by a review of the separate holdings of the three-judge panel in regard to the composition claims.  It is hoped that the series will be particularly valuable to the non-specialist patent attorney as well as other readers of this series. The following are the links to the series:

https://intellectualip.com/2012/03/28/gene-patents-part-1-the-science/

https://intellectualip.com/2012/04/03/gene-patents-part-2-the-science-continued-2/

https://intellectualip.com/2012/04/10/gene-patents-part-3-the-science-continued/

https://intellectualip.com/2012/04/20/gene-patents-part-4-the-science-continued/

 https://intellectualip.com/2012/07/02/gene-patents-part-5-the-law/

AIA – Summary of new § 102(a) and (b)

The America Invents Act of 2011 contains a number of very important changes to United States patent law. Probably the most discussed change is that of a “first to invent” system to a “first inventor to file” system.  This change is implemented in Sections 102(a) and 102(b) of Title 35 of the United States Code, and will go into effect on March 16, 2013.  These two sections contain a lot of changes making them significantly different from their current counterparts.  It is difficult to read the text of the statute and understand its full impact without going through a number of scenarios.  The link in this post is to a Powerpoint presentation that lays out most of the significant timing questions via a number of distinct scenarios.  The presentation also includes a number of “take-aways” and practice tips that are immediately significant for applicants to understand even prior to March 16, 2013.

USPTO Proposed Rules on First-inventor-to-file under the AIA Require Statement regarding Claim to the Benefit of the Filing Date of an Application Filed Prior to March 16, 2013

On July 26, 2012, the United States Patent and Trademark Office issued proposed rules implementing the first-inventor-to-file provisions of the America Invents Act (AIA). These proposed rules will be in effect for any United States Patent Application filed after March 16, 2013. The proposed rules in the Federal Register are available for public comment until October 5, 2012.

Among other things, the Office is proposing additional requirements for nonprovisional applications filed on or after March 16, 2013, that claim the benefit of the filing date of a foreign, provisional, or nonprovisional application filed prior to March 16, 2013. If such a nonprovisional application contains at any time a claim to a claimed invention that has an effective filing date on or after March 16, 2013, the applicant must provide a statement to that effect. A statement is also required if the nonprovisional application does not have a claim to a claimed invention that has an effective filing date on or after March 16, 2003 but discloses subject matter not also disclosed in the foreign, provisional, or nonprovisional application.

The Office stated that examination costs will “significantly increase” if the Office must determine on its own the effective filing date of every claim ever presented in an application filed on or after March 16, 2013, that claims priority to or the benefit of a foreign, provisional, or nonprovisional filed prior to March 16, 2013.

Please see our earlier post on the implications of this portion of the AIA at https://intellectualip.com/2012/07/23/america-invents-act-aia-effective-filing-date-a-trap-for-the-unwary/.

America Invents Act (AIA) Effective Filing Date: a Trap for the Unwary

Many inventors and businesses believe that they do not need to worry about the “first inventor to file” changes of the AIA until March 16, 2013. Here we show why they need to start worrying about it now.

Section 3 of the America Invents Act (AIA), 35 U.S.C 146, becomes effective on March 16, 2013. However, paragraph (n) of this Section of the AIA contains a particularly hazardous trap in regards to the “effective filing date” of a patent application. The section reads:

(n) EFFECTIVE DATE-

(1) IN GENERAL- Except as othewise provided in this section, the amendments made by this section…shall apply to any application for patent, and to any patent issuing therefrom, that contains or contained at any time —

(A) a claim to a claimed invention that has an effective filing date…that is on or after the effective date described in this paragraph or

(b) a specific reference under section 120, 121, or 365(c) of title 35, United States Code, to any patent or application that contains or contained at any time such a claim.

Let’s try to unpack the text and understand the trap.

First, the simple case – no trap. Smith files a patent application on March 16, 2013. March 16, 2013 is the “effective filing date.”  This is the first such patent application that Smith has filed for the claimed invention. The invention does not claim priority to an earlier-filed patent application. Result: the AIA “first inventor to file” provisions apply. Assuming Smith is the first inventor to file a patent application for the claimed invention, Smith will be entitled to a patent (providing, of course, that the invention is patentable under other provisions, such as novelty and nonobviousness, not successfully challenged under the post-grant review provisions of the AIA, or other possible reasons for unpatentability).

Under the Patent Act of 1952, as amended, in effect through March 15, 2013, a patent applicant could claim priority to a previously-filed patent application, as long as at least one inventor of the current patent application was named in the previously-filed patent application and the current patent application contained a reference to the previously-filed application. If both the effective filing date and the priority date of the current application are before March 16, 2013, the “first to invent” law that most inventors and businesses are familiar with will apply. However, under the AIA, Section 3(n), if even one claim in the current application is not entitled to a filing date before March 16, 2013, all of the claims will be treated under the new “first inventor to file” provisions.

So here is an example of the trap. On August 1, 2012, Smith (thinking that he does not need to worry about the AIA “first inventor to file” changes), files patent application A. Application A contains only one claim, with three elements, (a), (b), and (c). Elements (a) and (b) are thoroughly described in the patent application, but the description of element (c) is not very good. Smith plans to do some more experimentation on element (c). Patent application A receives an effective filing date of August 1, 2012. On March 16, 2013, with the experimentation on element (c) complete, Smith files a new patent application B with exactly the same claim with exactly the same elements: (a), (b) and (c). The new patent application B contains a reference under 35 U.S.C. 120 to the previously-filed application, A.

If Smith had filed application B on March 15, 2013, Smith would not have gotten an effective filing date for claim 1 of application B of August 1, 2012, because element (c) was not adequately described in patent application A. But it might not matter. If someone else filed a patent application C before Smith’s filing date, and the other application C was not a statutory bar under 35 U.S.C. 102(b), Smith could “swear behind” the other application C by showing that he, Smith, invented the claimed invention before the filing date of the other application C. Thus, Smith could have taken advantage of the “first to invent” law.

However, when Smith delays only one day, until March 16, 2013, to file application B, he has fallen into the trap. Elements (a) and (b) receive a priority date of August 1, 2012. But element (c)  receives an effective filing date of March 16, 2013 because it was not adequately described in application A.  This puts all of claim 1 (and any other claims) under the “first inventor to file” law. Now, Smith can not “swear behind” application C because “first inventor to file” is in effect. Smith does not get a patent on application B (unless Smith can show by the new “derivation proceedings” that the inventor of application C derived the invention from Smith, or unless Smith and the other inventor were both obligated to assign their patent applications to the same person).

Note also that Smith can’t cure this situation by deleting element (c) of claim 1 before a first Office Action citing application C, because the AIA applies to any patent application that contained at any time a claim with an effective filing date on or after March 16, 2013!

Inventors who file patent applications in the United States need to be aware of this trap. Smith either should have done enough experimentation to support element (c) in patent application A as of August 1, 2012, or Smith should have filed application B as soon as the experimentation on element (c) was complete but before March 16, 2013. The moral of the story is: file early and file often starting now.

USPTO Implements Third-party Pre-issuance Submissions

On July 17, 2012, the United States Patent and Trademark Office (USPTO) announced the final rules regarding third-party pre-issuance submissions under the Leahy-Smith America Invents Act (AIA), which amends 35 U.S.C. 122 by adding 35 U.S.C. 122(e). The new rules will be effective on September 16, 2012 for any patent application filed before, on, or after that date.  The new rules are implemented in 37 CFR 1.290.

The new rules provide a “mechanism for third parties to contribute to the quality of issued patents by submiiting to the Office, for consideration and inclusion in the record of a patent application, any patents, published patent applications, or other printed publications of potential relevance to the examination of the application.” This provides a way for a third party to potentially block the issuance of a patent that the party feels does not meet the requirements of the Patent Act, instead of or in addition to attempting to challenge an issued patent by a re-examination procedure.

In order to be considered by the office, a third-party submission must pay a fee and provide a copy of each printed item and a statement of relevance. The submission must be filed prior to the earlier of (1) a notice of allowance or (2) the later of (i) six months after the date on which the application is first published under 35 USC 122(b), or (ii) the date of the first rejection of any claim. Extensions of time will not be allowed. The submission may be filed electronically through the Office’s EFS-Web system or by mail.

For further information, the text of the new rule can be found at the following link: http://www.gpo.gov/fdsys/pkg/FR-2012-07-17/pdf/2012-16710.pdf.

Gene Patents (Part 5 – the Law)

This is the fifth in a series of articles on the Myriad Genetics case. Here are the links to the previous articles in the series:

 ‎ https://intellectualip.com/2012/03/28/gene-patents-part-1-the-science/

 https://intellectualip.com/2012/04/03/gene-patents-part-2-the-science-continued-2/

 https://intellectualip.com/2012/04/10/gene-patents-part-3-the-science-continued/

https://intellectualip.com/2012/04/20/gene-patents-part-4-the-science-continued/

The previous posts in this series attempted to provide sufficient background in molecular biology to enable the non-specialist patent practitioner to understand the issues in Association for Molecular Pathology v. U.S. Patent and Trademark Office, No. 2010-1406) (Fed. Cir. July 29, 2011) (“the Myriad Genetics case”). We now return to the case with this background in mind.

It will be useful to begin by looking at some representative composition claims of the underlying patents, as did the majority in Myriad Genetics.  Claims 1, 2, and 5 of U.S. Patent N0. 5,747,292 (“the ‘282 patent) are:

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.

The USPTO uses sequence identifiers (SEQ IDs) to unambiguously identify the nucleotide or protein sequence in a macromolecule. The ‘282 patent identifies SEQ ID NO:1 as being of the molecular type cDNA and having a length of 5914 base pairs. Further, the ‘282 patent identifies SEQ ID NO:2 as being of the molecular type protein and having a length of 1863 amino acids. Simple math (each amino acid requires 3 nucleotides in a cDNA) indicates that only 5589 base pairs would be required in a cDNA to encode the protein of SEQ ID NO:2. Although the ‘282 patent also includes sequence id’s to smaller and larger molecules (85 sequence id’s total), none of these sequence id’s is directly claimed in the ‘282 patent.

The ‘282 patent also includes in its Specification a number of important definitions.  For example, “coding for” in claim 1 would be defined by “Encode. A polynucleotide is said to ‘encode’ a polypeptide if, in its native state or when manipulated by methods well known to those skilled in the art, it can be transcribed and/or translated to produce the mRNA for and/or the polypeptide or a fragment thereof.” (‘282 patent, column 19 lines 1-5). Further, “isolated” is defined as a nucleic acid “which is substantially separated from other cellular components which naturally accompany a native human sequence or protein, e.g. ribosomes, polymerases, many other human genome sequences and proteins. The term embraces a nucleic acid sequence or protein which has been removed from its naturally occurring environment and includes recombinant or cloned DNA isolates and chemically synthesized analogs or analogs biologically synthesized by heterologous systems.” (‘282 patent, column 19 lines 8-18)

Under the above definitions, claim 1 encompasses all polynucleotides which can be transcribed or translated into the polypeptide of SEQ ID NO:2. As the reader will know from the previous posts in this series, this includes the full gene or open reading frame that encodes the BRCA1 polypeptide, as well as smaller portions of the open reading frame such as cDNAs resulting from removal of the introns from the gene. Claim 2 is much narrower than claim 1, claiming only the 5914 base pair sequence of SEQ ID NO:1, presumably the cDNA resulting from reverse transcription of mRNA with the introns removed. Claim 5 is really no narrower than claim 1, since it claims “at least 15 nucleotides” and thus encompasses a genus of all polynucleotides that “encode” the BRCA1 polypeptide from 15 nucleotides in length up to the full  open reading frame. All other terms of the above claims are self-defining to one of ordinary skill in the art.

The Federal Circuit’s decision in the Myriad case was by a three-judge panel. Judge Lourie wrote the opinion of the Court, with Judge Moore concurring in part and Judge Bryson concurring in part and dissenting in part.

Judge Lourie held that “the challenged claims to isolated DNAs, whether limited to cDNAs or not, are directed to patent-eligible subject matter under Section 101.” (Association for Molecular Pathology at 39) Judge Moore joined the majority opinion with respect to claims to isolated cDNA sequences and concurred in the judgment with respect to the other sequences. He wrote separately to explain his reasoning. Judge Bryson concurred with respect to the patentability of the cDNA claims but dissented with respect to the gene claims, finding them to not be patent-eligible.

Judge Lourie’s opinion discusses the law of patentability of isolated DNA molecules, and I refer the reader to his opinion for the details. In summary, the Supreme Court’s opinions in the Chakrabarty and Funk Brothers cases are controlling. Chakrabarty’s holding was that a claim to “a non-naturally occurring manufacture or composition of matter — a product of human ingenuity ‘having a distinctive name, character [and] use” is patent-eligible under 35 U.S.C. 101. In contrast, the bacteria in Funk Brothers were found to be non-patent eligible under that statute, the difference being that Chakrabarty’s bacteria had “markedly different characteristics from any [bacterium] found in nature” based on the efforts of the patentee. According to Judge Lourie, the distinction rests on a “change in the claimed composition’s identity compared with what exists in nature.” Judge Lourie applied this law to the facts of the Myriad case, finding that because isolated DNA had covalent bonds in its backbone chemically severed, “BRCA1 and BRCA2 in their isolated state are not the same molecule as DNA as it exists in the body; human intervention in cleaving or synthesizing a portion of a native chromosomal DNA imparts on that isolated DNA a distinctive chemical entity from that possessed by the native DNA.” He rejected the plaintiff’s argument that, because the isolated DNAs have the same nucleotide sequence as native DNAs, they do not have any “markedly different” characteristics. For Judge Lourie, the information content of the DNA is not what makes a DNA markedly different from another: rather, it is the molecule’s chemical structure and not its function.

Judge Moore’s concurrence is aimed more directly at the chemical nature of the DNA sequences claimed. He pointed out that DNA is a chemical polymer that is “no different than any other well known polymer, for example, nylon.” Polymerization of the 4 mononucleotides “results in a molecule with a different ionic charge, different chemical bonds, and a different chemical composition, as compared to the monomers in aggregate.” Like Judge Lourie, Judge Moore takes a position that it is not the information content of DNA that is significant for patentability, but rather its chemical structure: “just because the same series of letters appears in both the chromosome and an isolated DNA sequence does not mean they are the same molecule.” He found the cDNA claims such as claim 2 of the ‘282 patent to be patentable under 35 USC 101. He expressed greater concern for the genomic DNA claims such as claim 1. In exploring these differences, he focused on the utility of the claimed DNAs. He found the short sequences of claim 2 to have clear utility in diagnostic testing as primers and probes, stating that “the body does not naturally engage in this type of testing….” However, he also found that the longer DNA sequences as claimed in claims 1 and 5 do not have such utility. He stated: “Whether an isolated gene is patentable subject matter depends on how much weight is allocated to the different structure as compared to the similarity of the function to nature.” Under this test, he implies, the longer DNA sequences would not be patentable because, although they are structurally different from naturally-occurring DNA, they do not have a significantly different function.  However, he declines to rule the longer DNA sequences unpatentable because of the settled expectations of the scientific community created by the thousands of gene patents that have been issued by the U.S. Patent and Trademark Office.

Judge Bryson’s opinion takes a stronger position against the gene claims, finding that they are not directed to patentable subject matter, while concurring that the cDNA claims are patentable. His concern is that upholding patentability of the gene claims may preempt methods for whole-genome sequencing. Although the isolated genes have a different chemical structure from those found in the body, the “only material change made to those genes from their natural state is the change that is necessarily incidental to the extraction of the genes from the environment in which thay are found in nature.” He sees this isolation process as not significantly different from extracting a mineral or taking a cutting from a wild plant. For Judge Bryson, “there is no magic in a chemical bond that requires us to recognize a new product when a chemical bond is created or broken, but not when other atomic or molecular forces are altered.” There is no difference in terms of patentability between breaking a chemical bond and separating a cutting of a wild plant by scissors. The claimed genes have merely been isolated “according to nature’s predefined boundaries, i.e., at points that preserve the ability of the gene to express the protein for which it is coded.” Here, of course, he is referring to the removal of introns from the naturally-occurring gene to produce a cDNA. I refer the reader to Part 2 of this series. Thus, he concludes, claims to the short cDNA sequence are patentable under 35 U.S.C. 101, but claims such as claims 5 and 6 are not. He supports this position by noting that claim 6 would cover each BRCA1 exon, and also the cDNA of “more than 4% of human genes.”

Gene Patents (Part 4 – the Science, continued)

In Part 3 of this series, we looked at the standard molecular biology tools that can be used to create and manipulate cDNA.  In this part, we will look at the ways in which the function of the cDNA may be determined.

Once enough cDNA has been isolated and/or synthesized, we use standard tools to find the sequence of nucleotides in the particular cDNA of interest.  Once this is determined, we can determine the chemical structure and characteristics of the cDNA. The particular cDNA could in theory be the subject of a patent application which claims the cDNA as a chemical molecule (more about this in a future post).

However, in addition to its chemical properties, cDNA has informational properties: it contains the genetic code for a particular protein. Knowing the chemical structure will not by itself tell us the protein that it codes for and the function of that protein in the eukaryotic cell from which the cDNA was derived.  We will probably have great interest in writing patent claims for the protein and its function (again, more about claiming in a future post).

There are a number of standard methods that can be used to determine the protein that the cDNA codes for. These methods are known as screening methods. Screening methods may be classified as follows.

In silico screening refers to methods that compare the nucleotide sequence of the cDNA of interest or the amino acid sequence of a protein of interest to databases of expressed sequence tags (ESTs) or databases of the complete or partial genome of the organism of interest. This can be done relatively rapidly by computer software such as BLAST (Basic Local Alignment Search Tool). Another variation would be that we have a database of the genome of a related organism (a homologue). Because of the inherent uncertainty of the mathematics, however, we will only have a probability (perhaps quite high) of identifying the protein that the cDNA codes for.

More accurate screening methods are screening by nucleic acid hybridization, screening by expression in vivo, and screening by expression of coding sequences in vitro (Christopher Howe, “Gene Cloning and Manipulation,” Cambridge University Press, 2007).

Screening by nucleic acid hybridization relies on the base pairing (A to T, G to C) through hydrogen bonds between complementary polynucleotides. It uses a probe DNA (labelled in some way such as by radioactivity) to find complementary sequences in the target cDNA. For example, PCR amplification of a known cDNA as described in Part 3 may yield a product that can be used as a probe to find the same sequence in a target cDNA.

Screening by expression in vivo generally relies on selection of a cDNA clone from a library by using a vector to insert the cDNA into a host species (such as E. coli) and then testing for the recombinant host species that expresses the gene of interest, i.e., the genetic phenotype, as described in Part 3.

Screening by expression of coding sequences in vitro relies on the ability of an extract of a bacterial species (e.g. E. coli) to transcribe and translate a plasmid containing the cDNA of interest and detection of the translated product through  the incorporation of radiolabelled amino acids into the expressed protein. Transcription and translation were explained in Part 1.

In all of the above methods except the in silico method, the goal is to physically isolate a cDNA that has a high probability of coding for a particular protein of interest, either through expression of the gene in the eukaryotic cell or in another host, or through detection of the protein expressed by the cDNA outside the eukaryotic cell or another living host.

Gene Patents (Part 3 – the Science, continued)

In Part 2 of this series, we looked at one type of DNA, complementary DNA, also known as cDNA, in terms of its basic structure. cDNA has many uses in molecular biology. Because the sequence of nucleotides in a molecule of cDNA is the same as that in the genomic DNA, cDNA can be sequenced to determine that nucleotide sequence. This is possible because cDNA is synthesized from the messenger RNA (mRNA) that is made in the cell by transcription from the gene or open reading frame. The cDNA will have only the exons (the coding portion) and not the introns (the non-coding portion) of the gene.

In this part, we will look at the standard molecular biology tools that can be used to create and manipulate DNA, and particularly cDNA.

In eukaryotic cells (i.e., those cells that have a nucleus), genomic DNA is packaged into the chromosomes. Human beings have 23 pairs of chromosomes.  Each chromosome contains billions of nucleotides in the DNA. Standard techniques have been developed for isolating the genes or open reading frames in this DNA and determining the nucleotide sequence. Space does not permit a detailed study of these techniques, but we can discuss the general idea.

In order to obtain enough DNA to sequence, the candidate DNA must be “amplified.” Sequencing uses automated machines that analyze the DNA chemically.  Although these machines can work with very small quantities of DNA, there is a minimum amount. Eukaryotic cells (e.g., human tumor cells) express many genes as mRNA. Only a fraction of the total mRNA in a cell will be the mRNA that is expressed by the gene of interest. Eukaryotic cells divide relatively slowly, and it would take a very long time, even if the cells of interest were grown outside the body, to obtain enough cells to extract the DNA of interest.

Instead, the entire eukaryotic genomic DNA may be digested into smaller segments by “restriction enzymes.”  These enzymes break the covalent bonds (see Part 2) between the nucleotides only at certain nucleotide sequences. If the genomic DNA is partially digested by a restriction enzyme, the size distribution of the resulting restriction segments will depend upon how many nucleotides are in the recognition sequence for that particular restriction enzyme.  By using the correct restriction enzyme (which are commercially available) and adjusing the conditions of the enzymatic reaction, a desired restriction segment size may be obtained.  It will then be possible to obtain a mix of restriction segments containing all of the nucleotide sequences in the genomic DNA, including that for the target gene.  However, there may not be enough DNA in each restriction segment to sequence.

The next step is to clone the restriction segments into an organism, such as the bacterium E. coli, whose cells divide very rapidly. Cloning is generally done by inserting each restriction segment into small segments of the bacterial DNA called “plasmids” that replicate within the bacterial cell.

Plasmids

  Commercially available plasmids contain multiple restriction sites (corresponding to the restriction site that was used to digest the eukaryotic DNA, and others), some sort of selection site (e.g., a gene that gives the bacterial cell resistance to a particular antibiotic), and a “marker” for the detection of the clones.  Plasmids such as these are called “vectors.” One commercially available vector, call pUC19, is shown below. The site amp confers resistance to the antibiotic ampicillin. The site lacZa is a marker for the enzyme beta galactosidase. The “polylinker” is a segment of plasmid DNA that contains several restriction sites, including the restriction site for the restriction enzyme that was used to digest the eukaryotic DNA.

Vector PUC19

If the partially digested DNA from the eukaryotic cells is mixed with a digest of the plasmid, and the bacterial cells are cultured in a growth medium, a certain number of the bacterial cells will contain a plasmid that contains the restriction segment that in turn contains the genomic DNA of interest. These cells can than be plated out onto a growth medium that contains the antibiotic, and only those bacterial cells that contain the plasmid with the gene that gives resistance to the antibiotic will grow. Further selection can be done by using a marker, such as a gene that codes for the enzyme beta galactosidase. This gene, if intact in the cell, will give the cell a white color, and if the marker gene is not intact, the cell will have a blue color. If a restriction segment is inserted into the polylinker, the lacZ site will not be intact. Colonies of bacteria that are white will then each contain a plasmid that includes a restriction segment. Each colony is then grown separately in culture, resulting in separate batches of cells for each restriction segment. The DNA is then extracted from each batch of cells and used to produce cDNA by the reverse transcriptase enzyme discussed in Part 2 of this series. Each restriction segment from the original eukaryotic DNA will then be represented by a cDNA molecule. The collection of such cDNA molecules is called a “library.” If the eukaryotic DNA was extracted from a tissue that would be expected to be enriched for the DNA of interest (if, for example, the DNA was extracted from a tumor and we were looking for the DNA that encodes a protein that is implicated in the tumor), then the cDNA is called a “shelf” in the library.

The restriction enzyme/vector method of amplifying cDNA involves the breaking of the covalent phosphodiester bonds in the polynucleotide chain. A different method, polymerase chain reaction (PCR), involves the breaking and re-forming of the hydrogen bonds between the two polynucleotide chains. Unlike the covalent bonds in the backbone of the DNA strands, the hydrogen bonds between the two strands can be denatured by heating the DNA, and can then be re-formed by cooling the DNA. If we know part of the polynucleotide sequence of the DNA of interest, we can incorporate a polynucleotide having this sequence and the individual nucleotides (A, T, G and C) in a reaction mixture with a DNA polymerase enzyme.  The polynucleotide is called a “primer.” The mixture is heated to denature the DNA, the mixture is cooled to anneal the primer to each strand of the denatured DNA, and the DNA polymerase synthesizes a matching strand to each strand of the DNA. Then the new double-stranded DNA molecules are denatured, cooled, and annealed to the primer again. This cycle continues many times until a large number of copies of the original DNA have been synthesized. This can be done automatically by machines.  The following figure shows the steps of PCR.

Polymerase Chain Reaction

Once there is enough pure DNA, either through cloning or PCR, or both, standard biochemical techniques can be used to determine the sequence of the nucleotides in the DNA.  These techniques are so standardized that it is not necessary to explore them in greater depth for the purpose of this series of articles.

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