Saturday, July 30, 2011

ACLU Responds to Myriad’s Letter Challenging Standing of Dr. Osterer

On Thursday I posted a letter from Myriad's attorneys to the Federal Circuit judges pointing out that the key plaintiff in the case (Dr. Osterer, the only plaintiff found to have standing in yesterday's decision from the Federal Circuit) has moved from NYU to Albert Einstein College of Medicine. Myriad asserts in the letter that Dr. Osterer will not be able to perform clinical genetic testing at Albert Einstein, and thus will not be because it into start conducting clinical BRCA testing if the Myriad gene patents are invalidated.

Yesterday, the ACLU responded with its own letter to the Federal Circuit, stating that Dr. Osterer will continue to offer clinical genetic testing at his new institution. It would seem to be an important point, since the District Court decision would have been vacated if the Federal Circuit had held that all of the plaintiffs lacked standing to bring suit. The only plaintiff that the Federal Circuit found to have standing was Dr. Osterer, and this was based explicitly on the court's understanding that he intended to begin conducting clinical BRCA testing if the patents could be invalidated. One wonders if this information could have altered the outcome if it had come to light sooner.

Thursday, July 28, 2011

Myraid Alerts Federal Circuit Judges that Key Plaintiff in AMP v. PTO Apparently Cannot Perform Clinical BRCA Testing

During oral arguments in AMP v. PTO (the ACLU/PubPat attack on Myriad Genetic’s BRCA gene patents, previously discussed here), the panel of Federal Circuit judges hearing the case evinced some skepticism as to whether any of the named plaintiffs have standing to bring the lawsuit. For example, many of the plaintiffs are patients who would not appear to be in any real threat of being sued by Myriad for patent infringement.

The plaintiffs most likely to have standing are probably the clinicians who the ACLU argues would engage in BRCA testing were it not for the Myriad patents. However, the declarations by these plaintiffs do not unambiguously state that the plaintiff would begin doing BRCA testing if the patents are invalidated. Instead, they merely declare that the plaintiff has the "capability and desire" to perform the tests, and that the plaintiff "has all the personnel, expertise, and facilities necessary to do various types of sequencing." These declarations were drafted by lawyers, and I think the language used is meaningful, reflecting the fact that these clinicians have not committed to performing BRCA testing if the patents are invalidated.

During oral arguments the Federal Circuit judges pushed the ACLU attorney to clarify whether this language indicated a commitment to perform the tests, implying that a mere "capability and desire" to perform the test might not be sufficient to generate the degree of controversy necessary for standing. In my opinion, the ACLU attorney never provided a clear answer to the question, which suggests that in fact these clinicians have not committed to performing the tests.

Yesterday, Myriad's attorneys sent a letter to the Federal Circuit judges informing them that one of the key clinician plaintiffs who submitted this sort of declaration, Dr. Harry Osterer, has left his position at the NYU Langone Medical Center, and apparently is no longer in a position to offer clinical BRCA genetic testing. Attached to the letter is a printout from the Albert Einstein College of Medicine, identifying Dr. Osterer as a new professor at Albert Einstein. In the letter, Myriad's attorneys state that Albert Einstein does not offer, and is not qualified offer, clinical genetic testing. If this is correct, this seems to further undercut any pretense that he is committed to offering clinical BRCA testing if the patents are invalidated. A copy of the letter is attached here.

Sunday, July 24, 2011

Myriad Genetics Files Amicus Briefs in Joint Infringement Cases Akamai and McKesson

Personalized medicine company Myriad Genetics has filed amicus briefs in Akamai and McKesson, two cases currently pending before the en banc Federal Circuit that address the doctrine of joint infringement (aka divided infringement). These cases have been the subject of much discussion elsewhere, see for example the Patently-O and Patent Docs blogs. In a nutshell, the Federal Circuit seeks to delineate the circumstances under which a party will be held liable for patent infringement when multiple parties perform all steps of the patented method in concert, but no single party performs all of the steps.

In its amicus briefs, which are largely redundant, Myriad points out that while the recent joint infringement cases coming out of the Federal Circuit have tended to involve claims directed towards business methods and software, the decisions have created case law with substantial negative implications for patents on diagnostics and personalized medicine. Molecular diagnostics generally involve the discovery of a correlation between a molecular marker (e.g., a genetic variation, or the level of a metabolite) and a clinically relevant indication (e.g., whether an individual has a predisposition to a disease such as cancer, or would be likely to benefit from a particular drug or course of therapeutic treatment). Patent protection for these discoveries is generally achieved by means of a method claim reciting two steps-(1) detecting the molecular marker in a patient, and (2) recognizing the correlation. As noted in the Myriad briefs, product claims on the molecular markers themselves (e.g., isolated DNA molecules or proteins), and methods of testing for them, are generally precluded in the post-Human Genome Project era by prior art (not to mention efforts by the ACLU and others to render such products unpatentable).

The problem from the perspective of a molecular diagnostic innovator company such as Myriad is that the Federal Circuit's recent joint infringement decisions would seem to dictate that such a method claim would not be infringed under circumstances where one party (e.g., a diagnostic testing laboratory) performs the first step and an independent second party (e.g., a doctor) performs the second. Under recent Federal Circuit case law, assuming that the parties are not in an agency relationship, it seems likely that in most instances no party would be found infringing, and the patent owner would be left without a remedy, even in the face of substantial infringement in competition with its business.

In its briefs, Myriad notes that the Federal Circuit has repeatedly admonished patent owners that problems of divided infringement could have been avoided if the claims have been better drafted, i.e., in a manner such that a single party performs all of the steps of a method claim. However, Myriad argues (correctly I think) that the patent eligibility doctrine effectively forecloses this course of action. The Federal Circuit's recent decision in Prometheus (discussed previously on this blogs), in particular, interprets Bilski as rendering patent ineligible a claim reciting nothing more than the mere recognition of a correlation per se (which the court equates with patenting a mental step). In order to be patent eligible, Prometheus seems to require a diagnostic method claim to explicitly recite a transformative step, such as detecting the marker, or treating a patient. This creates a Catch-22 for the diagnostic inventor. The discovery of the correlation is the core of the invention, providing substantial therapeutic benefits to patients, but under Prometheus and Bilksi a claim to the correlation must also include an additional step which will often render the claim highly susceptible to circumvention by two parties separately performing the steps.

To avoid this problem, Myriad proposes the following as an appropriate test for infringement of method claims by multiple parties:

When a first party performing one or more steps of a method claim actively causes another party to perform the other steps of the same method claim, or when two parties act in a concerted manner to perform all steps of a method claim, then the first party and the parties acting in concert should each be deemed a direct infringer.

Thursday, July 14, 2011

District Court Rules That Genencor Products Infringe Novozymes Patent

On July 7, a federal district court in the Western District of Wisconsin ruled on a motion for summary judgment that a number of Genencor's thermostable alpha-amylase products (sold under trade names such as Spezyme) infringe Novozyme’s US patent number 7,713,723. I have discussed earlier decisions in this case on this blog, including decisions by the District Court denying a motion to invalidate the claims for failure to satisfy the written description requirement (available here) and denying a motion for preliminary injunction (available here).

Claim 1 is representative of the claims found to be infringed:

1. An isolated variant of a parent alpha-amylase, wherein:
(a) the variant has at least 90% sequence identity to SEQ ID NO: 6,
(b) the variant comprises a substitution of serine at position 239 relative to the parent alpha-amylase, using the amino acid sequence of SEQ ID NO: 8 for determining position numbering, and
(c) the variant has increased thermostability relative to the parent
alpha-amylase, wherein thermostability is determined at pH 4.5, 90° C. and
5 ppm calcium and has alpha-amylase activity.

Prior to deciding the issue of infringement, the court had to construe several terms appearing in the claims.

For example, the court had to define what "thermostability" means in the context of the claims. The defendant Genencor argued that the term is so indefinite that the claims should be invalidated, but the judge disagreed and held that the term was not so ambiguous as to render the claims invalid. The court spent a lot of time discussing the ambiguity of the term, noting that it could be the case that a protein variant would have more activity than wild type at some time points after exposing the proteins to elevated temperature, but less activity at other time points, and it was not entirely clear from the patent whether this would constitute increased thermostability. However, the court held that even under a relatively narrow interpretation of the term, pursuant to which the protein variant would have to be more active at all time points under elevated temperature, the Genencor products still infringed because the retained higher activity than wild type at all times after exposing the proteins to high temperature.

Another claim term, which the court spent a lot of time was "isolated." Novozymes argued that "isolated" was not a limitation on the claim scope because it is part of the claims’ preamble. The district court spent some time considering this argument, but ultimately sided with Genencor and held that "isolated" does limit the scope of the claim. In part, it reached this decision because "isolated" did not appear in the claim originally but was introduced during prosecution of the patent application, which the court found implied that the term "isolated" was significant.

The parties disputed the meaning of the term “isolated,” with Novozymes arguing for a broad interpretation that would cover protein existing at a higher concentration in a cell or cell extract than it would naturally, while Genencor argued for a narrower interpretation in which the protein must to some extent be separated from other cellular components. The court adopted the narrower interpretation, but nonetheless found that most Genencor products infringed because they included isolated protein. However, the court did find that some Genencor products are not infringing in which the thermostable alpha-amylase is not separated from other cellular components, which the court referred to as "whole broth" products, because the protein is not isolated.

The proper interpretation of "isolated" in claims such as this has important implications for biotechnology patenting outside the confines of this particular case. For example, the patent office will not issue patents claiming naturally occurring gene sequences unless the claims specifically recite that the DNA molecule is isolated, purified, and/or recombinant, in order to exclude genes as they occur naturally (for example in the human genome). The assumption is that inclusion of the term "isolated" in the claim limits the scope of the claim. I don't think it is even accurate to consider the use of the term "isolated" in claims of this format as preamble, but in any event it should generally be treated as limiting the scope of the claim.

Furthermore, the scope of the term isolated is important in the context of gene patent. As I have discussed elsewhere, the question of whether genetic diagnostic testing or whole genome sequencing infringes gene patents could in many cases dependent on how broadly a court interprets the term isolated in these claims (I have always assumed that "isolated" is a meaningful limitation on claim scope in this context).

In this case, the prosecution history was apparently silent as to why Novozymes amended the claim to include the "isolated" language. It would not seem to be necessarily required in this case if the claim only covers non-naturally occurring variants, because then there would be no danger of the claim reading on a naturally occurring biomolecule. But perhaps Novozymes intended for the claim to cover naturally occurring thermostable variants, in which case limiting the claim to isolated variants would be necessary in order for the claim to be valid.

In any event, the fact that "isolated" was introduced by amendment was significant, because it led the court to rule that under Festo the term could not be expanded beyond its literal scope under the doctrine of equivalents.

Thanks to Docket Navigator for bringing this decision to my attention.

Monday, July 11, 2011

PTO Agrees to Reexamine Broad Codon-Optimization Patents

Many important applications of biotechnology involve the expression of recombinant genes in heterologous systems. Since the genetic code is degenerate (ie each amino acid can be coded by on average three different codons), the DNA sequence can be modified by synonymous nucleotide substitutions without altering the amino acid sequence of the encoded protein. A biotechnologist might find it useful to make a synonymous substitution for any of a variety of reasons, e.g., to introduce or remove restriction sites, or to remove repeats.

Today genes are also often altered for the specific purpose of optimizing expression, i.e., the entire coding region of the gene is recoded to fit one of a variety of codon optimization schemes. Examples of popular codon optimization schemes used in designing a gene for recombinant expression include:

A) Replace a degenerate codon with the most common codon present in the host chromosome; the rationale being that the most common codon correspond to the most common tRNA results in most protein yield.

B) Reengineer the gene so that it uses the same frequency of codons that are present in the host chromosome; the rationale being that the recombinant gene should have the same codon bias as the host chromosome to fit the translational machinery.

C) Re-code the pattern of rare and common codons found in the wild type by replacing it with the corresponding rare/common codons in the heterologous host; the rationale being that protein folding and expression requires rare (slow) and common (fast) codons distributed according to the folding domains in the protein.

D) Empirically identify codons and other variables that correlate with high protein expression in a systematically varied recombinant gene.

Codon optimization has become standard practice in the recombinant expression of heterologous proteins such as biologic drugs. Gene synthesis companies such as DNA2.0 and Blue Heron assist their customers by providing codon optimization as a part of their services.

Two U.S. patents (both assigned to the Massachusetts General Hospital) include claims directed towards codon optimization, both the method and the resulting codon-optimized gene (US Patent Numbers 5,786,464 and 6,114,148). These patents are very broad, purporting to cover any "synthetic gene encoding a protein normally expressed in an eukaryotic cell wherein at least one non-preferred or less preferred codon . . . has been replaced by a preferred codon encoding the same amino acid, [and wherein the replacement results in at least 10% increase in the level of protein expressed] in an in vitro mammalian cell culture system under identical conditions”

These patents appear to not only cover any successfully codon-optimized recombinant gene, but also many genes that have been reengineered for purposes other than codon optimization. For example, a silent mutation introduced for the purpose of removing a restriction site could easily constitute infringement if it results in the introduction of any of the 17 codons identified in the patent as “preferred,” if it turns out that the substitution results in a modest 10% increase in expression in any in vitro mammalian cell culture system. Rarely would an experimenter test for such an increase in expression at that level of accuracy, and a practical matter it would be virtually impossible to rule out the possibility of a 10% increase in expression in some mammalian cell culture system.

In view of their scope, and the pervasive use of codon replacement in the expression of high-value heterologous proteins (such as biologic drugs), these patents could potentially have sweeping implications for biotechnology. However, although the patents issued in 1998 and 2000, they have never been asserted in court and until recently appear to have received little attention.

However, the patents have recently become a thorny issue for those involved in the business of expressing heterologous proteins, particularly gene synthesis companies providing codon optimized genes for their customers. Last year Geneart (a German gene synthesis company owned by Life Technologies) began sending letters to companies engaged in the expression of heterologous proteins announcing that "we are very pleased to inform you that Geneart has acquired a license under [the Massachusetts General Hospital (MGH) Patents].” The letter goes on to state that under the license “Geneart is in the excellent position to offer a broad range of sublicensing opportunities." The licensing “opportunities” include a royalty-free sublicense to use synthetic genes purchased from Geneart in internal R&D, and a royalty-bearing commercial sublicense for synthetic genes used for purposes other than internal research and development. According to the letter, Geneart has executed a non-prosecution agreement with respect to synthetic genes delivered by Geneart to customers prior to May 30, 2010, so these customers are apparently free to use the genes in any manner without liability for infringement.

The letter goes on to imply that customers who choose to purchase synthetic genes from competing gene synthesis companies could be sued for infringing the MGH Patents, stating that "to Geneart’s knowledge, no other Gene Synthesis Service Provider has obtained a respective license under the MGH Patents."

This poses a problem for any biotechnologist wishing to use a synthetic or partially modified gene. Even slight variations to the wild-type sequence, such as restriction site removal or addition, could infringe.
It certainly poses a problem to other synthetic gene companies, whose customers might switch to Geneart in order to avoid a perceived threat of patent infringement liability for using synthetic genes not purchased from Geneart.

DNA2.0, a leading provider of synthetic genes headquartered in Menlo Park California, has responded to this perceived threat by successfully petitioning for reexamination of both patents, arguing that the broad claims are anticipated and/or rendered obvious by prior art not previously considered by the PTO. The orders granting the ex parte reexamination of the ‘148 and ‘464 patents were issued on December 14, 2010 and January 26, 2011, respectively.

The orders granting reexamination state that a number of references cited by DNA2.0 in the request for reexamination raise substantial new questions of patentability with respect to most of the claims in the patents, particularly the broadest claims. For example, an article published in the Journal of Virology in 1992 by Schwartz et al. describes the characterization of inhibitory RNA elements in the gag region of human immunodeficiency virus type I (HIV-1). This involved replacing many of the codons in the wild type gene with synonymous codons defined as "preferred" in the MGH Patents, resulting in at least a five-fold increase in expression. As another example, the PTO found an article disclosing a computer program for optimizing DNA sequences for protein expression, in combination with another article disclosing the most frequent human codon usage together with preferred codon choice patterns, also raise substantial new questions of patentability for many of the claims.

It is interesting to note that the corresponding codon optimization patent issued to MGH in Europe (EP 0 781 329 B2) is much narrower in scope, claiming a method for preparing a synthetic gene wherein at least 50% of the non-preferred codons and less preferred codons are replaced by preferred codons and resulting in a 10% increase in expression. In contrast, the US patents purport to claim any method that involves replacing even one codon with a preferred codon, and any gene made by such a process.

It is my understanding that, as a practical matter, the European patent only poses a substantial impediment to the “A” form of codon optimization described above, i.e., replacement of all degenerate codons with the most common codon present in the host chromosome. Most other codon optimizations do not require the substitution of 50% of non- or less preferred codons. In contrast, the U.S. patents would appear to cover the majority of recombinant protein expression that has been done in recent years. The patents should expire 2015, but the pending reexamination could be important if it results in cancellation or narrowing of the claims in the US patents, thereby providing assurance that companies will not be sued for expressing recombinant proteins prior to patent expiration.