By Donald Zuhn --
Yesterday, we posted a response from Dr. Chris Mason of Cornell University to a recent Patent Docs post and an article posted by Dr. Chris Holman on Holman's Biotech IP Blog. Dr. Mason co-authored an article in the current issue of Genome Medicine, which contends that due to the non-specificity of sequence uniqueness across the genome and the broad scope of claims to nucleotide sequences, the Supreme Court and Congress should limit the patenting of existing nucleotide sequences. In his response, Dr. Mason comments on several aspects of the Holman and Patent Docs posts, which he says suggest that the analysis from his paper "was mistaken or did not embody an accurate characterization of the claims' construction."
In response to Dr. Holman's assertion that Dr. Mason and his co-author Jeffrey Rosenfeld "seem to assume that every patent with a claim mentioning a gene sequence also claims every 15mer present in the sequence," Dr. Mason states that the authors did not make such an assumption, and that their paper instead describes the results of two distinct analyses. In the first analysis, the authors "examined the uniqueness of 15mers in general, which was shown to be exceedingly non-unique genome-wide." However, as we noted in our first post on Dr. Mason's paper, the conclusion regarding the broad scope of claims to 15mers -- and in particular claims 5 and 6 of Myriad's U.S. Patent No. 5,747,282 -- is not particularly ground-breaking given that Kepler et al. similarly concluded in a 2010 Genomics paper that claim 5 of the '282 patent was "exceptionally broad" (see "Caught in a Time Warp: The (In)validity of BRCA1 Oligonucleotide Claims"). Kepler et al. also suggested that "if human genes were random strings of nucleotides, one would expect a human gene to contain an average of 15 15-mers claimed under the ['282] patent," and in fact found that 80% of 713 human mRNAs deposited in 1994 (the earliest effective filing date of the '282 patent is August 12, 1994) contained at least one of the claimed 15mers.
With respect to their second analysis, Dr. Mason states that the authors "used patents that claimed 15mer sequences in their construction, and we indicated the matches we could find given their sequence composition." Unfortunately, given Dr. Mason's views regarding the subject matter encompassed by the claims of U.S. Patent No. 7,795,422 -- one of "58 patents [according to Dr. Mason] whose claims covered at least 10% of the bases of all human genes," and a patent Dr. Mason labeled as their "top patent . . . whose claims' sequences matched 91.5% of human genes" -- it is not entirely clear what Dr. Mason means when he says that the authors "used patents that claimed 15mer sequences in their construction" (emphasis added). An analysis of the claims in the '422 patent, as well as those in U.S. Patent No. 7,468,248 (a second patent discussed in the Genome Medicine article), clearly indicates that Dr. Mason's top two candidates do not contain "explicit claims for 15mers that matched 84% of human genes," as asserted in his paper (assuming that by "explicit claims," Dr. Mason means that the claims cover or encompass 15mers). It is also abundantly clear from both the Genome Medicine paper and his subsequent response that Dr. Mason does not understand the process of claim construction (which is not surprising given that Dr. Mason is not a patent practitioner).
So, what follows is a short primer on claim construction. Claim construction is the process of giving proper meaning to the language of the claims. Abtox Inc. v. Exitron Corp., 122 F.3d 1019, 1023 (Fed. Cir. 1997). The language of the claim frames and ultimately resolves all issues of claim interpretation, since it is the language of the claim that defines the scope of the protected invention. Id. However, in determining the scope and meaning of a claim term, three additional sources may be considered: the descriptions in the rest of the patent specification, the prosecution history, and relevant extrinsic evidence. Phillips v. AWH Corp., 415 F.3d 1303, 1315, 1317 (Fed. Cir. 2005).
With regard to the use of the specification and prosecution history to construe claim terms, the Federal Circuit has stated that:
Claims must be read in view of the specification, of which they are a part. The specification contains a written description of the invention that must enable one of ordinary skill in the art to make and use the invention. For claim construction purposes, the description may act as a sort of dictionary, which explains the invention and may define terms used in the claims. . . . The written description part of the specification itself does not delimit the right to exclude. That is the function and purpose of the claims.
To construe claim language, the court should also consider the patent’s prosecution history[.] . . . Although the prosecution history can and should be used to understand the language used in the claims, it too cannot "enlarge, diminish, or vary" the limitations in the claims.
Markman v. Westview Instruments, Inc., 52 F.3d 967, 979-80 (Fed. Cir. 1995) (in banc), aff’d, 517 U.S. 370 (1996) (citations omitted).
In Phillips, the Federal Circuit noted that where the intrinsic evidence (i.e., claim language, specification, and file history) does not resolve ambiguity in the meaning of a claim term, a court may also consider extrinsic evidence, such as expert testimony, dictionaries, and treatises. Phillips, 415 F.3d at 1317-19. Such "extrinsic evidence can help educate the court regarding the field of the invention and can help the court determine what a person of ordinary skill in the art would understand claim terms to mean." Id. at 1319.
With the above legal principles in mind, we turn back to the claims of the '422 and '248 patents. The '422 patent contains five claims, only one of which is an independent claim (i.e., does not depend from, and include the limitations of, another claim):
chemically modified short interfering nucleic acid (siNA) molecule, wherein:
(a) the siNA molecule comprises a sense strand and an antisense strand, each strand having one or more pyrimidine nucleotides and one or more purine nucleotides;
(b) each strand is independently 18 to 27 nucleotides in length, and together comprise a duplex having between 17 and 23 base pairs;
(c) the antisense strand is complementary to a human Hypoxia Inducible Factor 1 (HIF1) RNA sequence comprising SEQ ID NO:567;
(d) a plurality of pyrimidine nucleotides present in the sense strand are 2'-deoxy-2-fluoro pyrimidine nucleotides and a plurality of purine nucleotides present in the sense strand are 2'-deoxy purine nucleotides; and
(e) a plurality of pyrimidine nucleotides present in the antisense strand are 2'-deoxy-2'-fluoro pyrimidine nucleotides and a plurality of purine nucleotides present in the antisense strand are 2'-O-methyl-purine nucleotides.
A cursory analysis of claim 1 (a more thorough analysis being unnecessary) indicates that the claim is directed to a "chemically modified short interfering nucleic acid (siNA) molecule." Therefore, claim 1 does not cover or encompass molecules other than chemically modified short interfering nucleic acids (siNAs). More importantly, the siNA molecules that are covered or encompassed by claim 1 must possess a sense strand having "a plurality of pyrimidine nucleotides [that] are 2'-deoxy-2-fluoro pyrimidine nucleotides," and an antisense strand having "a plurality of pyrimidine nucleotides [that] are 2'-deoxy-2'-fluoro pyrimidine nucleotides." 2'-deoxy-2'-fluoro pyrimidine nucleotides are not naturally-occurring nucleotides.
In response to Dr. Holman's statement that "DNA does not contain 2'-deoxy-2-fluoro pyrimidine nucleotides and 2'-deoxy purine nucleotides," Dr. Mason notes that "'2'-deoxy purine nucleotides' are simply the 'A' and 'G' nucleotides in normal DNA." He does not, however, contend that 2'-deoxy-2'-fluoro pyrimidine nucleotides are found in "normal DNA." Dr. Mason also takes Patent Docs to task for stating that "the lone independent claim of the '422 patent is directed to a 'chemically modified' double-stranded nucleic acid molecule," and "[i]t is therefore difficult to see how the claimed sequences of the '422 patent could 'match 91.5% of human genes.'" Dr. Mason counters that "[i]t is notable that one of the claimed chemical modifications allowed from [the '422 patent] claims is '2'-deoxyribonucleotides,' which is the same thing as dexoyribonucleotides, or DNA." However, as noted above, the siNA molecules of claim 1 of the '422 patent must possess a sense strand having "a plurality of pyrimidine nucleotides [that] are 2'-deoxy-2-fluoro pyrimidine nucleotides," and an antisense strand having "a plurality of pyrimidine nucleotides [that] are 2'-deoxy-2'-fluoro pyrimidine nucleotides." And 2'-deoxy-2'-fluoro pyrimidine nucleotides are not naturally-occurring nucleotides found in "normal DNA." Dr. Mason also lists "six other potential embodiments (of many) from [the '422] patent that could easily cover unmodified bases or fragments thereof," adding that "[t]he claims must be interpreted in plain language first, of course, but also in light of their specifications of the patent." Notwithstanding the importance of the specification in claim construction, absent a clear and specific statement giving a claim term a special definition, that term should be construed as having the plain and ordinary meaning given by persons experienced in the field of the invention. Renishaw plc v. Marposs Societa' per Azioni, 158 F.3d 1243, 1249 (Fed. Cir. 1998). Therefore, the disclosure in the '422 patent specification of unclaimed embodiments such as unmodified siNA molecules does not trump the express recitation in claim 1 of "[a] chemically modified short interfering nucleic acid (siNA) molecule" possessing a sense strand having "a plurality of pyrimidine nucleotides [that] are 2'-deoxy-2-fluoro pyrimidine nucleotides," and an antisense strand having "a plurality of pyrimidine nucleotides [that] are 2'-deoxy-2'-fluoro pyrimidine nucleotides." Thus, contrary to Dr. Mason's assertion, the claims of the '422 patent do not "claim 15mer sequences."
The same is true for the claims of the '248 patent. As we noted in our last post, the claims of the '248 patent are directed to methods of inferring a trait of a bovine subject, determining a nucleotide occurrence of a polymorphism in a bovine sample, and identifying a bovine single nucleotide polymorphism (SNP) associated with a trait, and not 15mer nucleic acid molecules. In response to Dr. Holman's observation that the independent claims of the '248 patent are method claims, Dr. Mason agrees, but suggests that "their specifications allow for a broad interpretation." However, the disclosure of "an isolated polynucleotide that includes at least 20 contiguous nucleotides of any one of SEQ ID NOS:24493 to 64886" in the specification simply does not convert a claim directed to a method into a claim directed to a oligonucleotide. As with the '422 patent, therefore, the claims of the '248 patent simply do not "claim 15mer sequences."
To put the above in layman's terms, Dr. Mason could make or use a 15mer derived from the human Hypoxia Inducible Factor 1 (HIF1) RNA sequence comprising SEQ ID NO:567 or the nucleotide sequence of SEQ ID NO:21645 and not be found liable for infringing either the '422 or '248 patents -- provided, of course, that he was not using either sequence to generate the claimed siNA of the '422 patent or practice the claimed methods of the '248 patent.
In his response, Dr. Mason argues that even if one disagrees with his analysis of the '422 patent, related U.S. Patent No. 8,273,866 supports his assertions. Claim 1 of the '866 patent recites:
short interfering RNA (siRNA) molecule having a sense strand and an antisense
strand that mediates RNA interference, wherein:
(a) each strand is between 18 and 24 nucleotides in length;
(b) the sense strand comprises 10 or more 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, or universal base modified nucleotides, and a terminal cap molecule at the 3'-end, the 5'-end, or both 3' and 5'-ends of the sense strand;
(c) the antisense strand comprises 10 or more 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, or universal base modified nucleotides; and
(d) 10 or more pyrimidine nucleotides of the sense and antisense strand are 2'-deoxy, 2'-O-methyl or 2'-deoxy-2'-fluoro nucleotides.
Dr. Mason argues that "any sequence that is 18-24 bases can be constructed from these claims, [and] this may mean that every single 18-24mer is potentially claimed by this patent." Not quite. Claim 1 is directed to "[a] short interfering RNA (siRNA) molecule having a sense strand and an antisense strand that mediates RNA interference." A "single 18-24mer" is not "[a] short interfering RNA (siRNA) molecule having a sense strand and an antisense strand that mediates RNA interference."
Turning back to Dr. Mason's response, he counters Dr. Holman's assertion that the 15mer claims of Myriad's '282 patent are "extremely rare" by pointing out that "[a]fter searching for a short time on Google Patents, I was able to find two potential examples of recently published patent applications that directly claim a large subset of genes." As noted in an editorial comment to Dr. Mason's response, the response was revised per Dr. Mason's request to indicate that the documents Dr. Mason identified were published patent applications rather than patents as he stated in the original version of his response. However, it is unclear whether Dr. Mason understands that identifying two "published patent applications" as "issued patents" was not merely an unfortunate typographical error. Instead, Dr. Mason's citation of two published patent applications provides no support for his argument that 15mer claims can be readily found in recently issued patents because infringement liability arises only when an individual "without authority makes, uses, offers to sell, or sells any patented invention" (35 U.S.C. § 271(a)), and the published patent applications he cites are not patents.
Finally, when defending the assertion in paragraph 10 of his Declaration that "Claim #1 and #2 of '282 are so broad that they can include up to 100% of the genes in the human genome," Dr. Mason counters with more of the same flawed argument. He first notes that "55% homology is a very low threshold," and then points to claim 6, which is directed to "[a]n isolated DNA having at least 15 nucleotides of the DNA of claim 2." But claims 1 and 2 do not recite 15mer fragments of DNA encoding the amino acid sequence of SEQ ID NO:2 or the nucleotide sequence of SEQ ID NO:1 that share 55% identity with those sequences. Instead, claims 1 and 2 are directed to a nucleic acid encoding a protein of 1863 amino acids and a nucleic acid of 5914 nucleotides.