The Federal Circuit decision in Genetics Institute, LLC v. Novartis Vaccines & Diagnostics, Inc. is interesting in several respects. In this article, I look at the court’s decision to permit unexpected results discovered after the patent applications at issue were filed to support non-obviousness.

The Technology At Issue

The technology at issue relates to truncated forms of Factor VIII, an essential blood-clotting protein. As explained in the Federal Circuit opinion, the proper functioning of Factor VIII depends on its ability to bind another protein, von Willedbrand factor (“vWF”), although Factor VIII can exhibit a procoagulant effect without complexing to vWF.

Full-length Factor VIII consists of 2332 amino acid residues in the following regions:

amino acids 1-740: A1, A2
amino acids 741-1648: B
amino acids 1649-2332: A3, C1 and C2, including a3 at amino acids 1649-189

(In accordance with the Federal Circuit opinion, this amino acid numbering does not include the 20 amino acid signal peptide.)

Truncated forms of Factor VIII are based on the discovery that certain portions of the protein are not required for its procoagulant activity, and that region a3 is critical to vWF binding.

The Patents At Issue

Genetics Institute owns U.S. Patent 4,868,112, which was filed April 11, 1986 with a priority claim to April 12, 1985. The patent was granted September 19, 1989. The patent’s term was extended to February 28, 2010 under 35 USC § 156 based on the regulatory review of Genetics’ ReFacto® product. Independent claims 1 and 10 recite:

1. A recombinant DNA which upon expression results in a truncated Factor VIII protein which is an active procoagulant wherein the recombinant DNA encodes for a protein having the amino acid sequence of a human Factor VIII:C except for having a deletion corresponding to at least 581 amino acids within the region between Arg-[740] and Ser-[1690] . . . .

10. A truncated human Factor VIII:C protein which is an active procoagulant protein having a peptide sequence of human Factor VIII:C but lacking a peptide region selected from the group consisting of:
(a) the region between Pro-[981] and Asp-[1563];
(b) the region between Thr-[759] and Pro-[1640]; and,
(c) the region between Thr-[759] and Glu-[1675].

(The amino acid numbering is adjusted from that used in the patent claims so as not include the 20 amino acid signal peptide.)

Novartis owns U.S. Patent 6,228,620 and U.S. Patent 6,060,447, both of which claim priority to an application filed January 27, 1986. Claim 68 of the ’620 patent and claim 1 of the ’447 patent are relevant:

68. A nucleic acid [encoding] …  all or a portion of the B domain of human Factor VIII, wherein said recombinant protein consists of:
a first amino acid sequence . . . having at least 90% sequence identity with . . . amino acids 1 to 740 of the native, mature A domain of human Factor VIII and optionally up to 10 amino acids of the human Factor VIII B domain sequence contiguous to amino acid 740 . . . ; and
a second amino acid sequence . . . having at least 90% sequence identity with . . . amino acids 1649 to 2332 of the native, mature C domain of human Factor VIII and optionally up to 10 amino acids of the human Factor VIII B domain sequence contiguous to amino acid 1649 . . . ;
wherein said nucleic acid encodes said first and second amino acid sequences, and further wherein said recombinant protein is capable of coagulation activity in a coagulation activity assay.

1. A composition comprising Factor VIII:C proteins, wherein the Factor VIII:C proteins consist essentially of
a first polypeptide comprising an amino acid sequence of the A domain of human Factor VIII:C . . . or an amino acid sequence that differs therefrom in having not more than 10 number % amino acid substitutions, and
a second polypeptide comprising an amino acid sequence of the C domain of human Factor VIII:C . . . or an amino acid sequence that differs therefrom in having not more than 10 number % amino acid substitutions.

The Interference Proceeding

Genetics brought an interference action against Novartis under 35 USC § 291 in the U.S. District Court for the District of Delaware. As summarized by the Federal Circuit, “Genetics asserted that all three patents are directed to the same subject matter, viz., truncated Factor VIII proteins lacking all or part of the B domain while retaining procoagulant activity.”

Novartis moved to dismiss on two grounds:

  1. The court “lacked subject matter jurisdiction because the extension of the ’112 patent under 35 USC § 156 applied to fewer than all of that patent’s claims.
  2. There was no interference in fact “because the Novartis patents—unlike the ’112 patent—are directed to truncated Factor VIII proteins that preserve the functional a3 acidic region.”

I will discuss the first issue in a future article. For now, I focus on the second.

The Two-Way Test For An Interference In Fact

As noted by the Federal Circuit, “[a]n interference in fact under § 291 requires that the two patents claim ‘the same or substantially the same subject matter.’” A court makes this assessment using the same two-way test that the USPTO uses, which is set forth in 37 CFR § 41.203(a):

An interference exists if the subject matter of a claim of one party would, if prior art, have anticipated or rendered obvious the subject matter of a claim of the opposing party and vice versa.

As explained by the Federal Circuit. “for two claims to interfere, each claim must anticipate or render obvious the other; failure of either claim to anticipate or render obvious the other defeats the test for interfering patents.”

The District Court Proceedings

Genetics argued that the claims of the Novartis ’620 patent were obvious in view of the claims of the Genetics ’112 patent because the deletion claimed in the ’620 patent “is subsumed entirely by the deletion claimed by the ’112 patent.”

Novartis took a contrary position, arguing that “the broader range of deletions permitted by the claims of the ’112 patent does not anticipate or render obvious the narrower range claimed in the Novartis patents.” In particular, according to Novartis, only the Novartis patents “retain the a3 region and possess increased stability associated with vWF binding.”

The district court noted several differences between the truncated Factor VIII proteins claim by Genetics and Novartis:

  • the size and location of the permitted amino acid deletions, with the Genetics deletions ranging in size from 581 to 949 amino acids and located between amino acids 740 and 1690, and the Novartis deletions ranging in size from 889 to 909 amino acids and located between amino acids 740 and 1649.
  • the deletion in amino acids 1649-1689 region permitted in the Genetics patent, but not permitted in the Novartis patents.
  • the substitution of up to 10% of the amino acids permitted in the Novartis patents, but not permitted in the Genetics patent.

In view of these differences, the district court considered whether Genetics had identified “some reason that would have prompted a researcher to modify the prior art compounds in a particular manner to arrive at the claimed compounds,” and found that it had not.

The district court also credited evidence that the Novartis proteins exhibited unexpected results. In particular, because the Novartis proteins retain the a3 region, they also retain the ability to bind vWF. Genetics had challenged the relevance of this evidence because the significance of the a3 region was not known until after the Novartis patents were filed.

The Federal Circuit Decision

The opinion for the court was authored by Judge Lourie and joined by Judge Plager.  Judge Dyk dissented from the section of the opinion addressing the interference in fact issue. The majority opinion agreed that there was no reason to modify the truncated proteins claimed in the Genetics patent to arrive at those claimed in the Novartis patents, distinguished the case from its 2003 decision in In re Peterson, and agreed that post-filing date evidence could be used to support non-obviousness.

On the first point, the majority opinion states:

[T]he dissent challenges well-established law requiring the identification of some reason that would have prompted a researcher to substantially modify a prior art compound to produce the claimed compound. . . . [T]he dissent nonetheless contends that, because of “structural similarity” in the patented proteins, no reason for chemical modification need be shown. The dissent vastly oversimplifies the differences in the claimed proteins, however. . . . [T]he claimed truncated proteins vary enormously in structure: for example, the a3 region alone contains 40 amino acid residues and has a relative molecular mass of about 4,500. . . . The dissent’s oversimplification violates our longstanding admonition that “generalization is to be avoided insofar as specific structures are alleged to be prima facie obvious one from the other.”. . . On the facts of this case, the nontrivial differences in the proteins at issue compel the requirement of identifying a reason for the chemical modification.

On Peterson, the majority opinion states:

In Peterson, we stated that “[a] prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.” . . . The facts here do not present the “typical[]” case contemplated in Peterson, however.

The majority noted the following distinctions over Peterson:

  • the “very large number” of proteins encompassed by the Genetics patent (“about 68,000″)
  • the motivation to make smaller truncated Factor VIII proteins that would have led away from the larger proteins claimed in the Novartis patents
  • the differences between the claimed proteins (size of deletions, location of deletions, extent of substitutions) go beyond the selection of an optimal narrow range within a broader range, which was the difference at issue in Peterson.

To support its approval of the use of unexpected results discovered post-filing date to support non-obviousness, the majority relies primarily on the principle that “the structure of a claimed compound and its properties are inseparable for purposes of § 103.”

(I find this interesting because this principle typically is used to defeat patentability, for example, by preventing the grant of a patent based on the discovery of a new property of a known product.)

The majority cites the 2004 decision in Knoll Pharm. Co. v. Teva Pharms. USA, as holding that “every property of a claimed compound need not be fully recognized as of the filing date of the patent application to be relevant to nonobviousness,” and that “evidence of unexpected results may be used to rebut a case of prima facie obviousness even if that evidence was obtained after the patent’s filing or issue date.” 

The majority acknowledges the principle that an analysis under § 103 is focused “at the time the invention was made,” but emphasizes that most of the secondary considerations of non-obviousness outlined by the Supreme Court in Graham v. John Deere are “not manifest even until well after the issuance of a patent.” Thus, the majority rejects Judge Dyk’s position that evidence of unexpected results must be tied to “an express prediction . . . in the patent specification or a showing of the inventors’ contemporaneous knowledge of such properties.”

The Federal Circuit therefore affirmed the district court’s finding that there was no interference in fact, because the claims of the Genetics patent did not render obvious the claims of the Novartis patents.

Judge Dyk’s Dissent

Judge Dyk disagreed with every aspect of the majority’s finding on the non-obviousness of the Novartis proteins.

In my view, there are four fundamental flaws with the majority’s conclusion of non-obviousness.

First, the majority holds that the Novartis patents could not be obvious over the ’112 patent unless Genetics could identify “some reason that would have prompted a researcher to modify” the ’112 patent to retain the a3 region. . . . Rather, we should look to whether there was enough structural similarity between the patents-in-suit to make a prima facie case of obviousness, given what was known to the inventors at the time of the invention.

Second, under our prior authority, a prima facie case of obviousness can also exist if the range of an earlier patent incorporates the range of later patents. That is the case here where it is clear that the range of retentions in the ’112 patent fall within the range of retentions of the Novartis patents, as discussed above.

Third, the majority appears to suggest that the “ret[ention] of amino acids in the [a3] region” was “contrary to the teachings of the ’112 patent.” . . . The majority ignores that some variants of the ’112 patent actually retain the a3 region and therefore have the ability to bind to vWF.

Finally, the majority found that the later-discovered, undisclosed benefits of retaining the a3 region qualified as unexpected results to help defeat the prima facie case of obviousness, even though the role of the a3 region was not appreciated as of the Novartis patents’ priority date. I disagree. The majority’s finding of nonobviousness is based entirely on hindsight and happenstance, and not on what the inventors knew at the time the Novartis patents were filed. . . . I do think that unexpected properties must either be set forth in the specification or contemporaneously known to the inventors, rather than being discovered long after the fact.

Judge Dyk raises some interesting policy issues on the post-filing date evidence question:

An applicant should not be able to avoid an obviousness determination . . . without any showing [of] . . . any known benefit over the prior art at the time the invention was made. Just as a challenger to a patent must rely on a known motivation to combine existing prior art to achieve what the invention was designed achieved, so too the patent holder must prove that he actually contemplated the unexpected results at the time the patent was filed and not at some later time.

It is significant that if Genetics had brought this action at an earlier time—before it was discovered that vWF binding resided in the a3 region—the Novartis patents would likely have been found obvious. Instead, by happenstance and on hindsight, Novartis can now claim an advantage over the ’112 patent based on information it did not know at the time of filing and based on research that was conducted by other parties.

An Issue Of Enduring Significance

Although this case arose in the context of an interference, the admissibility of evidence of unexpected results discovered post-filing date to support non-obviousness will remain important even after interference proceedings are no longer available. While the majority adopted a permissive approach in this case, applicants may want to consider including a discussion of “unexpected results” in their patent applications, documenting them in their laboratory notebooks, and/or making them of record during prosecution, in case the court revisits this issue and reaches a different conclusion.