Patent Docs

Teva Pharmaceutical Industries Ltd. v. AstraZeneca Pharmaceuticals LP (Fed. Cir. 2011)

By Andrew Williams --

Last week, in Teva Pharma. Indus. Ltd. v. AstraZeneca Pharma. LP, the Federal Circuit reiterated that, in the context of 35 U.S.C. § 102(g), "[t]o establish prior invention, the party asserting it must prove that it appreciated what it had made."  The complication is, however, how do you define what the invention is?  This is because the invention is not necessarily what is claimed -- "'[t]he invention is not the language of the [claim] but the subject matter thereby defined'"(citing Dow Chemical Co. v. Astro-Valcour, Inc., 267 F.3d 1334 (Fed. Cir. 2001)).  Therefore, in this case, because AstraZeneca "appreciated" that it had a formulation with a stable compound (the defined invention), and it knew what the components of the formulation were, it conceived and reduced to practice a stabilized pharmaceutical composition of rosuvastatin (a statin) before Teva's date of invention, even though AstraZeneca did not appreciate the stabilizing property of one of the components, which was a limitation found in Teva's claims.

The technology at issue in this case involved statin formulations, which are inherently unstable and as a result need to be stabilized to be medically viable.  Teva discovered that, among other things, amido-group containing polymeric compounds ("AGCP compound") can be used to stabilize statins, and obtained a patent (RE39,502) with the following representative claim:

1.  A stabilized pharmaceutical composition for the treatment of dyslipidemia, comprising
    an active component consisting essentially of one or more compounds selected from the group consisting of (i) an HMG-CoA reductase inhibiting ring-opened 7-substituted-3,5-dihydroxyheptafloic acid or a pharmaceutically acceptable acid salt thereof, and (ii) an HMG-CoA reductase inhibiting ring-opened 7-substituted-3,5-dihydroxyheptenoic acid or a pharmaceutically acceptable acid salt thereof, and
    a stabilizing effective amount of at least one amido-group containing polymeric compound or at least one amino-group containing polymeric compound, or combination thereof, wherein said stabilized pharmaceutical composition does not contain a stabilizing effective amount of another stabilizer or a combination of other stabilizers.

(emphasis as found in the opinion).  Teva's earliest effective filing date was April 10, 2000, and the earliest date that it alleges it could establish conception and reduction to practice was December 1, 1999.  Teva sued AstraZeneca for infringement in October 2008 for the stabilized statin (rosuvastatin calcium) formation that it was marketing for the treatment of dyslipidemia.  The relevant facts were uncontested, and AstraZeneca conceded infringement for the limited purpose of advancing its summary judgment motion (AstraZeneca appears to have been able to challenge infringement because its formulation contained a second stabilizer, tribasic calcium).  The facts related to AstraZeneca's prior invention allegation included:  (1) AstraZeneca had manufactured a 10,000-unit batch of the formulation with the same ingredients as its commercial drug in mid-1999, (2) it had made additional batches in the summer and fall of 1999, (3) it had disclosed the ingredients and quantities for the formulation that match all commercial drug dosage strengths, and (4) it included crospovidone, an AGCP-compound, as a disintegrant, but did not understand that it had a stabilizing effect on the statin.  As a result, the sole legal question for the Court was whether AstraZeneca conceived and reduced to practice the claimed invention before Teva.

It is clear that prior invention in the context of 102(g) requires a showing that the challenging party (1) reduced its invention to practice first, or (2) was the first to conceive and then exercised due diligence in reducing the invention to practice.  In order to conceive, the inventor needs a specific and settled idea, a particular solution to a problem at hand.  Reduction to practice, on the other hand, requires that the inventor constructed an embodiment that met all of the claim limitations, and determined that it would work for its intended purpose.  However, the inventor need not understand precisely how the invention worked.  There is another requirement that is relevant in the chemical and biotech arts -- conception of something reduced to practice requires more than an unrecognized accidental creation, but instead, the inventor must appreciate what he has invented.  In other words, "'a party who first reduced to practice, but who 'fail[ed] to recognize that he had produced a new form [of matter] . . . is indicative that he never conceived the invention''" (quoting Dow at 1341 (quoting Heard v. Burton, 333 F.2d 239, 243 (C.C.P.A. 1964)).

Teva argued that because AstraZeneca did not appreciate that crospovidone was a stabilizing agent, it could not have appreciated the invention of a formulation with "a stabilizing effective amount" of an AGCP.  The lower court, however, held that all AstraZeneca had to appreciate was the stabilization of its overall pharmaceutical composition that contained crospovidone.  On appeal, Teva complained that the District Court implicitly construed the claims to encompass stabilized statin formations that contained AGCP, without taking into account that AGCP had to act as a stabilizer.  However, the Federal Circuit pointed out, while quoting William Shakespeare, that AstraZeneca was not required to appreciate the invention in the same terms as those recited by the claims ("[T]hat which we call a rose [b]y any other name would smell as sweet.").  Therefore, because AstraZeneca appreciated that the statin in its formulation was stable, and because it appreciated what the components of the formation were, it appreciated the invention.

On its face, this outcome appears to be inequitable.  After all, reducing Teva's claim to "a stabilized [statin-containing] pharmaceutical composition" appears to ignore the rest of the claim, including Teva's alleged inventive contribution.  In fact, the panel questioned both sides during the hearing as to whether Teva should be entitled to this patent because it provided the public with something that it didn't have before the filing of the application -- the knowledge that AGCPs can act as stabilizing agent for statins.  Nevertheless, this line of reasoning has its limits, in part because Teva did not claim the use of AGCPs as stabilizing agents in this patent.  Instead, Teva claimed a composition that used such stabilizing agents.  The important thing to consider is that AstraZeneca was using its composition (the same one that Teva alleged infringed) before Teva's elucidation of the mechanism of action of AGCPs.  And, it is still true that, that which infringes after, anticipates before, even if the use before was without the benefit of the knowledge as to why it worked.  Teva should not be allowed to now take this composition out of the public domain just because it discovered why the composition was so successful -- specifically, because it determined the inherent stabilizing effect that crospovidone has on statins.  This case does have the flavor of inherent anticipation.  The panel was very clear in its opinion and during the hearing that the concept of inherency was not implicated in this case or its decision.  However, one cannot help think that this outcome smells a lot like inherency jurisprudence.  Perhaps this rose just has a different name.

Teva Pharmaceutical Industries Ltd. v. AstraZeneca Pharmaceuticals LP (Fed. Cir. 2011)
Panel: Chief Judge Rader and Circuit Judges Linn and Dyk
Opinion by Circuit Judge Linn

Star Scientific, Inc. v. R.J. Reynolds Tobacco Co. (Fed. Cir. 2011)

By Kevin E. Noonan --

The Federal Circuit reaffirmed the primacy of the factual disclosures used to establish obviousness, and how deficiencies thereof can defeat an obviousness claim, in reversing an invalidity determination in Star Scientific, Inc. v. R.J. Reynolds Tobacco Co.  It also showed how persistently defendants pursue the tarnish of inequitable conduct even under circumstances where the Federal Circuit has held that no inequitable conduct occurred.

The patents-in-suit, U.S. Patent Nos. 6,202,649 and 6,425,401 (filed as a continuation of the '649 patent), were directed to methods for curing tobacco in a way that reduced the amount of a carcinogen, tobacco-specific nitrosamines (TSNAs), in the cured product used in cigarettes and other tobacco-containing products.  The patents were specifically directed to "indirect" flue curing with gas or propane heaters.  Former methods used "direct" flue curing that mixed the exhaust gasses with the tobacco, but this resulted in an oxygen-free environment that fostered the growth of bacteria on the leaves, leading to production by the bacteria of the carcinogenic TSNAs.  The patented methods can be used with either direct or indirect curing methods by using "controlled conditions" involving humidity, temperature, rate of temperature exchange, carbon monoxide levels, carbon dioxide levels, oxygen levels, and how the tobacco plants are arranged in the curing shed.  The claims specify "controlling conditions" by "determining and selecting" the "appropriate" values for these variables that results in the reduction of TSNA production "at least one").  However, the patents admit that the choice of these conditions are "more art than science," so need to choose the appropriate combination of these variables; however, the important consideration is maintaining an aerobic environment that prevents bacterial growth.

Claims 4 and 12 of the '649 patents are set forth for the Court as being representative (emphasis in the opinion):

4.  A process of substantially preventing the formation of at least one nitrosamine in a harvested tobacco plant, the process comprising:
    drying at least a portion of the plant, while said portion is uncured, yellow, and in a state susceptible to having the formation of nitrosamines arrested, in a controlled environment and for a time sufficient to substantially prevent the formation of said at least one nitrosamine;
    wherein said controlled environment comprises air free of combustion exhaust gases and an airflow sufficient to substantially prevent an anaerobic condition around the vicinity of said plant portion; and
    wherein said controlled environment is provided by controlling at least one of humidity, temperature, and airflow.

12.  The process according to claim 4, wherein the treatment time is from about 48 hours up to about 2 weeks.

The lawsuit arose after R.J. Reynolds (RJR) acquired previous licensee Brown and Williamson and terminated the license.  In addition, RJR has its own patents (referenced in the opinion as the Peele reference), issued as U.S. Patent No. 6,805,134 that specified a "not direct" heat source and curing in the absence of nitrocv oxide gas, which was performed by retrofitting direct cure barns into indirect-cure barns.

As an initial matter, the District Court granted summary judgment that the '649 and '401 patents were not entitled to priority to a provisional application, based on disclosure in the provisional that the claimed methods utilized an air flow of "at least 28,000 cubic feet per meter (CFM)" whereas the common specification of the '649 and '401 patents specified an air flow of "approximately 25,000 CFM."  As a consequence, the District Court was able to consider intervening art to be prior art, and to decide that the patentee did not disclose the best mode (based on development of the commercial embodiment (and acknowledged best mode) in the period between the provisional and non-provisional filing dates.

In an earlier decision, the Federal Circuit reversed a finding that the claims were indefinite for reciting the term "anaerobic condition" and reversed a finding of inequitable conduct for failure to disclose a purported prior art reference (termed the "Burton letter").  Despite this decision, the District Court permitted defendants to display a slide (below) during closing argument showing a shadowy person disclosing information to the PTO examiner but holding the disputed Burton letter reference behind his back, during part of closing argument relating to invalidity rather than inequitable conduct.

The jury delivered a verdict of non-infringement and invalidity based on obviousness, anticipation, indefiniteness, and failure to disclose the best mode.  The obviousness determination was based on a prior art scientific journal review relating to methods for air curing and a published Japanese patent.  In view of the District Court's decision on the priority question, the jury applied the method disclosed in the Peele '134 patent as well as the practice of methods at two farms (Spindletop and the Brown farm) as a public use (the Brown tobacco farm being under contract to RJR).  The indefiniteness determination was directed at the term "controlled environment," which the Court found as a matter of law was incapable of being construed because the disclosed "controlled environment" conditions overlapped with "conventional" curing conditions so that the skilled worker could not understand the difference.  The best mode determination was based squarely on the District Court's priority determination, since it was uncontested that the best mode commercial embodiment was not disclosed and had been developed prior to the non-provisional filing dates.  Finally, the jury found that there was no infringement, based on oxygen levels in RJR's barns alleged to be infringing.  The District Court denied Star's motions for JMOL of these adverse decisions.

The Federal Circuit, in an opinion by Chief Judge Rader, joined by Judge Linn and by Judge Dyk in part, who dissented as to the Court's decision to reverse invalidation for indefiniteness, reversed the District Court's grounds for invalidating the '649 and '401 patents, and affirmed the District Court's denial of JMOL on the jury's non-infringement decision.  The Federal Circuit also reversed the finding that the '649 and '401 patents were not entitled to the provisional filing date, on the basis that the specification satisfied the priority standard:  that the specification disclosed an adequate written description and enabled the patents' claims.

This part of the opinion was supported by an intervening decision by the USPTO in a reexamination of the '649 and '401 patents that these patents were entitled to the priority date (although the PTO found certain of the claims were invalid for obviousness).  The Court based its decision on language in the provisional specification that the recited air flow speed (in CFM) could "vary according to conditions and may be determined on a routine basis," and thus held that the District Court had improperly narrowed the claim scope based on later examples in the non-provisional application.

As a consequence of the Court granting the priority date of the provisional application to the '649 and '401 patents the best mode violation evaporated, since it was equally undisputed that the commercial method was not known at the time the provisional application was filed.  Another consequence, germane to anticipation and obviousness is that the Peele '134 patent was not prior art that could be asserted against the patents in suit.

In reversing the District Court's indefiniteness determination, the majority opinion cites Datamize LLC v. Plumtree Software Inc. for the standard that a claim must be "insolubly ambiguous" or "not amenable to construction" to be found indefinite.  However, the majority cautioned that "[a]bsolute clarity [is] not required" and that the term at issue -- "controlled environment" -- does not require disclosure of exact values for the various parameters because the skilled worker would understand the variable and empirical nature of determining these conditions.  In this the opinion cites language from the Peele '134 patent -- owned by RJR -- consistent with its interpretation of the understanding of the worker skilled in the art.

Regaring obviousness, the Court disagreed with jury verdict that the references render the claims obvious.  The opinion characterized the Japanese patent as being directed at improving fast curing to avoid "nasty odor" (an advantage not related to TSNA production) and found the Wiernik reference to be inconclusive on whether bacteria were involved in TSNA production.  In addition, the opinion notes that neither reference discusses exhaust gases or anaerobic conditions.  Thus, the Court found that there would be no motivation (or in the mantra approved by the KSR Court, "reasoned basis") for the skilled worker to combine these references to arrive at a solution to the problem of TNSA production during tobacco curing.  The Court also found significant evidence of secondary considerations, including:  a recognized, unmet need in the art for reducing TSNA in cured tobacco; unsuccessful attempts (i.e., failure) by others to solve this recognized problem; purported unexpected results (never expressly set forth in the opinion); and commercial success (ironically for RJR, using the lucrative B&W licenses as evidence thereof).

The Court reversed the jury's anticipation finding as to the Peele method because it was no longer prior art in view of the earlier priority date.  The two "public uses" were not prior art, because the Court found that the "Spindletop" use involved tobacco cured before treatment in the drying shed (so that it was not "uncured" tobacco, as required by the claims).  The "Brown farm" use did not anticipate, according to the Court's opinion, because the reported test results were below the detection threshold for TNSAs and thus provided no evidence that this method satisfied the specifically recited range of TSNA reduction required by the claims.

Finally, the Court upheld the non-infringement decision based on the jury's prerogative to believe one (RJR's) expert over another (Star's), and that the evidence did not establish that no reasonable jury could come to such a decision (i.e., the District Court properly denied Star's JMOL motion).

The Court also refused to deny Star's appeal on evidentiary rulings permitting (inter alia) display of the "shadowy figure" slide (although the Court found its use "troubling"), because Star did not show harm resulting from the objectionable evidence.

Judge Dyk dissents in part, arguing that the patents are invalid for indefiniteness -- in his view, the specification did not sufficiently distinguish the "controlled" conditions from "conventional" conditions and thus did not "particularly point out and distinctly claim" the invention so that the skilled worker could not ascertain the metes and bounds of infringing behavior.

Star Scientific, Inc. v. R.J. Reynolds Tobacco Co. (Federal Circuit 2011)
Panel: Chief Judge Rader and Circuit Judges Linn and Dyk
Opinion by Chief Judge Rader; opinion concurring-in-part and dissenting-in-part by Circuit Judge Dyk

Mitsubishi Chemical Corp. v. Barr Laboratories, Inc. (Fed. Cir. 2011)

By Donald Zuhn --

Yesterday, the Federal Circuit affirmed a decision by the District Court for the Southern District of New York finding that Defendants-Appellants Barr Laboratories, Inc. and Pliva-Hrvatska d.o.o. ("Barr") infringed U.S. Patent No. 5,214,052.  The '052 patent, which is assigned to Plaintiff-Appellee Mitsubishi Chemical Corp., relates to argatroban solutions containing ethanol, water, and a saccharide.  Argatroban is an anticoagulant used in the treatment of heparin-induced thrombocytopenia.

The '052 patent discloses that the solubility of argatroban increases dramatically when it is dissolved in ethanol, water, and a saccharide.  At the time the application that issued as the '052 patent was filed, argatroban was known to have low aqueous solubility at neutral pH levels, which presented problems for its use in pharmaceutical compositions.  The '052 patent has four claims:

1.  A method for dissolving an arginineamide, comprising:
    dissolving [argatroban] and/or its salt in a solvent containing ethanol, water and a saccharide.

2.  The method according to claim 1, wherein the saccharide is at least one member selected from the group consisting of sorbitol, glucose, glycerin and sucrose.

3.  A pharmaceutical composition for injection, comprising:
    [argatroban] and/or its salt together with ethanol, water and a saccharide.

4.  The composition according to claim 3, wherein the saccharide is at least one member selected from the group consisting of sorbitol, glucose, glycerin and sucrose.

Seeking approval to market a generic version of Misubishi's Argatroban Injection product, which consists of a high concentration of argatroban dissolved in a solution of ethanol, water, and sorbitol at a pH between 3.2 and 7.5, Barr filed an Abbreviated New Drug Application (ANDA) with the FDA.  In response to Barr's ANDA filing, Mitsubishi brought suit against Barr for infringement of the '052 patent.  The parties stipulated that Barr's ANDA product would infringe all four claims of the '052 patent.  Barr answered by asserting that the claims were invalid as anticipated by an article published by Mitsubishi employee Toshihiro Yamamoto, and rendered obvious by several combinations of nine other references.

At trial, Mitsubishi and Barr battled over the proper translation of a single sentence in the Yamamoto reference that described the preparation of an argatroban solution administered to rats for experimental purposes.  The District Court considered four translations of the sentence, concluding that the translation submitted by Mitsubishi's expert was the only reliable translation.  Mitsuibishi's expert translated the relevant sentence as follows:  "In 7.5% D-sorbitol-4% ethanol, an argipidine solution dissolved under hydrochloric acid acidity (pH 1.5 to 1.7) was intraperitoneally administered at a dosage of 1 ml/kg, 15 minutes before common carotid artery occlusion."  Using this translation, the District Court determined that Yamamoto does not anticipate claims 1 and 2 because a person of ordinary skill in the art would have understood Yamamoto to teach dissolution of argatroban in hydrochloric acid alone, i.e., without ethanol or a saccharide (another Mitsubishi expert, and native Japanese speaker, testified that the disputed sentence from the Yamamoto reference should be understood to mean "in hydrochloric acid the [argatroban] was dissolved and after that it's been put into D-sorbitol and ethanol").  The District Court concluded, therefore, that the phrase "[i]n 7.5% D-sorbitol-4% ethanol" referred to how the argatroban solution was administered and not how it was dissolved.  As for claims 3 and 4, the District Court concluded that Yamamoto's argatroban solution was not "[a] pharmaceutical composition for injection" because a pharmaceutical composition must have a pH above 3 (the District Court based this conclusion on the testimony of a third Mitsubishi expert).

With respect to Barr's obviousness argument, the District Court dismissed four of Barr's nine references as not addressing argatroban solubility or methods of formulating the drug.  The District Court found that while the other five references described solvent systems including ethanol, water, and a saccharide, none of these references directed the skilled artisan to use ethanol, water, and a saccharide to dissolve argatroban.  The District Court therefore determined that the claims of the '052 patent would not have been obvious.

On appeal, Barr first challenged the District Court's selection of the Mitsubishi expert's translation of Yamamoto, arguing that two other translations were not prepared for purposes of this litigation.  The Federal Circuit noted that "[t]he district court's selection of the appropriate translation in this case was based in large part on a credibility determination, and such determinations are 'virtually never' overturned for clear error."  The opinion also discounted Barr's argument that the translation adopted by the District Court should be disregarded because it was prepared for purposes of this litigation, stating that this was "not a sufficient reason to conclude that the district court's choice of the [Mitsubishi expert's] translation was clearly erroneous."

With respect to claims 3 and 4, Barr argued that the phrase "pharmaceutical composition for injection" in the preamble of claim 3 means "a medicinal drug composition that can be administered by injection," and that this claim therefore covers any composition that includes a "medicinal drug" (i.e., argatroban), along with ethanol, water, and a saccharide, regardless of whether it can be injected into a patient with therapeutic effect.  In dismissing Barr's argument, the Court noted that "[t]he problem with Barr's construction is that the word 'pharmaceutical' in claim 3 modifies the entire 'composition' referred to in the claim, not simply the argatroban component of the composition."  The Court pointed out that "Barr's claim construction would allow a 'plainly toxic composition, such as a cleaning fluid or a pesticide,' to meet the limitations of claim 3, even though such a composition would not be medicinal under any definition of that word."  The Court "therefore reject[ed] Barr's attempt to broaden the phrase 'pharmaceutical composition for injection' to cover any composition that includes a medicinal product, regardless of its suitability for injection into humans."  Because the District Court concluded that the pH of the Yamamoto argatroban solution was below 3, and that such a solution would not be acceptable for use as a medicine, the Federal Circuit determined that Barr had failed to show by clear and convincing evidence that Yamamoto disclosed a pharmaceutical composition for injection.

As for Barr's obviousness argument, the Federal Circuit determined that the District Court did not clearly err in determining that the prior art taught away from the use of ethanol to dissolve argatroban.  The Federal Circuit also found no reason to disturb the District Court's determination that a number of Barr's references were not specific to argatroban, despite describing solvent systems including ethanol, water, and a saccharide.

Mitsubishi Chemical Corp. v. Barr Laboratories, Inc. (Fed. Cir. 2011)
Nonprecedential disposition
Panel: Circuit Judges Bryson, Dyk, and Prost
Opinion by Circuit Judge Bryson

Billups-Rothenberg, Inc. v. Associated Regional and University Pathologists, Inc. (Fed. Cir. 2011)

By Donald Zuhn --

Last week, in Billups-Rothenberg, Inc. v. Associated Regional and University Pathologists, Inc., the Federal Circuit determined that the District Court for the Central District of California had properly granted summary judgment of invalidity with respect to U.S. Patent Nos. 5,674,681 and 6,355,425.  In particular, the panel affirmed the District Court's decision that the asserted claims of the '681 patent were invalid for lack of written description, and its decision that the asserted claims of the '425 patent were invalid as anticipated by U.S. Patent No. 6,025,130.

In 2009, Plaintiff-Appellant Billups-Rothenberg, Inc. sued Defendants-Appellees Associated Regional and University Pathologists, Inc. (doing business as ARUP Laboratories) and Bio-Rad Laboratories, Inc. ("ARUP"), asserting that ARUP infringed certain claims of the '681 and '425 patents by providing or using diagnostic assays or kits for detecting Type I hereditary hemochromatosis.  Type I hereditary hemochromatosis, which is an iron disorder characterized by excessive iron absorption by the body, is caused by specific mutations in the High Fe ("HFE") gene, which is located on the short arm of chromosome six in humans.

The '681 patent, which issued from an application filed by Billups in 1994, discloses that the gene responsible for hemochromatosis is located on human chromosome six.  The '681 application also discloses that "[a] mutation in a nucleic acid sequence can be detected by various methods to analyze nucleic acids [which] are well known to those in the art."  Claim 2 of the '681 patent recites:

2.  A method to identify an individual having or predisposed to having hemochromatosis, comprising the steps of:
    a)  providing from the individual a sample containing a gene encoding a nonclassical MHC class I heavy chain and
    b)  detecting a mutation in said gene, which mutation results in the reduced ability of said heavy chain to associate with said β2 microglobulin, wherein the presence of said mutation identifies said individual as having or predisposed to having hemochromatosis.

The '681 patent does not, however, disclose the HFE gene or identify any mutations associated with hemochromatosis.

In 1996, a different group of researchers isolated and sequenced the hemochromatosis (or HFE) gene and identified three mutations in the gene that are associated with hemochromatosis:  C282Y, H63D, and S65C.  This research led to the issuance of the '130 patent, which discloses the HFE gene sequence and the C282Y, H63D, and S65C mutations (identified in the '130 patent as 24d1, 24d2, and 24d7, respectively):

The '130 patent, which is owned by Bio-Rad and licensed to ARUP, also discloses genetic tests for hemochromatosis that utilize the mutations and sequence variants identified in the patent.

Using the sequences disclosed in the '130 patent, Billups developed a method for diagnosing an iron disorder by testing for the S65C mutation.  In 1999, Billups filed an application directed to this method, which issued as the '425 patent.  Claim 1 of the '425 patent recites:

1.  A method of diagnosing an iron disorder or a genetic susceptibility to developing said disorder in a mammal, comprising determining the presence of a mutation in exon 2 of an HFE nucleic acid in a biological sample from said mammal, wherein said mutation is not a CàG substitution at nucleotide 187 of SEQ ID NO: 1 and wherein the presence of said mutation is indicative of said disorder or a genetic susceptibility to developing said disorder.

At trial, Billups and ARUP filed cross-motions for summary judgment, Billups seeking summary judgment of infringement and ARUP seeking summary judgment of invalidity.  The District Court denied Billups' motion and granted ARUP's motion of invalidity for lack of written description (as to the '681 patent) and anticipation (as to the '425 patent).  With respect to the '681 patent, the District Court noted that neither the sequence of the HFE gene nor any mutations in the HFE gene were disclosed in the patent, and the "patentee has merely directed the person of ordinary skill in the art to a general location of a mutation on a chromosome and suggested that the mutation may be found in that vicinity."  With respect to the '425 patent, the District Court determined that the '130 patent was prior art to the '425 patent, and further, that the '425 patent claims the same genetic test for the S65C mutation that is disclosed in the '130 patent.

Writing for the Federal Circuit, and addressing the issue of written description first, Judge Gajarsa noted that "Billups claims that its disclosure of the mutation's general location somewhere 'within less than a 300 base pair region of a defined exon of a well studied multi-gene family,' combined with the knowledge that existed at the time of filing the '681 patent, established that [the inventors] possessed the claimed invention."  While "[t]he '681 patent claims a test for mutations," he also noted that "it is undisputed that the specification and originally filed claims of the '681 patent disclose neither the hemochromatosis gene sequence nor any specific mutations within that gene."  In summarizing Billups' argument on appeal, Judge Gajarsa stated that:

Billups contends that the '681 patent taught structure, i.e., that hemochromatosis has a genetic basis, and function, namely, its adverse effect upon the binding of β2 microglobulin with a non-classical MHC class I heavy chain.  Specifically, Billups argues that the '681 patent's correlation of function with the general location of the C282Y mutation, combined with the knowledge of a person of ordinary skill in the art in the field at the time of filing, satisfied the written description requirement by localizing the mutation to a 300 base pair region.

Agreeing with the District Court's findings that "[p]atentee's general location disclosure is too imprecise to constitute structural features necessary to meet the written description requirement," and that the "specification for the '681 patent contains only functional, not structural, characteristics of the predicted mutations," Judge Gajarsa determined that the District Court properly granted summary judgment of invalidity for lack of written description.

Turning to the issue of anticipation, Judge Gajarsa quickly concluded that:

The asserted claims of the '425 patent are invalid because they are anticipated by the '130 patent.  The '130 patent was filed nearly three years before the '425 patent and is prior art under § 102(e).  The district court correctly ruled that the '130 patent discloses use of the S65C mutation as a "HH [(hereditary hemochromatosis)] diagnostic," and, thus, Billups was not the first to disclose diagnosis of hemochromatosis using the S65C mutation.

While Billups argued on appeal that the '130 patent concludes that "the S65C mutation was only a clinically insignificant polymorphism unrelated to disease state," and therefore that "the '130 patent did not teach using the S65C mutation to diagnose hemochromatosis," Judge Gajarsa countered that "[d]espite the inventors' uncertainty regarding the utility of the S65C mutation because of their small sample size, the '130 patent describes two genetic tests for hemochromatosis that involve detection of the S65C mutation as an input for the diagnosis of hemochromatosis."  Citing Celeritas Techs., Ltd. v. Rockwell Int’l Corp., 150 F.3d 1354, 1361 (Fed. Cir. 1998), Judge Gajarsa noted that "[a]lthough the '130 patent discounts the utility of the S65C mutation in diagnosing hemochromatosis, we have held that a 'reference is no less anticipatory if, after disclosing the invention, the reference then disparages it.'"  Thus, "[e]ven though the inventors of the '425 patent performed experiments revealing greater diagnostic utility of the S65C mutation than initially suspected," Judge Gajarsa concluded that "the use of the S65C mutation as a diagnostic tool was already contemplated by the '130 patent," and therefore affirmed the District Court's finding of invalidity with respect to the '425 patent.

Billups-Rothenberg, Inc. v. Associated Regional and University Pathologists, Inc. (Fed. Cir. 2011)
Panel: Circuit Judges Gajarsa, Linn, and Moore
Opinion by Circuit Judge Gajarsa

King Pharmaceuticals, Inc. v. Eon Labs, Inc. (Fed. Cir. 2010)

Inherent Anticipation and Inherent Obviousness?

By Andrew Williams --

Last week, in King Pharmaceuticals, Inc. v. Eon Labs, Inc., the Federal Circuit affirmed a grant of summary judgment of invalidity of U.S. Patent Nos. 6,407,128 (the "'128 patent") and 6,683,102 (the "'102 patent"), although not necessarily for the same reasons articulated by the U.S. District Court for the Eastern District of New York.  King initiated the litigation after Eon filed an ANDA to market and sell a generic 800 mg metaxalone tablet for the treatment of "discomforts associated with acute, painful musculoskeletal conditions."  Metaxalone was first discovered in the 1960s, and had been sold under the brand name Skelaxin since 1962 -- first by A.H. Robins Co., then by Elan Pharma, Inc ("Elan"), and finally by King.  The '128 and '102 patents issued on June 18, 2002 and January 27, 2004, respectively, and claimed methods for increasing the bioavailability of metaxalone, and methods of using metaxalone in the treatment of musculoskeletal conditions.  The inventors of these two patents discovered and claimed that the oral bioavailability of metaxalone increases when it is administered with food.  The Federal Circuit determined, however, that all of the claims could be found inherently in the prior art.

Inherent Anticipation of Claims 1-3, 8-11, and 15-17 of the '128 Patent

Claim 1 of the '128 patent recites:

A method of increasing the oral bioavailability of metaxalone to a patient receiving metaxalone therapy comprising administering to the patient a therapeutically effective amount of metaxalone in a pharmaceutical composition with food.

The Federal Circuit agreed with the District Court that three references -- Fathie, Musculoskeletal Disorders and Their Management with a New Relaxant, Clinical Medicine 678 (April 1965) ("Fathie II"); Joseph A. Albanese, Nurses' Drug Reference 427 (2nd ed. 1982) ("Albanese"); and Anne C. Abrams, Clinical Drug Therapy 145 (1995) ("Abrams") -- each inherently anticipated this claim, because they each taught taking metaxalone with food.  Specifically, Fathie II taught that nausea associated with metaxalone treatment can be alleviated if taken with food, Albanese taught that administration of metaxalone with meals can help reduce gastric upset, and Abrams instructed nurses to give metaxalone with "milk or food" to decrease gastrointestinal distress.  Therefore, the only potential point of novelty was the preamble requiring the increase of oral bioavailability of the drug.  Nevertheless, the District Court held that an increase in metaxalone bioavailability was an inherent property of taking metaxalone with food as taught by all three of these references.

King argued that the District Court erred because Eon did not provide any evidence that these references would necessarily result in the claimed invention, as required for a finding of inherent anticipation.  King noted that the '128 patent specification provides precise conditions for food consumption that can accomplish the stated goal of the claim, while the prior art references only provide vague conditions.  The Federal Circuit found this position untenable.  Even though the specification provided examples with specific conditions, the disclosure did not indicate that these conditions were essential, and the Federal Circuit pointed out that the claim terms cannot be limited by specific conditions found within the specification.  In other words, the patentees erred by broadly claiming "with food," and perhaps they would have been better served by narrowing the claim scope to specific conditions required to achieve the stated goal of increasing oral bioavailability.  Of course, this is conditional on whether there were, in fact, specific conditions.  Moreover, the Federal Circuit pointed out the general rule that discovering a new benefit of an old process cannot render the process patentable again.  To inherently anticipate, the prior art need only meet the limitation to the extent the patented method does.  And because the claimed methods require no more than taking metaxalone with food, the prior art references that teach the same thing inherently anticipate.  The Federal Circuit also found that because claims 2-3, 8-11, and 15-17 had the same or similar preamble, they were also inherently anticipated.

Inherent Anticipation of Claims 4-6, 12-14, and 18-20 of the '128 Patent

The '128 patent also contained dependant claims that limit the time-frame in which the food must be ingested.  These ranged from "30 minutes prior to 3 hours after consumption," to "substantially at the same time," to "immediately after the consumption of food up to 1 hour after."  Even though none of the prior art references recited specific time requirements, King's own experts explained that "with food," as taught in the prior art, could mean "1 hour prior to up to about 2 hours after eating."  Because every claim included at least part of this range, the Federal Circuit had no difficulty finding that claims 4-6, 12-14, and 18-20 of the '128 patent were also inherently anticipated.

Claim 21 of the '128 Patent is Patent Eligible, but Nonetheless is Inherently Anticipated

Claim 21 depended from claim 1 (shown above), but included the limitation "informing the patient that administration of a therapeutically effective amount of metaxalone in a pharmaceutical composition with food results in an increase in the maximal plasma concentration (Cmax) and extent of absorption (AUC(last)) of metaxalone compared to administration without food."  The District Court invalidated this claim as patent ineligible pursuant to 35 U.S.C. § 101, because the act of informing was not transformative, as required by In re Bilski.  The Federal Circuit disagreed, pointing out that the District Court focused on the "informing" limitation, and not the claim as a whole.  Instead, the Court noted that Claim 21 as a whole is a method of treatment claim, and as such is always transformative, citing Prometheus Labs., Inc. v. Mayo Collaborative Serv., 581 F.3d 1336, 1346 (Fed. Cir. 2009).

Nevertheless, the Federal Circuit also found this claim invalid, not as patent ineligible, but as inherently anticipated.  As claim 1 was already found anticipated, the only potential source of novelty was the "informing" limitation.  The Court considered whether an inherently anticipated claim could be rendered novel by requiring that the patient be told about the existence of the inherent property.  Answering its own question, the Federal Circuit analogized the case to "printed matter" cases, such as In re Gulack, 703 F.2d 1381, 1385 (Fed. Cir. 1983), which hold that if claimed printed matter is not functionally related to a claimed product, it cannot be used to distinguish the invention from the prior art.  And because informing the patient about the benefits of a drug do not transform the process of taking the drug (even if it increased the likelihood that the patient will take the drug), claim 21 was inherently anticipated.

Claim 22 of the '128 Patent is Also Inherently Anticipated

Claim 22 also depends from claim 1, but includes the further limitation that the container have a printed label advising that administration with food results in an increase in the maximal plasma concentration (Cmax) and extent of absorption (AUC(last)) of metaxalone compared to administration without food.  This, of course, brings the case squarely within the "printed matter" cases as described above.  King tried to distinguish on the bases that this claim was a method claim, and the previous "printed matter" cases involved product claims.  However, the Federal Circuit found this to be a distinction without a difference and invalidated the claims based on inherent anticipation.

The Claims of the '102 Patent Are Inherently Anticipated or Inherently Obvious?

Claim 1 of the '102 recited:

A method of using metaxalone in the treatment of musculoskeletal conditions comprising:
providing the patient with a therapeutically effective amount of metaxalone; and
informing the patient that the administration of metaxalone with food results in an increase in at least one of C(max) and AUC(last) of metaxalone compared to administration without food.

Again, the District Court invalidated this claim as patent ineligible, but the Federal Circuit affirmed on alternate grounds, specifically that the claim was inherently anticipated.

Of more interest, the District Court also found claim 5 invalid, but as inherently obvious.  Claim 5 depends from claim 1, and limits metaxalone to a "unit dosage form."  The District Court found this claim obvious over Albanese in view of 18 R.W. Dent Jr. and Dorthey K. Ervin, A Study of Metaxalone (Skelaxin) vs. Placebo in Acute Musculoskeletal Disorders: A Cooperative Study, Current Therapeutic Research (1975) ("Dent").  King's apparently only new challenge to this holding was that the District Court did not consider the secondary considerations of non-obviousness.  Specifically, King alleged that the District Court failed to consider sales of Skelaxin from 1998 to 2003.  However, the Federal Circuit noted that sales of the drug actually began to increase before the discovery that ingesting metaxalone with food increased bioavailability.  Moreover, King apparently did not show any nexus between the alleged commercial success and the claimed invention.  As such, the District Court correctly did not give much weight to commercial success.

The Federal Circuit affirmed the obviousness of this claim because it found that "it would be obvious to a person of ordinary skill in the art to combine Dent's teaching of taking a tablet dosage of metaxalone four times a day with Albanese's teaching of administrating metaxalone with food."  However, no mention was made as to why one of skill in the art would have combined these references.  If Albanese had explicitly anticipated the other claims of these two patents, than obviousness would have probably been clear.  However, Albanese inherently anticipated the prior claims, because the newly claimed property was inherently present.  In other words, it was not known prior to the determination by the patentees.  The obviousness determination needs to take into account why one of skill in the art would have combined these two references, especially when the person of ordinary skill would have been unaware of this inherent property.  It is possible that such a reason existed, for example, it is possible that the use of the unit dosage form would have caused increased nausea and/or gastrointestinal distress (thereby leading one to take it with food).  However, no such reason was articulated in the Federal Circuit's opinion, and without articulating such a reason, it would appear that one of skill in the art would have only combined these references by mere happenstance.  As obviousness determination requires more.  The Court did point out that the person of ordinary skill is also a person of ordinary creativity, and not an automaton.  Nevertheless, such a hypothetically person needs to have a reason to be creative, and the Federal Circuit did not even address this fact.  As such, it is not clear that claim 5 of the '102 patent should have been invalidated.

Jurisdiction of Elan, the Prior Patent Holder

The Federal Circuit also addressed the issue whether the District Court had jurisdiction over Elan, because the lower court had entered the order against both King and Elan.  Elan had previously owned the '128 patent, and the application that led to the '102 patent.  However, before the filing of the present suit, Elan sold the patent and application to King, recording the assignment with the Patent and Trademark office.  Nevertheless, Eon filed declaratory counterclaims against Elan.  Elan even provided a letter to the District Court that stated that it waived any rights to pursue any damages or relief from Eon based on Elan's past ownership of the '128 patent.  The District Court did not address whether it had jurisdiction over Elan.  The Federal Circuit said was a mistake, and found that Eon had not met its burden of demonstrating that an actual case or controversy existed between it and Elan.  The broad and unrestricted covenants not sue were determinative.  Consequently, the Court vacated the order of invalidity as entered against Elan.

King Pharmaceuticals, Inc. v. Eon Labs, Inc. (Fed. Cir. 2010)
Panel: Circuit Judges Bryson, Gajarsa, and Prost
Opinion by Circuit Judge Gajarsa

Enzo Biochem, Inc. v. Applera Corp. (Fed. Cir. 2010)

    By Donald Zuhn --

On March 26, the Federal Circuit reversed the judgment of the District Court for the District of Connecticut that U.S. Patent Nos. 5,328,824 and 5,449,767 are invalid, affirmed the judgment of the District Court that U.S. Patent No. 5,476,928 is anticipated, and affirmed the judgment of the District Court that 5,082,830 is not infringed.

The '824, '767, '928, and '830 patents, which are owned by Plaintiffs-Appellants Enzo Biochem, Inc., Enzo Life Sciences, Inc., and Yale University ("Enzo"), are directed to various techniques for labeling and detecting nucleic acids.  More particularly, the '824, '767, and '928 patents are directed to a compound, or a method of using that compound as a detection probe.  In this compound (shown below), a nitrogenous base B is covalently attached, either directly or through a "linkage group" (dotted line), to a chemical moiety A.

In the asserted claims, the linkage group is recited functionally (rather than structurally) as "not interfering substantially" with both hybridization and detection (in the '824 and '767 patents) or detection alone (in the '928 patent).  Chemical moiety A is a label that facilitates detection, "compris[ing] at least three carbon atoms and represent[ing] at least one component of a signalling moiety capable of producing a detectable signal" (claim 1 of the '824 and '767 patents) or "represent[ing] at least three carbon atoms and an indicator molecule selected from the group consisting of fluorescent dyes, electron-dense reagents, enzymes which can be reacted with a substrate to produce a visually detectable reaction product, and radioisotopes" (claim 1 of the '928 patent).  The '830 patent is directed to a compound and a method of detection using a compound, wherein the claimed compound is a nucleotide labeled with "at least one non-radioactive moiety directly or indirectly attached to each of the 5′ and 3′ end nucleotides thereof," and the detection method is accomplished using a "preformed detectable molecular complex."

In June 2004, Enzo brought suit against Defendants-Appellees Applera Corp. and Tropix, Inc. ("Applera") for infringement of the '824, '767, '928, and '830 patents (as well as U.S. Patent Nos. 4,711,955 and 4,994,373, which were not at issue in the appeal).  In October 2006, the District Court issued a claim construction ruling, determining that the "not interfering substantially" functional language for the linkage group means that "the linkage group neither substantially interferes with the ability of the compound to hybridize with the nucleic acid nor substantially interferes with the ability of [moiety] A to be detected."  As for moiety A, the District Court determined that for the '824 and '767 patents, "[moiety] A may be a part of or the entire signalling moiety"; for the '928 patent, the plain language of the patent "precludes a construction where A is the entire [indicator] molecule"; and for the '830 patent, the term "non-radioactive moiety" means "a moiety that is utilized in indirect detection, i.e., a moiety that can be detected with a preformed detectable molecular complex."

Enzo conceded that under the District Court's construction, it could not prove infringement of the '830 patent, and the District Court granted summary judgment of noninfringement to Applera.  Applera then moved for summary judgment of lack of written description, lack of enablement, indefiniteness, and anticipation with respect to the three remaining patents.  The District Court granted summary judgment of indefiniteness and anticipation, finding the "not interfering substantially" language in the asserted claims to be indefinite because "[t]he specifications neither set forth how one would gauge substantial interference, nor delimit the threshold at which interference with the procedure prevents [the claimed] method from being implemented," and determining that the asserted claims were anticipated by three references (Kasai et al., 1979; Pingoud et al., 1977; and Bauman, 1980).

Indefiniteness

On appeal, Enzo argued that the District Court incorrectly determined that the "not interfering substantially" language in the '824, '767, and '928 patents is indefinite.  In particular, Enzo argued that the specifications provide specific examples of linkage groups that do not substantially interfere with hybridization and detection and a test for measuring the degree of interference (i.e., comparing the melting temperature of a modified polynucleotide with that of an unmodified polynucleotide).  Applera countered that nothing in the patents explains how to measure "interference" or how to determine whether such interference is "substantial."

In determining that the claims of the '824 and '767 patents are not indefinite, the Federal Circuit noted that "[t]he claims in this case provide at least some guidance as to how much interference will be tolerated."  Pointing to a dependent claim that recites the structure –CH=CH–CH₂–NH–, the panel observed that "[a] person of ordinary skill would presume that a structure recited in a dependent claim will perform a function required of that structure in an independent claim," and "[t]hus, it may be presumed that the term 'not interfering substantially' in the independent claims allows for at least as much interference as that exhibited when the linkage group has the structure specified in the dependent claims."

The panel also looked to examples of suitable linkage groups, as well as criteria for selecting such linkage groups, disclosed in the specification.  For example, the specification discloses that more preferred chemical linkage groups be derived from a primary amine and have the structure –CH2–NH–, and further, that thermal denaturation profiles and hybridization properties of a polynucleotide can be used to measure the degree to which a linkage group interferes with hybridization.  In view of the teachings in the specification, the panel concluded that the specification indicates that "when a linkage group is incorporated into a DNA strand having a length and sequence similar to those used in the specification, a decrease in Tm of up to 5 ^oC implies that the linkage group does not 'substantially interfere' with hybridization, and a decrease of up to 15 ^oC is acceptable if the degree of cooperativity and the extent of hyperchromicity are the same for the modified and unmodified strands."

Finally, the panel noted that during the prosecution of the patents, Enzo overcame an indefiniteness rejection by submitting a declaration under 37 C.F.R. § 1.132 listing eight specific linkage groups, including the –CH=CH–CH2–NH– group listed in the patents' dependent claims.  Thus, the panel concluded that:

Because the intrinsic evidence here provides "a general guideline and examples sufficient to enable a person of ordinary skill in the art to determine [the scope of the claims]," the claims are not indefinite even though the construction of the term "not interfering substantially" defines the term without reference to a precise numerical measurement.  When deciding whether a particular linkage group is or is not "substantially" interfering with hybridization within the meaning of the district court's construction, a person of ordinary skill would likely look to the thermal denaturation profiles and hybridization properties (including Tm) of the modified nucleotide, to see whether they fall within the range of exemplary values disclosed in the intrinsic evidence.

(citations omitted).

The Federal Circuit similarly found the claim language not indefinite with respect to detection  (Wherein the '824 and '767 patents concern the effect of the linkage group on hybridization and detection, the '928 patent only concerns the effect of the linkage group on detection.)  In support of this additional finding, the panel noted that the eight linkage groups listed in the declaration "were said not to 'interfere[] with the ability of biotin in an oligo- or polynucleotide probe of this invention to form a detectable complex with one of avidin, streptavidin or antibodies to biotin or iminobiotin.'"  Thus, the panel concluded that:

So long as moiety A can be detected within the level of detection achieved by the applicants using the exemplary linkage groups disclosed in the intrinsic evidence, a person of ordinary skill would understand that a different linkage group (one that is not disclosed in the intrinsic evidence) likewise does not "substantially interfere" with the detection of moiety A.

Anticipation

The Federal Circuit next addressed the issue of anticipation, finding that Enzo had raised a genuine issue of material fact as to the Kasai et al. and Pingoud et al. references sufficient to survive summary judgment of anticipation of the '824 and '767 patents, but that Enzo had failed to raise a genuine issue of material fact with respect to the Bauman reference and '928 patent.  Looking at the first two references, the panel noted that each "employ[s] a –CH2–NH– linkage group, which arguably belongs to the set of linkage groups disclosed in the patents-in-suit as 'even more preferred' embodiments," adding that "[i]f unopposed, this evidence would entitle Applera to judgment as a matter of law."  At trial, Enzo responded by offering an expert declaration stating that the –CH2–NH– linkage group of Kasai et al. "would not provide sufficient rigidity to prevent significant interference with hybridization of a complementary polynucleotide," and "[i]ndeed, one would predict based on the flexibility of this functional group and the concomitant high degree of motion, there would be significant interference due to free rotation about the single bonds."

On appeal, Applera argued that Enzo's expert declaration could not be credited because it conflicted with Enzo's Rule 132 declaration, and further, because Enzo's expert offered no support for his assertion that Kasai et al. would substantially interfere.  The Federal Circuit, however, determined that:

Viewing the [expert] declaration in a light most favorable to Enzo requires that [the expert's] explanation be read as limited to the specific one-carbon aminomethyl group [i.e., –CH2–NH–] disclosed in Kasai and not as a sweeping condemnation of single bonds or an unyielding requirement of double bonds.  . . .  [The expert's] statement that the aminomethyl group disclosed in Kasai would substantially interfere and [the Rule 132 declaration's] statement that a six-carbon diamine group would not are not inconsistent, particularly when viewed in a light most favorable to Enzo, as it must be.

The panel also noted that while Enzo's expert focused on the impact of the nature of the bonds in the linkage group (i.e., single or double) on hybridization and detection, the specification also recognizes that the length of linkage group impacts hybridization and detection.

Lastly, the panel addressed Applera's argument that the –CH2–NH– linkage group, which is described in Kasai et al., was also within Enzo's "even most preferred" embodiments.  In response, the Court determined that Enzo's counterargument that "the 'even more preferred' language is properly read as describing a subset of the preferred embodiments -- i.e., those with carbon-carbon double bonds at the α-positition -- such that the most preferred embodiments have both a carbon-carbon double bond at the α-position, and are derived from a primary amine and include a –CH2–NH– group," was reasonable and should have been credited on summary judgment.

Turning to Pingoud et al., the Court noted that "[o]n its face, Pingoud notes that there was substantial interference with hybridization."  In particular, the panel pointed to a statement in the reference that "[c]odon-anticodon interaction . . . is severely affected by the [fluorescent labeling] modification," stating that "'[c]odon-anticodon interaction' is indicative of hybridization, and 'severely affected' suggests substantial interference."  The panel therefore concluded that there was a genuine issue of material fact as to whether the linkage group disclosed in Pingoud et al. substantially interferes with hybridization.  The Court also rejected Applera's argument that the –CH2–NH– linkage group, which is similarly described in Pingoud et al., was within Enzo's "even most preferred" embodiment.

Turning to the final reference, the panel noted that in Bauman, hybridization is performed before moiety A is attached to base B via the linkage group.  Enzo argued that in view of this chronology, Bauman did not anticipate the '928 patent.  However, the Court determined that "[i]t is irrelevant, for purposes of anticipation, what method is used, much less what order of steps is used, to attach both moiety A and the linkage group to base B."  The Court also noted that because the '928 patent is silent as to hybridization, "[a]ll that is required of this particular linkage group is that it not substantially interfere with the ability of A to be detected."

Infringement

Addressing the last issue on appeal (i.e., infringement of the '830 patent), the Federal Circuit first reviewed the District Court's construction of the term "non-radioactive moiety," which the lower court had found to mean "a moiety that is utilized in indirect detection, i.e., a moiety that can be detected with a preformed detectable molecular complex."  The Federal Circuit found the District Court's construction to be reasonable, and affirmed the lower court's judgment of noninfringement with respect to the '830 patent.  In response to Enzo's argument that the District Court's construction violated the doctrine of claim differentiation because dependent claim 14 adds "a preformed detectable molecular complex" to claim 1, the panel stated that:

[T]he district court's construction imposes no requirement that a preformed detectable molecular complex is actually present in claim 1; rather, it simply requires the "non-radioactive moiety" to be capable of performing a function:  "can be detected with a preformed detectable molecular complex."  Claim Construction, 2006 WL 2927500, at *11 (emphasis added).  Claim 1, unlike claim 14, is infringed even in the absence of a preformed detectable molecular complex.

Enzo Biochem, Inc. v. Applera Corp. (Fed. Cir. 2010)
Panel: Chief Judge Michel and Circuit Judges Plager and Linn
Opinion by Circuit Judge Linn

Caught in a Time Warp: The (In)validity of BRCA1 Oligonucleotide Claims

    By Kevin E. Noonan --

Albeit a bit anticlimactically, a study published in the journal Genomics assesses the patentability of one of the claims invalidated on Monday by Judge Robert W. Sweet of the Southern District of New York in Association of Molecular Pathology v. U.S. Patent and Trademark Office.  The study is interesting in that it illustrates the pitfalls in patents on oligonucleotides related to isolated genes, filed at a time prior to the elucidation of the human genome by the Human Genome Project.  Most relevant to the question of whether such claims are patentable are the many revelations from the HGP that overturned settled dogma based on a now-recognized unrealistic view of the randomness of genomic DNA sequences, as illustrated by the results reported in this study.

The research was performed by Thomas B. Kepler, from the Department of Biostatistics and Bioinformatics at Duke University, and the Center for Computational Immunology; Colin Crossman, a lawyer and owner of Memento Mori, LLC; and Robert Cook-Deegan from the Institute for Genome Science and Policy and the Sanford School of Public Policy, Duke University (Kepler et al., "Metastasizing patent claims on BRCA1").  According to these authors, one of the claims of U.S. Patent No. 5,747,282 seemed "exceptionally broad" -- this is claim 5 that depends on claim 1 (which is directed to an isolated DNA molecule encoding a BRCA1 polypeptide):

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

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

The authors estimate that "the human genome contains over one million oligonucleotides covered by this claim," and follow up this statement with the following calculations:

Accounting for bias in the usage of amino acids as reported, for example, in [7], the usage-weighted geometric mean codon degeneracy per amino acid is 3.107.  Therefore, the mean number of 15-mers encoding a polypeptide of length 5 chosen at random from a vertebrate proteome is 3.107⁵, about 290.  There are 5,575 15-mers in BRCA1, so, if we consider all of the nucleotide sequences that encode the BCRA1 protein, there are about 1.6 x 10⁶ 15-mers embodied by the claim.  There are 4¹⁵=1.07 x 10⁹ different 15-mers altogether, so the probability that a 15-mer chosen at random will be covered by the claim is p=1.6 x 10⁶ / 1.07 x 10⁹=0.0015 (roughly, 1 in 600 possible 15-mers).  A typical human gene (before RNA editing) contains 10,000 bases, so, 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 patent.

The predicted results of this analysis were found in the study.  The authors analyzed the nucleotide sequence of human chromosome 1 looking for only a subset of 15-mers encompassed by claim 5.  ("Computing time" was minimized by excluding two of the six degenerate codons for serine, leucine and arginine amino acids, a reduction said to only "slightly underestimate the degree of redundancy and breadth of claim 5.")  The authors reported finding 340,000 "matches" of the claimed sequences in the 250,000,000 nucleotides comprising chromosome 1.

The authors also examined 713 entries in GenBank representing complete coding sequences for human mRNAs deposited in 1994, reporting that 80% (568/713 contained at least one of the claimed 15-mers.

There is nothing incorrect about this analysis; however, it benefits from current knowledge and (in its implied conclusion of intentional overreaching) neglects to consider the state of the genomics art on August 12,1994, the earliest priority date of the '282 patent.  The calculation was much more simple (or perhaps naïve) then:  any particular 15-mer was expected to occur once in every 1.07 x 10⁹ nucleotides, and thus in a completely random genome the size of the human genome (haploid size of about 3 x 10⁹ nucleotides), to occur about 3 times; a 16-mer would be expected to occur four times less frequently, etc.  Thus, the results set forth in this paper were almost completely unexpected when approached from the outlook of the person of skill in the art in 1994.

As it turns out, the human genome (and most other genomes) are much more inhomogeneous than expected, and the effects of evolution and the relatedness of all organisms (as well as the conservation of motifs and functional domains between species) were equally unexpected.  Indeed, even the number of genes encoded in the human genome turns out to be much smaller (2- to 3-fold fewer genes) than was expected.  As the authors state:  "human genes are not random strings [of nucleotides.]"  Evident now, not so evident 16 years ago.

No one wants an invalid patent.  The in terrorem effect of such a patent is greatly exaggerated, particularly when its invalidity is so easily demonstrated.  Here, these claims, as well as similar claims in other patents, turn out to be sufficiently overbroad as to be easily invalidated.  It is unlikely that the University of Utah, the National Institutes of Health, or Myriad Genetics (all owners of this patent) wanted this result.

Nevertheless, the remainder of the paper discussed the policy implications of this invalid claim.  The authors correctly note that their results indicate that claim 5 was anticipated by the 15-mers known in the prior art as exemplified by the GenBank results.  Thus, "[i]f challenged by re-examination or in litigation, claim 5 may be deemed invalid due to readily identifiable prior art covered by the claim."  The paper cites U.S. Patent Examiner James Martinell, examining a 1991 expressed sequence tag patent application, for recognizing that certain 15-mers could be found in "many genes" and that it was impossible using then-current computer technology to search all known sequences for the 700,000 15-mers claimed in that patent.  Perhaps for that reason, there is no evidence in the prosecution history of the '282 patent that such a search was ever performed.

Despite this strong evidence that claim 5 of the '282 patent is invalid (even before the District Court's decision yesterday), the paper speculates on the scope and reach of the claim (including oligonucleotide primers for performing the polymerase chain reaction).  Regarding the effects of this claim (and Myriad's patents) on basic research, the authors recognize what many others have noted:  no appreciable effect (which belies the introductory sentence of this section that "[t]he effect of this claim on research is very difficult to assess"):

A PubMed search for the term "BRCA1" returned 7,107 articles.  This suggests a large body of research on the gene has been published in the technical literature.  Myriad has not enforced its patents against most research, with the exception of laboratories engaged in clinical research that entailed giving test results to individuals beyond their home institutions [11–13].  Any such research that entailed analysis of DNA molecules containing BRCA1 sequences in the United States very likely infringed this claim, however, so enforcement of this claim would have substantial impact on research.  (Claims to BRCA1 sequences are somewhat narrower in other English-language jurisdictions such as Canada, Australia and New Zealand, and a fortiori in Europe, where the claims that emerged from opposition proceedings were dramatically narrowed.)  There is a very narrow "research exemption" from infringement liability in the United States under common law, and a broader exemption for research that results in data contributed to the government for a regulated medical product or service [14].  Since laboratory-developed tests are not currently subject to Food and Drug Administration approval, however, this exemption may not apply.

The simplest conclusion about the effect of claim 5 and Myriad's other BRCA1 patents on research and clinical testing is that Myriad has only rarely enforced its patents in research, has vigorously enforced its patents against commercial genetic testing, and has selectively enforced its patents in clinical research.  It is also apparent that research on BRCA1 for the past 12 years has entailed massive pervasive infringement of this claim, even if the claim's scope were restricted to BRCA1 research.  Any such research in the United States was thus undertaken under risk of infringement liability and its associated uncertainty.  While Myriad has stated publicly that it has not enforced its patents against basic research [11,12,15], it has not stated it will not do so in the future, and therefore BRCA research in the United States continues only with Myriad's indulgence.

The authors are correct that there is no exemption from infringement liability for basic research, but they admit that Myriad has not enforced (or attempted to enforce) the '282 patent against any basic researchers.  The absence of the exemption may be the problem, not claim 5 of the '282 patent (in view of the results of this research).  Myriad's track record with regard to basic research is consistent with its public statements that it would not enforce its patents against basic research; there is very little else it can do.  And after yesterday's decision, basic or clinical researchers or commercial entities that practice the oligonucleotides recited in claim 5 no longer risk infringement liability.

Ortho-McNeil Pharmaceutical, Inc. v. Teva Pharmaceuticals Industries, Ltd. (Fed. Cir. 2009)

    By Donald Zuhn --

The Federal Circuit today vacated-in-part and affirmed-in-part an order by the District Court for the District of New Jersey granting summary judgment of invalidity of U.S. Reissued Patent No. 39,221 based on anticipation and obviousness.

Plaintiff-Appellant Ortho-McNeil Pharmaceutical, Inc. owns the '221 patent, which relates to a tramadol and acetaminophen composition for use in prescription pain relief.  Ortho first claimed this composition in U.S. Patent No. 5,336,691, and after receiving FDA approval, began marketing a tramadol/acetaminophen tablet under the brand name Ultracet®.

Seeking approval to market a generic version of Ortho's tramadol/acetaminophen tablet, a number of generic companies filed Abbreviated New Drug Applications (ANDAs) with the FDA.  In response to these ANDA filings, Ortho filed multiple lawsuits for infringement of the '691 patent.  The generic companies argued that the '691 patent was invalid for anticipation and obviousness in view of U.S. Patent No. 3,652,589, which relates to tramadol, and which discloses a tramadol, p-acetamino-phenol, pentobarbital sodium, and ethoxy benzamide composition.  During the course of this litigation, Ortho learned that p-acetamino-phenol was an archaic name for acetaminophen.  Because the '589 patent discloses a 1:10 ratio of tramadol to p-acetamino-phenol (i.e., acetaminophen) in its four-compound composition, and this ratio falls within the scope of several claims in the '691 patent, Ortho sought to reissue the '691 patent.

During reissue proceedings, Ortho redrafted all but one of the asserted claims of the '691 patent to narrow them, and amended the lone remaining claim to independent form.  The redrafted claims and amended claim (claim 6 of the '221 patent) were allowed to reissue.  Following reissue, Ortho amended its complaints against the generic companies to assert the reissue claims.  Ortho's cases against Defendants-Appellees Teva Pharmaceuticals Industries, Ltd., Teva Pharmaceuticals USA, Inc., Watson Laboratories, Inc. ("Teva"), and Caraco Pharmaceutical Laboratories, Ltd. ("Caraco") were then consolidated.

Teva and Caraco filed summary judgment motions of invalidity, asserting that the '221 patent was anticipated and rendered obvious by the '589 patent and a series of German publications that were cited during the reissue proceedings (and which disclose a method of managing cancer pain by customizing a co-administration of pain relievers and dosing regimens for particular patients).  Ortho disputed Teva's and Caraco's interpretations of the references and submitted expert testimony explaining why the references did not anticipate or render obvious the asserted claims.  The District Court, however, granted summary judgment invalidating claim 6 as anticipated and obvious over the prior art, and invalidating the other asserted claims as obvious over the prior art.

In vacating the District Court's summary judgment invalidating the asserted claims other than claim 6, the Federal Circuit determined that these claims recite a pharmaceutical composition of tramadol and acetaminophen in a ratio of about 1:5 to about 1:19, and that "[a] single tablet containing only tramadol and acetaminophen in a fixed dose ratio within the claimed range is not disclosed in the cited prior art."  The majority also determined that the '589 patent discloses a four-compound composition and "does not suggest that the pentobarbital sodium and ethoxy benzamide are merely optional for the combination to work as desired."  The Court also took note of Ortho's expert testimony that "one of ordinary skill in the art would not find it obvious to try to remove two of the four active ingredients disclosed in [the four-compound composition of the '589 patent] to arrive at the claimed composition."  As for the series of German references, the majority noted that Ortho's expert explained that these references "actually teach away from the claimed composition because they emphasize the importance of flexibility in choosing combinations and doses of medications based on individual needs," and also disparage the claimed fixed-dosage combination tablet.  The majority concluded that Ortho's reading of the prior art, and expert testimony regarding the understanding of one skilled in the art, raised material questions of fact as to whether a skilled artisan would have found the claimed tramadol/acetaminophen composition obvious, and therefore vacated the District Court's grant of summary judgment as to the asserted claims other than claim 6.

Claim 6 of the '221 patent recites a pharmaceutical composition comprising a tramadol material and acetaminophen, wherein the ratio of the tramadol material to acetaminophen is a weight ratio of about 1:5.  With respect to this claim, the Federal Circuit first determined that while the '589 patent discloses a composition comprising tramadol and acetaminophen, the parties were at odds as to whether the '589 patent discloses the recited weight ratio.  Stating that "[t]he district court improperly resolved disputed questions of fact" in agreeing with Teva's and Caraco's interpretation of the '589 patent, the majority vacated the District Court's summary judgment that claim 6 is invalid for anticipation.

The majority, however, affirmed as to the District Court's summary judgment that claim 6 is invalid as obvious.  The Federal Circuit stated that the ratio of tramadol and acetaminophen disclosed for the four-compound composition of the '589 patent (i.e., 1:10) is so close to the Court's prior construction of "about 1:5" (see Patent Docs report on the prior appeal) that the '589 patent "creates a prima facie case of obviousness with regard to claim 6."  The majority concluded that Ortho failed to rebut the prima facie case by "show[ing] that the prior art teaches away from the claimed range, or the claimed range produces new and unexpected results over the prior art range."

Judge Mayer, in his dissent, begins by declaring that:

The claimed invention does nothing more than combine two well-known pain relievers -- acetaminophen and tramadol -- in a single tablet.  Since the prior art clearly and unequivocally taught that these two analgesics could be combined for effective pain relief, the claimed invention is the epitome of obviousness.

With respect to the disclosure of a four-compound composition in the '589 patent, Judge Mayer states that:

The only alleged difference between the tablet disclosed in the asserted claims of the RE221 patent and the tablet disclosed in [the '589 patent] is that the latter also contains two additional ingredients, pentobarbital sodium and ethoxy benzamide.  Given that ethoxy benzamide was a known carcinogen and pentobarbital sodium was known to have antagonistic interactions with analgesics, it would have been obvious to remove these two drugs from [the '589 patent's] formulation.

Observing that "[n]owhere does [the '589 patent] state that pentobarbital sodium and ethoxy benzamide are required components in a tramadol/acetaminophen tablet," Judge Mayer concludes that the removal of these two compounds would have been "a predictable and simple variation" on the formulation disclosed in the '589 patent.  Moreover, in Judge Mayer's view, when the German publications (which disclose combining tramadol with acetominophen to provide pain relief) are read in the light of the '589 patent (which discloses a fixed-dose tablet), "they clearly suggest combining tramadol and acetaminophen in a single fixed-dose tablet."  Thus, in Judge Mayer's eyes "there is nothing even arguably new about what Ortho claims to have invented."

Ortho-McNeil Pharmaceutical, Inc. v. Teva Pharmaceuticals Industries, Ltd. (Fed. Cir. 2009)
Nonprecedential disposition
Panel: Circuit Judges Mayer, Prost, and Moore
Opinion by Circuit Judge Prost; dissenting opinion by Circuit Judge Mayer

In re Gleave (Fed. Cir. 2009)

    By Kevin E. Noonan --

The duality of nucleic acids has long posed a challenge to patent law.  A gene is, in one way of looking at it, "but a chemical compound, albeit a complex one," and this view of the gene's nature has informed the emphasis on "structure, structure, structure" taken by the Federal Circuit from Amgen Inc. v. Chugai Pharmaceutical Co. to Judge Rader's comment in the oral argument for In re Kubin.  On the other hand, a gene also contains, and is defined by, the information it embodies, encoding an amino acid sequence corresponding to a structurally entirely different molecule, a protein.  This aspect of a gene's nature, and the unpredictable variability of it, underlies both the increased stringency with which the written description requirement is applied to nucleic acid claims, as well as the Office's resistance to apply Judge Rader's "structure, structure, structure" rule in determining whether a novel nucleic acid sequence, identified using established methods, is non-obvious.

The latest example of this phenomenon is the Federal Circuit's decision last week to affirm rejection on 102/103 grounds of unpatentability in In re Greave.  The claims at issue include this generic claim:

[a] bispecific antisense oligodeoxynucleotide, wherein substantially all of the oligodeoxynucleotide is complementary to a portion of a gene encoding human IGFBP-2 and substantially all of the oligodeoxynucleotide is also complementary to a gene encoding human IGFBP-5, and wherein the oligodeoxynucleotide is of sufficient length to act as an antisense inhibitor of human IGFBP-2 and human IGFBP-5

(where IGFBP-2 and -5 stand for two different species of insulin growth factor binding protein).  Also among the rejected claims were claims directed to particular species as set forth in applicants' specification.  The prior art asserted in support of the rejection was a PCT Publication to Wraight (WO 00/78431), which disclosed a list of all 15-mer oligonucleotides that could be made from the (publicly-available) full-length IGFBP-2 sequence, as well as disclosure in the Wraight reference that antisense oligonucleotides could comprise any oligonucleotide that specifically could bind to (i.e., hybridize with) any of the disclosed 15-mer sense oligonucleotides, and the existence in the Wraight disclosure of several 15-mer sense oligonucleotides with sequence complimentarity overlap to the specific oligonucleotides disclosed and claimed by Gleave.

The Federal Circuit affirmed the rejection, in a decision by Judge Prost joined by Chief Judge Michel and Judge Moore.  The Court based this decision on its view that anticipation required merely that the oligonucleotide sequence was in the prior art, not that its usefulness was previously disclosed.  Gleave argued that the art disclosed a mere list comprising "ink," not disclosure of any functional antisense oligonucleotide (indeed, the cited art contained no disclosure of an antisense oligonucleotide at all), but such disclosure was unnecessary, according to the Court.  All that is necessary for a prior art reference to anticipate, said the Court, is that it enable the skilled artisan to make the claimed invention, not use it, citing Impax Lab., Inc. v. Aventis Pharm. Inc., 545 F.3d 1312, 1314 (Fed. Cir. 2008); and In re LeGrice, 301 F.2d 929, 940–44 (C.C.P.A. 1962).  The prior art disclosure need not show actual reduction to practice (Schering Corp. v. Geneva Pharm., Inc., 339 F.3d 1373, 1380–81 (Fed. Cir. 2003); In re Donohue, 766 F.2d 531, 533 (Fed. Cir. 1985)), and the description provided in the putatively anticipating reference "might not otherwise entitle its author to a patent," citing Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1562 (Fed. Cir. 1991).

Cases that could be interpreted to the contrary, such as Bristol-Myers Squibb Co. v. Ben Venue Lab., Inc., 246 F.3d 1368, 1374 (Fed. Cir. 2001) ("[t]o anticipate, the reference must also enable one of skill in the art to make and use the claimed invention") are "[t]aken out of context," according to the Court, insofar as they are interpreted to impose an operability or utility disclosure requirement for an anticipating reference.  A "thorough" reading of the Court's caselaw (including Novo Nordisk Pharm., Inc. v. Bio-Technology General Corp., 424 F.3d 1347, 1355 (Fed. Cir. 2005); Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326 (Fed. Cir. 2005); and In re Hafner, 410 F.2d 1403, 1405 (C.C.P.A. 1969)) imposes no such requirement, the Court concluded.  And the Court also noted that Gleave's claims themselves contained no limitation restricting their scope to functional antisense oligonucleotides.

The crux of the distinction the Court made, regarding the use of a list of sense oligonucleotides in the cited art and the traditional proscription against using a mere recitation of all possible compounds as anticipating claims to particular species, is found in the Court's consideration of the application of In re Wiggins, 488 F.2d 538, 543 (C.C.P.A. 1973) to the facts before it.  In Wiggins, the Court of Customs and Patent Appeals stated:

In our view, [the alleged anticipatory reference's] listing of the compounds by name constituted nothing more than speculation about their potential or theoretical existence.  The mere naming of a compound in a reference, without more, cannot constitute a description of the compound, particularly when, as in this case, the evidence of record suggests that a method suitable for its preparation was not developed until a date later than that of the reference.

If we were to hold otherwise, lists of thousands of theoretically possible compounds could be generated and published which, assuming it would be within the level of skill in the art to make them, would bar a patent to the actual discoverer of a named compound no matter how beneficial to mankind it might be.

488 F.2d at 543 (emphases added).

The Court noted that the CCPA in Wiggins stated that "'[t]he mere naming of a compound in a reference, without more, cannot constitute a description of the compound.'" 488 F.2d at 543.  But the distinction with this case, according to the Court's opinion, is that Wiggins involved the "mere naming of a theoretical compound, without more," and that was not anticipating.  Indeed, the Court emphasized that "'[w]ithout more' is the key phrase," because what is "more" is the capacity for the person of ordinary skill in the art to be able to make the claimed compound.  Here, these were not "potential or theoretical" compounds, but a class of compounds that fell within so limited a genus that the skilled artisan could "'at once envision each member of this limited class,'" citing Eli Lilly & Co. v. Zenith Goldline Pharm., Inc., 471 F.3d 1369, 1376 (Fed. Cir. 2006).  "In that limited circumstance, a reference describing the genus anticipates every species within the genus.  See Perricone [v. Medicis Pharm. Corp., 432 F.3d 1368, 1377 (Fed. Cir. 2005)]."

What was not anticipated by the cited art are methods of using these oligonucleotides, and the Court suggested that Gleave might be entitled to such claims.  As for the appealed composition of matter claims, the Court found that these sequences "are simply not new," and affirmed.  And here is where the duality of nucleic acids becomes important.  It was undisputed that the Wraight reference did not disclose a single antisense oligonucleotide -- it merely disclosed all 15-mer sense oligonucleotides, coupled with generic disclosure that antisense oligonucleotides would specifically hybridize to the disclosed sense oligonucleotides, and the knowledge in the art that such oligonucleotides could be made without undue experimentation.  Regardless of operability (although Gleave's arguments might have had additional force had they contained a functional limitation regarding operability as antisense oligonucleotides), the Court's decision suggests that nucleic acids can be anticipated by the mere recitation of any sequence, or its complement, in the prior art regardless of any disclosure as to operability.  This raises the question of whether an unidentified open reading frame, published in a publicly-available database, might not be enough to anticipate claims directed to an isolated nucleic acid encoding a novel protein.  Like the antisense oligonucleotides at issue in Gleave, the existence of the sequence in the prior art could be combined with the knowledge of the skilled worker that proteins are encoded by open reading frames to anticipate the sequence.  Known operability is not required, according to this panel opinion, raising the question of whether the availability of the published but unrecognized sequence would be enough.  There are certainly distinctions:  here, the oligonucleotides comprised a known protein, for example.  And there would be an In re Hall question about whether an unannotated open reading frame would be sufficiently accessible to qualify as prior art.  But the Federal Circuit's decision in Gleave amounts to yet another instance of differential application of the law to biotechnology claims, whose effects remain to be fully appreciated.

In re Greave (Fed. Cir. 2009)
Panel: Chief Judge Michel and Circuit Judges Prost and Moore
Opinion by Circuit Judge Prost

Ex parte Chuang (B.P.A.I. 2008)

    By Kevin E. Noonan --

The correspondence between a nucleic acid sequence and its encoded amino acid sequence is the basis for a great deal of how the U.S. Patent and Trademark Office examines biotechnology claims.  In many instances the Office treats these sequences differently.  For example, it is common practice for the Office to impose a restriction requirement between them, requiring applicants to elect to pursue examination of either nucleic acid claims or protein (amino acid sequence) claims in an application disclosing both.  Nucleic acid claims encompassing all of the nucleic acids encoding an amino acid sequence are typically granted, while amino acid sequence variants have become increasingly more difficult to obtain, based in part on the unpredictability of the effects of variants on biological activity.

In the recent non-precedential decision by the Board, Ex parte Chuang, the Office affirmed rejection under 35 U.S.C. § 102(b) of claims to an isolated protein over prior art disclosing a nucleic acid encoding the protein.  The rejected claims were directed to the isolated polypeptide:

Claim 4.  An isolated polypeptide, comprising the amino acid sequence of SEQ ID NO: 1.

Claim 20.  An isolated polypeptide, comprising a sequence that has at least 95% sequence identity to SEQ ID NO: 1, wherein the polypeptide reduces 15-keto prostaglandin but does not reduce leukotriene B4.

The Office cited three prior art references, directed towards large collections of isolated and sequenced mouse cDNA sequences.  These references disclosed the amino acid sequence encoded by the cDNA and identified it as a member of a zinc-containing alcohol dehydrogenase superfamily.  The references did not produce the encoded protein nor did they identify the biochemical activity of the protein encoded by the sequence.  Nevertheless, the Board affirmed the Examiner's rejection that disclosure in the prior art of a nucleic acid that encodes a protein isolated thereafter anticipates the protein, even if the cited art did not disclose the isolated protein.

The Board distinguished over an earlier Board decision, Lee v. Dryja, 79 U.S.P.Q.2d 1614 (B.P.A.I. 2005), holding that a "cDNA is at most an equivalent of its encoded protein but does not contain every element of the isolated protein encoded thereby."  Moreover, the Lee case further held:

[A]ssuming arguendo that it was well within ordinary skill in the art to prepare, isolate and purify the protein product of a given cDNA clone at the time the '163 application [the patent application at issue] was filed, the 4.7 kb cDNA described in the '163 specification would have made its encoded protein obvious at best.

The Board based its reasoning on In re Donohue, 766 F.2d 531 (Fed. Cir. 1985), which held that "[i]t is not, however, necessary that an invention disclosed in a publication shall have actually been made in order to satisfy the enablement requirement."  Accordingly, the Board reasoned that the references cited by the examiner provided an enabling disclosure of the protein encoded by the disclosed nucleic acids, and were anticipating.  The Board noted that the burden is on applicants to establish that the cited art is not enabling.

Specifically with regard to the Lee case, the Board first noted that Lee was an interference case, and the issue decided therein was whether Dryja had produced sufficient evidence that it had possession of a single enabled embodiment within the scope of the interference count.  This standard for interferences differs from the standard for anticipation, said the Board, although here that statement seems in error:  the Board would have been in the same position with regard to the cited references if each had only enabled the embodiment identified as SEQ ID NO: 1.  Second, the Board noted that Dryja did not disclose a complete coding sequence for the protein at issue in the interference count.  In that case, the presence of a translation stop codon in the cDNA prevented Dryja's cDNA from expressing full length protein.  None of the references cited against applicants in this case suffered from this infirmity, and it was undisputed that the cDNA could have (but had not) been used to produce the claimed protein.

While non-precedential, this case illustrates that the Office will now consider disclosed nucleic acids to be anticipating references to claims for isolated polypeptides.  This attitude has far-reaching implications for biotechnology, in view of the extensive public disclosure and annotation of open reading frames in sequences determined by the Human Genome Project.  It also contrasts starkly with the more stringent utility requirement for claiming such sequences, wherein applicants must show possession of not only the isolated nucleic acid and expressed protein thereof but also a specific, substantial, and credible utility for nucleic acids and proteins.  Thus, the Office imposes a standard of knowing the function of a protein encoded by a nucleic acid, but considers the mere disclosure of the nucleic acid to anticipate not only the nucleic acid but the protein encoded thereby.  Under these circumstances, it is likely that no later-filed claims to proteins encoded by open reading frames identified from the Human Genome Project will be patented, even if the protein has a unique, unappreciated biological activity.  This stance by the Office will put to the test the belief by many in the biotechnology community that patent protection is necessary to obtain investment in technologies derived from the explosion of genetic information that even now has not been completely elucidated, and that the absence of patent protection will retard if not preclude such investment.  It may be an expensive lesson to learn.

Ex parte Chuang (B.P.A.I. 2008)
Panel: Administrative Patent Judges Grimes, Lebovitz, and Fredman
Opinion by Administrative Patent Judge Fredman

Genetic code image: Madprime, Wikipedia Commons, GNU Free Documentation License

Sanofi-Synthelabo v. Apotex, Inc. (Fed. Cir. 2008)

    By Kevin E. Noonan --

Denial of an ANDA validity challenge by generic pharmaceutical company Apotex of Sanofi-Synthelabo's Orange Book-listed patent for Plavix® was affirmed by the Federal Circuit last week.  The decision, by Judge Newman, joined by Judges Lourie and Bryson, was unremarkable and should remain so, unless the Supreme Court were to grant certiorari and work more of its particular brand of mischief on U.S. patent law.

Sanofi-Synthelabo, Sanofi-Synthelabo, Inc., and Bristol-Myers Squibb Sanofi Pharmaceuticals Holding Partnership (collectively, Sanofi) brought suit under 35 U.S.C. § 271(e)(4) in response to a Paragraph IV certification submitted to the Food and Drug Administration by Apotex, Inc. and Apotex Corp., alleging that Sanofi's U.S. Patent No. 4,847,265 was invalid for anticipation and obviousness over Sanofi's U.S. Patent No. 4,529,596 and Canadian Patent No. 1,194,875.  The active pharmaceutical agent of Plavix®, clopidogrel bisulfite, is recited in claim 3 of the '265 patent:

3.  Hydrogen sulfate of the dextro-rotatory isomer of methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate substantially separated from the levo-rotatory isomer.

At trial, the District Court heard evidence that Sanofi synthesized many hundreds of derivatives of the basic structure of clopidogrel, thienopyridines, and that the first compound approved for use in humans, ticlopidine, was associated with serious side effects.  The unsatisfactory nature of this first thienopyridine drug led to Sanofi producing a second series of compounds, which were the basis for the prior art U.S. and Canadian patents asserted by Apotex as anticipating and/or rendering obvious the claims of the '265 patent.  These patents disclosed 21 specific examples, including a racemic mixture of clopidogrel termed PCR 4099, or by an acronym for its chemical name MATTPCA.  In addition, the evidence indicated that the hydrochloride salt of these compounds was similarly unsuitable for use in humans, due to severe side effects.  Finally, the Court heard testimony from both Sanofi and Apotex that separating enantiomers was both difficult and unpredictable, both in terms of whether the enantiomers could be separated and the properties of each of the enantiomers if they were successfully separated; indeed, the Federal Circuit opinion characterized the way actually used to separate the Plavix® enantiomer from the racemic mixture to be a "lucky combination" of chemical reagents.  For chiral thienopyridines other than PCR 4099 that had been separated into their component enantiomers, there was no evidence of any advantage over the original racemic mixture:  although one enantiomer was more biologically active, it was also more neurotoxic, a common side effect of these drugs.

Evidence heard by the District Court established that the Plavix® enantiomer displayed absolute stereoselectivity, i.e., all of the desired biological activity was found in the Plavix® enantiomer, while all of the neurotoxic side effects were found in its enantiomeric twin.  The Court characterized this distribution of properties to be rare, unexpected, and unpredictable.

In considering Apotex's anticipation defense, the District Court parsed claim 3 of the '265 patent into the following 4 elements:  1) the bisulfate salt; of 2) the "d" enantiomer; of the compound 3) methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)-(2-chlorophenyl) acetate (MATTPCA); that was 4) "substantially" separated from the "l" enantiomer.  Apotex argued that Sanofi's prior patents disclosed not only the racemic mixture, but that the separated enantiomers were encompassed by the invention.  Apotex argued that disclosure of the racemate, plus the knowledge of the skilled worker of methods for separating enantiomers, anticipated claim 3 of the '265 patent.

The District Court, and the Federal Circuit, disagreed, on the grounds that an anticipating reference must be enabling.  Moreover, according to Judge Newman's opinion, an anticipating reference requires "the specific description as well as enablement of the subject matter at issue," and that the art must disclose the elements "arranged as in the claim," citing the Federal Circuit's recent decision in Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 (Fed. Cir. 2008).  As stated in In re Arkley, 455 F.2d 586, 587 (C.C.P.A. 1972), cited in Net MoneyIN:

[The] reference must clearly and unequivocally disclose the claimed [invention] or direct those skilled in the art to the [invention] without any need for picking, choosing, and combining various disclosures not directly related to each other by the teachings of the cited reference.

Apotex cited In re Petering, 301 F.2d 676 (C.C.P.A. 1962), and In re Schaumann, 572 F.2d 312 (C.C.P.A. 1978) in support of its argument, but the Federal Circuit found that these cases required an enabling reference disclosing a genus to disclose "specific preferences" not disclosed by the art cited here.  Judge Newman asserted to the contrary In re May, 574 F.2d 1082, 1090 (C.C.P.A. 1978), which is explicit (according to the CAFC) that "the novelty of an optical isomer is not negated by the prior art disclosure of its racemate."

The Federal Circuit expressly held that knowledge that enantiomers may be separated is not anticipation of a specific enantiomer that has not been separated, identified, and characterized in the cited prior art.  The Federal Circuit agreed with the District Court that separation of these enantiomers was not enabled because such separation would constitute undue experimentation.  Judge Newman cited Forest Laboratories, Inc. v. Ivax Pharmaceuticals, Inc., 501 F.3d 1263, 1268-69 (Fed. Cir. 2007), that "this court recognized the known difficulty of separating enantiomers and the unpredictability of their properties, and held that a reference that stated that a compound has enantiomers did not enable the separation of those enantiomers, where the reference did not teach how to obtain the enantiomer."  The Federal Circuit rejected Apotex's argument that the cited '596 patent should be presumed to be enabled, under the Court's Amgen Inc. v. Hoechst Marion Roussel, Inc. decision, stating that the presumption could, and here was, overcome by the particular facts and circumstances of this case.

Turning to Apotex's obviousness defense, Judge Newman assessed how the District Court applied the Graham v. John Deere Co. factors in view of the Supreme Court's recent decision in KSR Int'l Co. v. Teleflex Inc.  Initially, the opinion defined the basis for doing this analysis for a chemical compound on the principle that a chemical compound and its properties are inseparable when assessing obviousness, citing In re Sullivan and In re Papesch.  The District Court had assumed that Apotex had made out a prima facie case of obviousness, but found that "the unpredictable and unusual properties of the dextrorotatory enantiomer and the therapeutic advantages thereby provided, weighed in favor of nonobviousness, and that Apotex had not met its burden of establishing otherwise."  The bases for this determination were, inter alia, the absolute stereospecificity of the Plavix®  enantiomer, which experts for both Sanofi and Apotex testified were both unpredictable and rare, and that it was even more rare that all of the biological activity would be in one enantiomer and all the neurotoxicity would be in the other.

Apotex's argument was substantially that the recognition in the art that enantiomers exist, and known methods for isolating them, were sufficient to overcome Sanofi's argument of unexpected results of the claimed enantiomer.  In this regard, the argument echoes the Patent Office position in Ex parte Kubin (as well as In re Deuel) that the obviousness of a method for isolating a nucleic acid sequence can make the nucleic acid itself obvious.  Here, the Federal Circuit rejected this argument:

Apotex argues that the district court applied an incorrect inquiry, and that the correct inquiry is not whether the results obtained with the separated enantiomer were unexpected, but whether it would have been obvious to separate and test the enantiomers, based on the general knowledge that enantiomers can exhibit different properties.

A more intriguing argument by Apotex was that recognition in the art that enantiomers existed provided sufficient motivation to separate them, using known methods, and that routine methods could be used to identify the properties of the separated enantiomers.  In this calculus, the very properties relied upon by Sanofi and the Court to establish that the Plavix® enantiomer is non-obvious can be considered inherent, albeit unrecognized, properties that (under Papesch) are inseparable from their chemical structure (which was recognized in the art).  Especially considering that obviousness references do not have the same enablement requirements as anticipatory references do, there is some (but here insufficient) force to this argument.

For both the District Court and the Federal Circuit, testimony from Sanofi's expert that enantiomeric separation was difficult and unpredictable was persuasive.  The District Court described the separation as a "paradigm of trial and error," and found that:

neither the chemists at Sanofi nor a person of ordinary skill in the art could have reasonably expected that the separate enantiomers of PCR 4099 could be obtained at the time that Sanofi was contemplating whether to investigate them and, if obtained, they could not have predicted by what method and configuration.

Judge Newman's opinion expressly contrasted the Forest Labs case and Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293 (Fed. Cir. 2007), noting that in Forest Labs "the (+) enantiomer of citalopram would not have been obvious in light of the known racemate, when it was shown that the therapeutic properties of the (+) enantiomer were unexpected."  In the Lupin case, on the other hand, "this court held that the ramipril isomer's potency was 'precisely what one would expect, as compared to a mixture containing other, inert or near-inert stereoisomers.'"  Although Apotex argued that the CAFC should come to the same decision it came to in the Lupin case, Judge Newman opined that "the evidence was directly contrary to that position.  The district court entered extensive findings in this case on the unexpected and unpredictable properties of clopidogrel, and there was no contrary evidence suggesting, based on the prior art, that the stereoselective properties were 'precisely what one would expect,'" as required for the Lupin case to be controlling.

In addition to the issue of the non-obviousness of the Plavix® enantiomer per se, the Federal Circuit also addressed the non-obviousness of the bisulfite salt as recited in claim 3 of the '265 patent.  The Court noted that the cited U.S. and Canadian prior art patents disclosed the HCl salt, and that there were 80 possible alternative candidate candidates, with 53 of these being FDA approved.  The Court noted that it was unpredictable whether a particular salt with a particular drug would form a "pharmaceutically-suitable crystalline salt."  Moreover:

The district court distinguished the facts of this case from those of Pfizer v. Apotex (480 F.3d 1348), where there was evidence that based on the prior art a person of ordinary skill would have narrowed the possible salts to only a few including the claimed besylate, whereas here Sanofi presented evidence that the prior art taught away from the use of sulfuric acid with an enantiomer, for strong acids could encourage re-racemization.

The Federal Circuit's decision in this case is both unremarkable and entirely consistent with its own and Supreme Court precedent.  Particularly with regard to chemical obviousness of separated enantiomers in view of the KSR decision, here the Federal Circuit has consistently relied on evidence of unexpected results of the separated enantiomer coupled with difficulties in achieving enantiomeric separation.  The Federal Circuit has avoided per se rules or mechanical or rigid application of any rubrics other than the Graham factors, based on a case-by-case determination of the facts disclosed in the prior art and underlying the claimed invention.

Nevertheless, Plavix® is a "blockbuster" drug, garnering $3 billion in revenue in 2007, and moreover is an example of a pharmaceutical company obtaining a "later-filed" patent to increase patent protection specifically directed to its commercial product.  These factors increase the political pressures surrounding this case, from a diverse cross-section of the public that opposes "high" drug prices and "lengthened" terms of patent protection for human drugs.  Plavix® has already been the target of efforts in countries like Thailand to exercise national preogatives granted under the Doha Declaration to void drug patent rights (see "EU trade Commissioner Sends Warning Letter to Thailand").  The next and final step for Apotex to challenge Sanofi's patent protection for Plavix® would be for the Supreme Court to grant certiorari.  If the legal issues were paramount, this might be considered unlikely.  But in view of the serious political pressures around this patent and this drug, and the Supreme Court's recent sensitivity to political considerations in patent law, there is a real possibility that the Supreme Court will decide to review this Federal Circuit decision.

Sanofi-Synthelabo v. Apotex, Inc. (Fed. Cir. 2008)
Panel:  Circuit Judges Newman, Lourie, and Bryson
Opinion by Circuit Judge Newman

Impax Laboratories, Inc. v. Aventis Pharmaceuticals Inc. (Fed. Cir. 2008)

    By Donald Zuhn --

Last Friday, the Federal Circuit affirmed the determination by the District Court for the District of Delaware that U.S. Patent No. 5,236,940 does not qualify as an enabling prior art reference, and therefore, does not anticipate claims 1-5 of U.S. Patent No. 5,527,814.

The '814 patent, which is owned by Defendant-Appellee Aventis Pharmaceuticals Inc., relates to the use of riluzole to treat amyotrophic lateral sclerosis (ALS), otherwise known as Lou Gehrig's disease.  Aventis markets riluzole under the trade name RILUTEK.

Seeking approval to market a generic version of riluzole, Plaintiff-Appellant Impax Laboratories, Inc. filed an Abbreviated New Drug Application (ANDA) with the FDA.  One year later, Impax filed suit for a declaratory judgment that it did not infringe, induce infringement of, or contribute to the infringement of the '814 patent, and further, that the '814 patent was invalid as anticipated and unenforceable.

After a bench trial, the District Court determined that Impax failed to show that the '814 patent was unenforceable or that claims 1-5 of the '814 patent were anticipated by the '940 patent.  Impax appealed that determination to the Federal Circuit, which affirmed-in-part, vacated-in-part, and remanded to the District Court (see Patent Docs report on Impax II).  On remand, the District Court found that because the '940 patent disclosed a formula encompassing hundreds or thousands of compounds for the treatment of several diseases, excessive experimentation would have been required to use riluzole to treat ALS (in view of the teachings of the '940 patent).  In addition, the District Court determined that nothing in the '940 patent directed the skilled artisan to the use of riluzole for treating ALS, rejecting Impax's argument that "the mere mention of riluzole is sufficient to put one skilled in the art in the possession of the claimed invention."

In the second appeal, the Federal Circuit affirmed the District Court's finding of non-enablement, stating that "each component of the claimed invention -- identifying riluzole as a treatment for ALS and devising dosage parameters -- would require undue experimentation based on the teachings of the '940 patent."  Because the District Court did not err in finding the '940 patent to be non-enabling, the Federal Circuit also found that the District Court had correctly determined that the '940 patent did not anticipate claims 1-5 of the '814 patent.

Impax Laboratories, Inc. v. Aventis Pharmaceuticals Inc. (Fed. Cir. 2008)
Panel: Circuit Judges Rader and Schall and District Judge Zobel
Opinion by Circuit Judge Rader

Additional Disclaimer:  MBHB represented Aventis in the above appeal.  To the extent that this case summary contains any opinions, the opinions would be of Dr. Zuhn and not Aventis or MBHB.

In re Omeprazole Patent Litigation (Fed. Cir. 2008)

    By Kevin E. Noonan --

The Federal Circuit today affirmed AstraZeneca's latest victory in its long-running battle against generic drug companies who filed ANDAs for its (former) blockbuster drug, Prilosec®.  The Court affirmed in toto the decisions of Judge Barbara S. Jones, the District Court judge sitting in the Southern District of New York who has handled the consolidated infringement actions brought by AstraZeneca under 35 U.S.C. § 271(e)(2)(A).  The two sets of defendants, Apotex Corp., Apotex, Inc., and Torpharm Inc. on the one hand and Impax Laboratories on the other, were found to infringe the patents in suit, and neither defendant had established that these patents were invalid by clear and convincing evidence.

The Federal Circuit characterized the decision appealed from in this case as the "second wave" of the consolidated, multidistrict litigation involving these patents and various generic company ANDA filers who filed Paragraph IV certifications that AstraZeneca's patents were invalid.  The Court had heard and affirmed the first wave decisions in In re Omeprazole Patent Litigation, 86 Fed. App'x. 76 (Fed. Cir. 2003) and In re Omeprazole Patent Litigation, 483 F.3d 1364 (Fed. Cir. 2007).  In this case, the Court addressed separately and rejected the contentions of each of the two parties defendant, in a unanimous decision by Judge Bryson, Judges Lourie and Gajarsa concurring.

There were two patents in suit, U.S. Patent Nos. 4,786,505 and 4,853,230.  Claim 1 of the '505 patent reads as follows:

An oral pharmaceutical preparation comprising:
    (a) a core region comprising an effective amount of a material selected from the group consisting of omeprazole plus an alkaline reacting compound, an alkaline omeprazole salt plus an alkaline reacting compound and an alkaline omeprazole salt alone;
    (b) an inert subcoating which is soluble or rapidly disintegrating in water disposed on said core region, said subcoating comprising one or more layers of materials selected from among tablet excipients and polymeric film-forming compounds; and
    (c) an outer layer disposed on said subcoating comprising an enteric coating.

And claim 1 of the '230 patent reads as follows:

A pharmaceutical preparation comprising:
    (a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance, an alkaline salt of an acid labile pharmaceutically active substance, or an alkaline salt of an acid labile pharmaceutically active substance and an alkaline reacting compound different from said active substance;
    (b) an inert subcoating which rapidly dissolves or disintegrates in water disposed on said core region, said subcoating comprising one or more layers comprising materials selected from the group consisting of tablet excipients, film-forming compounds and alkaline compounds; and
    (c) an enteric coating layer surrounding said subcoating layer, wherein the subcoating layer isolates the alkaline reacting core from the enteric coating layer such that the stability of the preparation is enhanced.

Impax challenged the District Court's decisions on both procedural and substantive grounds.  Procedurally, Impax asserted error in each of the District Court decisions regarding jurisdiction over the action after AstraZeneca's patents-in-suit had expired and denying its demand for a jury trial.  (The District Court dealt with the latter ground summarily, stating that it had once before rejected Impax's contentions with regard to its petition for a writ of mandamus, and upholding its prior determination as "the law of the case.")  On the jurisdictional question, the patents-in suit expired between the end of the bench trial and when the District Court entered judgment, and according to Impax, patent expiry eliminated any "case or controversy" between the parties.  The District Court also extended the time that the FDA was prohibited from allowing Impax's ANDA for six months from the date of patent expiry, as a consequence of the Agency's granting AstraZeneca a six-month period of pediatric exclusivity.  (Pursuant to 21 U.S.C. § 355(a), the FDA has the authority to request that an NDA holder perform pediatric studies on the effect of an approved drug.  If the NDA holder performs such studies, the Agency can extend the term of a patent-holder's exclusivity for an additional six months after Orange Book listed patents have expired.  In this case, that date was October 20, 2007.)

The Federal Circuit affirmed the District Court's interpretation of the statute, saying that the relevant provisions clearly give the District Court the authority to extend a patentee's period of exclusivity for the six-month additional period provided as a reward for performing pediatric testing at the FDA's behest.  The CAFC pointed to the express words of the statute, that "the period during which an ANDA may not be approved under section 355(j)(5)(B) 'shall be extended by a period of six months [i.e., the period of pediatric or market exclusivity] after the date the patent expires (including any patent extensions).'"  The Federal Circuit also rejected Impax's underlying basis for its argument, that patent expiry removed the District Court's jurisdictional basis under Article III's "case or controversy" requirement.  Stating the principle that what is required for a case to be justiciable is "a real and substantial controversy," the CAFC refused to permit patent expiry to be a ground for destroying jurisdiction when there clearly remained a "real and substantial controversy" between the parties (since Impax conceded that, even as they construed the situation, the District Court would have retained its authority if it had rendered its decision before the patents expired).  The Federal Circuit also rejected Impax's reliance on Kearns v. Chrysler Corp. and Roche Palo Alto v. Apotex, saying that the Kearns case concerned injunctive relief under 35 U.S.C. § 283 not § 271(e)(4)(A), and that in Roche, the dispute was on "the particular terms of the district court's order" (i.e., how the court worded its order), not a challenge on whether relief was available under the statute.

Impax's appeal of the District Court's decision that its ANDA product infringed the patents-in-suit was based on whether AstraZeneca had introduced sufficient and relevant evidence that each of the claim elements could be identified in its product.  First, Impax attacked the District Court's finding that the Impax formulation contains an "effective amount" of omeprazole and an alkaline reactive compound (ARC).  Second, Impax argued that there was insufficient evidence that its formulation contained an inert subcoating.  Since this appeal was from the District Court's decision after a bench trial, Impax had the burden of showing clear error in the District Court's decisions, a burden the Federal Circuit held it did not carry on either ground of appeal.  The CAFC had construed the meaning of the term "effective amount" in the so-called "first wave" phase of the litigation, to require the limitation applied to both the amount of omeprazole and the amount of the ARC.  Further, the CAFC had construed the meaning of the term "alkaline reacting compound" to mean "(1) a pharmaceutically acceptable alkaline, or basic, substance having a pH greater than 7 that (2) stabilizes the omeprazole or other acid-labile compound by (3) reacting to create a micro-pH of not less than 7 around the particle of omeprazole or other acid-labile compound."  Impax contended that this construction required AstraZeneca to introduce evidence of comparative stability testing to show that Impax's formulation fell within the scope of the claim.

The Federal Circuit rejected this contention, saying that the evidence AstraZeneca did introduce established that the ARC created the recited "'micro-pH' in the drug core," which the CAFC said was "the same evidentiary burden that the district court placed on Astra" in the first wave of the litigation.  Accordingly, the CAFC found no clear error in the District Court's determination that AstraZeneca had established infringement by a preponderance of the evidence.  Similarly, the CAFC rejected Impax's contention that, absent affirmative evidence that its formulation showed "enhanced stability," the District Court had "read [the limitation] out of the claims entirely" of the '230 patent.  All that was required, according to the Federal Circuit, was that AstraZeneca establish "the presence of an inert subcoating and a drug core having a micro-pH of not less than 7," and the CAFC found no clear error in the District Court's reliance on AstraZeneca's evidence in this regard.  Finally, the CAFC rejected Impax's contention that its decision in Warner-Lambert Co. v. Teva Pharmaceuticals USA, Inc. mandated a different result, since in that case the Federal Circuit reversed a summary judgment determination (where its review of the District Court's decision was de novo), while here it was reviewing a final judgment (requiring evidence of clear error).

The Federal Circuit also rejected Impax's second contention, that its formulation did not satisfy the "inert subcoating" limitation of the patents-in-suit, and that the District Court was in error for crediting AstraZeneca's expert testimony that the subcoating was formed "in situ," i.e., as a consequence of reaction between the components of the formulation rather than being introduced as a discrete step during formulation.  The Federal Circuit found no clear error in the District Court's determination that AstraZeneca's expert testimony and evidence was more credible than Impax's contrary interpretation of that expert testimony.

Finally, although disagreeing with the District Court's determination that AstraZeneca's Phase III clinical trials were an "experimental use" rather than a "public use," the Federal Circuit nonetheless upheld the District Court's decision that the patents-in-suit were not invalid based on public use prior to one year before their earliest priority date(s) under 35 U.S.C. § 102(b).  The basis for the CAFC's decision was evidence that AstraZeneca's invention was not "ready for patenting," as required by the Supreme Court's decision in Pfaff v. Wells Electronics, Inc.  The inventors testified that, although they had produced certain embodiments of the claimed invention prior to the Phase III clinical trials (and prior to the critical date), they did not (indeed, could not) know whether these embodiments would work for their intended purpose until receiving the results of the clinical trials.  Thus, according to the District Court, the claimed invention had not been reduced to practice until the clinical trials were over and thus were not "ready for patenting" during the clinical trials.  The Federal Circuit affirmed this determination, based on evidence of the uncertainty during development of the formulations and that the clinical trials were required to establish that the claimed invention had been reduced to practice.

Apotex also appealed the District Court's determination that its ANDA formulations infringed, as well as the District Court's rejection of its anticipation and obviousness challenges to the validity of the patents-in-suit.  Since the Federal Circuit characterized the infringement appeal as a dispute between the evidence presented by each side's experts, it found no clear error in the District Court's decision to credit AstraZeneca's expert testimony over the contrary expert testimony of the Apotex experts.  The CAFC also affirmed the District Court's determination that the patents-in-suit were not anticipated by two U.S. and one European prior art patent; here, the challenge was on claim construction, specifically the meaning of the term "alkaline salt" and "acid labile."  The CAFC rejected Apotex's contention that an "alkaline salt" was limited to salts comprising an element from Groups I and II of the periodic table, finding that it was contrary to the specification of the '230 patent and claim 8, which included within the scope of the term ammonium salts (which do not contain any Group I or Group II elements).  Regarding the term "acid labile," the Court interpreted the cited prior art to disclose acid-stable compounds that did not anticipate the claims at issue.

Apotex also asserted a large number of references to support its contention that the claims of the patents-in-suit were obvious.  The basis for the District Court's rejection of Apotex's obviousness claim is that the prior art did not recognize the need for a subcoating between the omeprazole/ARC-containing core and the enteric coating.  Even if the skilled worker in the art had recognized the need (i.e., that there would be a "negative interaction" between the core and the enteric coating), the District Court provided "multiple paths" that the worker of ordinary skill could consider in addressing the problem.  In this regard, Apotex raised the Supreme Court's discussion of the "obvious to try" standard set forth in the KSR Int'l. Co. v. Teleflex, Inc. decision.  The Federal Circuit distinguished on the grounds that the District Court "found that a person of skill in the art would not have seen a reason to insert a subcoating in the prior art formulation."  The District Court's finding of non-obviousness, affirmed by the Federal Circuit, "was based on Apotex's failure to demonstrate that a person of skill in the art would conclude that a negative interaction would take place between the enteric coating and the drug core," i.e., that the skilled worker would not have recognized that there was a problem to be solved in the first place, thus removing a necessary predicate to employing the "obvious to try" analysis.

This decision represents the latest (and perhaps the final) victory for AstraZeneca over its Prilosec® franchise.  These victories have about them, however, something of a Pyrrhic quality in view of events that have occurred since these suits were initiated almost ten years ago.  The most important of these is that AstraZeneca has transferred its focus from Prilosec® to Nexium®, the purified S-enantiomer of omeprazole.  Second, one ANDA filer, Kremers Urban Development Co., was found not to infringe AstraZeneca's patents and launched a generic omeprazole product almost five years ago; this launch was followed by others, and indeed AstraZeneca partnered with Proctor & Gamble to put an over-the-counter form of omeprazole on the market.  In this case, once Impax launched "at risk" prior to patent expiry, AstraZeneca amended its complaint to request damages, but before trial it stipulated for the District Court to dismiss its damages claims with prejudice in order for the Court to join Impax in the consolidated bench trial.  Accordingly, it appears that AstraZeneca actually gained very little, in market share, damages, or exclusivity, as a result of its participation in this protracted litigation.  This result provides a cautionary tale and to some degree refutes those who mischaracterize patent litigation as a "jackpot" or an impediment to innovation.  AstraZeneca protected its Prilosec® franchise at great cost, but it is reasonable to ask, to what end and for what benefit?  It doesn't appear to be an easy question to answer.

In re Omeprazole Patent Litigation (Fed. Cir. 2008)
Panel: Circuit Judges Lourie, Bryson, and Gajarsa
Opinion by Circuit Judge Bryson

Innogenetics, N.V. v. Abbott Labs. (Fed. Cir. 2008)

Innogenetics Loses Injunction; Abbott HCV Genotyping Test to Remain on the Market

    By Robert Dailey --

The Federal Circuit today released its opinion in the ongoing dispute between Abbott and Innogenetics over diagnostic tools for classifying hepatitis C virus (HCV) genotypes.  Patent Docs previously reported on the District Court order and its issuance of an injunction.

Innogenetics owns U.S. Patent No. 5,846,704 directed to methods of genotyping HCV.  Claim 1 recites:

A method of genotyping HCV present in a biological sample comprising hybridizing nucleic acids in a biological sample with at least one probe and detecting a complex as formed with said probe and said nucleic acids of HCV, using a probe that specifically hybridizes to the domain extending from the nucleotides at positions -291 to -66 of the 5' untranslated region of the HCV.

Abbott argued that its product could not infringe the claim because its product constitutes after-arising technology (i.e., it relies on developments that did not exist as of the '704 patent's priority date).  Therefore, the Federal Circuit could have used this case as an opportunity to refine the differences between two 2004 cases:  SuperGuide Corp. v. DirectTV Enterprises, Inc., 358 F.3d 870 (Fed. Cir. 2004) (holding that after-arising technology may infringe) and Chiron Corp. v. Genentech, Inc., 363 F.3d 1247 (Fed. Cir. 2004) (holding that claims that sweep in after-arising technology fail the written description requirement).  In the end, this didn't happen.  The Federal Circuit agreed with the District Court in finding that Abbott never properly raised the issue at trial.

The Federal Circuit affirmed the District Court's findings on patent validity and enforceability with one exception.  An Abbott expert had testified that a prior art patent, U.S. Patent No. 5,580,718 anticipated claim 1 of the '704 patent.  The District Court had rejected his testimony because the lower court assessed that the testimony was premised on a misunderstanding of its claim construction.  The Federal Circuit held that the expert's testimony was consistent with the claim construction, and asked the District Court to reconsider whether the '718 patent anticipates the Innogenetics patent.  The Federal Circuit resisted weighing in on the merits of this anticipation issue until the District Court can hold a new trial.

The Federal Circuit also dissolved the permanent injunction that the District Court had issued following the trial.  The District Court's damage award of $7 million had included $5.8 million market entry fee as well as an ongoing royalty of 5-10 euro per test.  The Federal Circuit held that Innogenetics could not collect a market entry fee and an ongoing royalty, and simultaneously benefit from a permanent injunction.  In general, the willingness of a patentee to accept royalty payments does not preclude issuance of a permanent injunction.  But the situation is different when the patentee also accepts damages covering market entry fees and ongoing royalty payments.

Hence, the case is headed back to the District Court in Madison, Wisconsin, for a mini-trial on the issue of whether the '718 patent anticipates the Innogenetics patent.  But now that the injunction has been dissolved, the two parties may be much closer to settling their dispute.

Innogenetics, N.V. v. Abbott Labs. (Fed. Cir. 2008)
Panel:  Circuit Judge Bryson, Senior Circuit Judge Clevenger, and Circuit Judge Moore
Opinion by Circuit Judge Moore

For additional information regarding this topic, please see:

• "Innogenetics Appeals Its Win over Abbott," January 30, 2007
• "Permanent Injunction Issued against Abbott HCV Genotyping Test Kit," January 12, 2007
• "Innogenetics Wins $7 Million Judgment against Abbott for Infringing HCV Genotyping Method," January 8, 2007

Additional information regarding this case can also be found at Patently-O.

Apotex Corp. v. Merck & Co., Inc. (Fed. Cir. 2007)

    By Donald Zuhn --

Last month, the Federal Circuit affirmed a District Court's finding on summary judgment that Merck & Co., Inc. had not obtained favorable rulings in two prior proceedings by fraud.  The prior proceedings included an infringement suit involving U.S. Patent Nos. 5,573,780 (the '780 patent) and 5,690,962 (the '962 patent) owned by Apotex Corp., and Apotex' appeal of that decision to the Federal Circuit.

In 1996, Apotex had filed suit against Merck (Apotex I), contending that Merck's process of formulating and producing enalapril tablets (under the brand name Vasotec®) infringed the '780 and '962 patents.  The District Court, however, determined that Merck had invented the claimed process before Apotex had made the invention, and therefore, found Apotex' patents invalid under 35 U.S.C. § 102(g).  In 2001, the Federal Circuit affirmed the District Court's finding (Apotex II).

In Apotex I and Apotex II, Apotex argued that Merck had suppressed or concealed its practice of the claimed invention, and therefore, that even if Merck had practiced the claimed process before Apotex, Merck's practice of the claimed process infringed Apotex' patents.  In Apotex I, the District Court rejected Apotex' argument, finding that Merck had not suppressed or concealed the invention because it had widely distributed a list of ingredients for its enalapril tablets and because a Merck executive had narrated a videotape describing the Merck process during a Canadian trial in 1991.  In Apotex II, the Federal Circuit affirmed, determining that the narration of the Merck process in the Canadian trial constituted a public disclosure of the process.

Following the unfavorable decisions in Apotex I and Apotex II, Apotex returned to the District Court (Apotex III), asserting that Merck had obtained favorable rulings in the two prior proceedings by fraud.  In particular, Apotex contended that Merck had misrepresented facts and made false statements in its summary judgment and appellate briefs (the alleged misrepresentations and false statements were primarily related to Merck's ingredient list and narration of its process in the Canadian trial).  According to Apotex, Merck had admitted that it had made false statements when one of its key witnesses gave contradictory testimony in 2004 in a different case involving a related compound, quinapril.

In Apotex III, the District Court again ruled against Apotex, finding that the 2004 testimony involved manufacturing details not disclosed or claimed in Apotex' patents, and further, that many of the allegedly false statements constituted only attorney argument, rather than evidence or testimony.  The Federal Circuit again affirmed, finding that the District Court had correctly ruled that the evidence and argument adduced and presented at trial did not establish fraud.

Apotex Corp. v. Merck & Co., Inc. (Fed. Cir. 2007)
Panel: Circuit Judges Newman, Rader, and Prost
Opinion by Circuit Judge Newman

Additional information regarding this case can be found at Patently-O.

Forest Labs., Inc. v. Ivax Pharm., Inc. (Fed. Cir. 2007)

    By Kevin E. Noonan --

The Federal Circuit today affirmed a District Court finding that ANDA filer Ivax Pharmaceuticals and co-Defendant Cipla had not shown by clear and convincing evidence that Forest Laboratories' patent-in-suit for Lexapro® was invalid.  In doing so, the CAFC answered (for now) the question of whether a patent on a particular, biologically-active enantiomer of a patented drug is obvious.

The case was brought by Forest under 37 U.S.C. § 271(e)(2)(A) upon Ivax's filing of an ANDA for Lexapro®, a selective serotonin reuptake inhibitor used to treat depression.  The patent-in-suit, U.S. Reissue Patent No. 34,712, claimed the substantially pure (+)-enantiomer of citalopram (termed "escitalopram"):

A compound selected from substantially pure (+)-1-(3-Dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof.

('712 patent, Claim 1); Lexapro® is an oxalate salt formulation.  The parties stipulated that the subject of Ivax's ANDA would infringe the '712 patent, and that if valid, filing the ANDA constituted infringement under the statute.  Accordingly, the issue at trial was whether the '712 was invalid as alleged in Ivax's Paragraph IV certification.

There were three grounds of invalidity asserted by Ivax and Cipla before the District Court.  First, the Defendants alleged that the compound claims of the patent-in-suit were invalid as being anticipated by a prior art reference (the Smith reference) that discussed selective serotonin reuptake inhibitors (including citalopram).  However, "substantially pure" (+)-enantiomer of citalopram was not explicitly disclosed in the reference, and the District Court found that the reference did not enable the skilled worker to produce it.  Specifically, the technique taught in the reference for separating enantiomers was new and unpredictable, and there was evidence that Smith himself, as well as others including the inventor of the '712 patent, failed in attempting to produce escitalopram using the method.  The District Court found that the Smith reference was not enabled for producing escitalopram, and thus that the claims of the '712 patent were not anticipated.

On the question of obviousness, the District Court found that the Smith reference would not provide the skilled worker with a reasonable expectation of success at separating the citalopram enantiomers, and that success was sufficiently uncertain that the worker would be motivated to discover new compounds rather than try to separate the enantiomers.  Regarding the method claim (claim 11), the District Court found that the art did not describe the reactions recited in the claim.

Finally, the District Court found that claim 11 was not invalid for being impermissibly broadened more than two years after the patent issued.  In reissue, claim 11 was amended to recite that a (-)diol intermediate was converted to (+)citalopram; the claim as issued recited that (+)citalopram was produced from a (+)diol intermediate.  The District Court found that the error was merely a typographical error, and would have been appreciated by a worker of ordinary skill.

The Federal Circuit affirmed the District Court on all three asserted grounds of invalidity in an opinion written by Judge Lourie; the opinion was unanimous on all issues except extension of the statutory injunction to co-Defendant Cipla (Judge Schall dissenting that the statute did not permit Cipla to be enjoined).  For both anticipation and obviousness, the Federal Circuit found that Ivax did not establish that the District Court had committed clear error; instead, the CAFC stated that Ivax had merely "emphasize[d] the evidence that is favorable to their desired outcome without addressing the evidence favorable to Forest."  In doing so, Ivax did not establish "why the district court was not entitled to rely on the evidence favorable to Forest or demonstrate that the evidence favorable to them heavily outweighed the evidence favorable to Forest" and thus did not satisfy their burden on appeal of showing that the District Court's factual determinations were clearly erroneous.

On the question of obviousness, the Federal Circuit relied on the District Court's factual determinations that were, according to the panel, applied using the analysis set forth in Graham v. John Deere Co.; KSR Int'l Co. v. Teleflex, Inc. was not cited by the CAFC, or apparently by the parties.  The Federal Circuit also affirmed that correction of the typographical error was not an impermissible broadening under the reissue statute.

The significance of this decision is found more in what the Federal Circuit did not say than in its relatively pedestrian affirmance.  An open question remaining after KSR is whether enantiomer patents would fall within the ambit of the Supreme Court's seemingly-expansive dicta regarding what is obvious to try:

When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.  If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.

Enantiomer patents can be fitted within at least a portion of this framework.  There are typically "market pressures" for producing a more effective drug; in cases where only one of the enantiomers is biologically-active, effectiveness should double.  Enantiomers also provide the ultimate in "finite number" of "identified" solutions:  namely, two.  The question is whether the "solution" - the substantially purified enantiomer - is sufficiently predictable and leads to anticipated success.  In the Lexapro® case, the art did not identify which of the two enantiomers was the active one, and the evidence established that separation of the enantiomers was sufficiently unpredictable that the District Court opined that the skilled worker was motivated to investigate new drugs rather than tackle separation of the enantiomers.  On these facts, the enantiomer claim satisfied the requirements for non-obviousness.

The dissent raises an interesting issue of statutory interpretation.  The majority affirmed the scope of the injunction to include Cipla, who was to have produced the drug for distribution by Ivax.  Cipla had not supplied Ivax with any infringing drug, however, and its contributions to Ivax's ANDA were limited to information on bioequivalence.  Judge Schall in dissent considered Cipla immunized from the District Court's injunction on two grounds:  first, that 35 U.S.C. § 271(e)(4)(B) provides for an injunction only against the ANDA filer; and second, that Cipla's activities fell within the scope of 35 U.S.C. § 271(e)(1) under the interpretation of that statute by the Supreme Court in Merck KGaA v. Integra Lifesciences I, Ltd.  Although the majority's policy imperative is understandable (without the injunction Cipla could partner with another ANDA filer and challenge the validity of the '712 patent anew), Judge Schall's analysis seems more firmly rooted in the plain language of the statute.

Forest Labs., Inc. v. Ivax Pharm., Inc. (Fed. Cir. 2007)
Panel: Senior Circuit Judge Friedman and Circuit Judges Lourie and Schall
Opinion by Circuit Judge Lourie, concurring-in-part and dissenting-in-part opinion by Circuit Judge Schall

Additional information regarding this case can be found at the Orange Book Blog and Patently-O.

Impax Labs., Inc. v. Aventis Pharm. Inc. (D. Del. 2007)

Aventis Prevails over Impax in Riluzole Dispute

    By Robert Dailey --

On remand from the Federal Circuit (see "Impax Labs., Inc. v. Aventis Pharm. Inc. (Fed. Cir. 2006)"), the District Court found that U.S. Pat. No. 5,527,814 is not anticipated by the prior art.  Particularly, the Court found that the anticipating reference cited by Impax does not enable one of skill in the art to use rizulole to treat amyotrophic lateral sclerosis (ALS).

The District Court had already reached this conclusion once, finding that the prior art failed to show that rizulole would be effective for treating ALS.  At the time of the Court's initial decision, this finding was probably sufficient to demonstrate that the anticipating reference was not enabled.

But between the date of the District Court's initial opinion and the date of the appeal, the Federal Circuit articulated a more nuanced approach to determining whether anticipating prior art is enabled.  See Novo Nordisk Pharms. v. Bio-Tech. Gen. Corp., 424 F.3d 1347 (Fed. Cir. 2005); Rasmusson v. SmithKline Beecham, 413 F.3d 1318 (Fed. Cir. 2005).  Under the more nuanced approach, the District Court cannot find a lack of enablement simply based on the anticipating reference's failure to show effectiveness.  According to the Federal Circuit, effectiveness is more relevant to questions of utility.  To determine lack of enablement, the fact-finder must look to whether the anticipating reference teaches one of ordinary skill in the art to practice the invention without undue experimentation, where undue experimentation is evaluated in light of the eight Wands factors.

In most situations, this distinction probably makes little difference.  In fact, Judge Rader dissented in part from the Federal Circuit opinion because he believed that the District Court's factual findings supported the validity of the Aventis patent under the old standard as well as the new standard.  But the majority preferred to remand the case to the District Court for re-evaluation in light of Rasmusson.

In last week's opinion, the District Court found that the anticipating prior art cited by Impax still lacked enablement.  While Rasmusson has changed the formal process for evaluating enablement, it probably will have little outcome-determinative effect in most cases.  Commentators have long recognized that utility and enablement are related.  Though the two doctrines rely on different legal tests, evidence that demonstrates lack of utility will often also demonstrate lack of enablement.  But in the context of anticipation, the federal courts have held that enablement, and not utility, is the relevant inquiry for determining whether an anticipating reference precludes patentability.

We may ponder, though, whether this nuanced distinction carries much of a punch.  After all, enablement and utility are both malleable concepts.  The former is judged against an eight-factor balancing test, while the latter requires one to wade through the shifting sands of Brenner v. Manson, In re Brana, and In re Fisher.  Moreover, is there a doctrinally sound reason why we look to enablement but not to utility in evaluating the value of an anticipating reference?  In looking back at old CCPA cases, see, e.g., In re Hoeksema, 399 F.2d 269 (C.C.P.A. 1968), patent courts appear to have applied this "enabling disclosure" requirement in a flexible manner that dually encompassed considerations of both enablement and utility.  And especially when the claims-in-suit are method claims, wouldn't we want to consider whether the anticipating reference failed to demonstrate the utility of the method?  After all, how can one of skill in the art make and use something that is not useful?

Impax Labs., Inc. v. Aventis Pharm. Inc., No. 02-581-JJF (D. Del. 2007)
Opinion by District Judge Farnan

Robert Dailey, Ph.D., is a physical chemist and regular Patent Docs contributor.  Dr. Dailey, who recently completed his studies at the University of North Carolina School of Law and passed the patent registration exam, will be joining MBHB this fall.

Additional Disclaimer:  MBHB represented Aventis in the above litigation.  To the extent that this case summary contains any opinions, the opinions would be of Dr. Dailey and not Aventis or MBHB.

In re Omeprazole Patent Litigation (Fed. Cir. 2007)

    By Kevin E. Noonan --

The end of the consolidated omeprazole litigation may have been reached this week, when the Federal Circuit ruled on AstraZeneca's appeal over the validity of U.S. Patent No. 6,013,281.  In its decision, the Court majority (Judges Rader and Bryson) upheld the District Court's finding that the '281 patent claims at issue were invalid as being inherently anticipated by a Korean patent publication, over a strong dissent by Judge Newman.

Unlike earlier incarnations of the dispute, which named several defendants, this case named generic pharmaceutical maker Andrx as the sole alleged infringer.  The patent claims at issue recited AstraZeneca's formulation method for omeprazole.  This formulation contains an alkaline reacting compound (ARC) to protect acid-sensitive omeprazole during transit through the stomach.  The Federal Circuit affirmed the District Court's finding that Andrx infringed, but also affirmed the District Court's determination that AstraZeneca's claims were invalid for being either anticipated or obvious.

The claimed process was directed at the formation of a water-soluble separating layer between the acid-sensitive omeprazole core and the enteric coating, wherein the separating layer was formed in situ by a reaction between the ARC in the core and the enteric coating.  As the Federal Circuit explained, "the '281 process produces an omeprazole formulation with three distinct layers, but starts with only two of the three layers," wherein the reaction produced a separating layer comprising a salt form of the enteric coating material.  Independent claim 1 recited a minimum ARC concentration in the core required to form the separating layer, and dependent claims recited specific ARC compounds.  Significant to the Federal Circuit's decision, the '281 specification contained process parameters (including temperature) not recited in the claims.

The prior art the District Court found invalidating was a Korean patent application that was in the art two years before AstraZeneca's earliest priority date.  This patent application was not unknown to AstraZeneca, because it had been the basis for a lawsuit in Korea between AstraZeneca and the Korean applicant, Chong Kun Dan (CKD) Corp. over one of AstraZeneca's own Korean omeprazole formulation patents.  CKD's patents did not provide any process conditions, which CKD was allowed to keep as trade secrets under Korean patent law.  However, AstraZeneca's own testing done with regard to this Korean action supported the conclusion that the CKD formulation indeed contained a separating layer (albeit, according to AstraZeneca, a conventionally-applied layer), and AstraZeneca scientists testified to that effect in the Korean action.  CKD's scientists steadfastly maintained throughout that their formulation did not contain a separating layer.

It was undisputed that AstraZeneca's inventors were unaware of the process conditions used by CKD when they conceived the '281 invention.  After the AstraZeneca inventors determined the proper conditions for producing a separating layer in situ they became aware of CKD's conditions, which differed from their own and did not produce a separating layer in situ.  One important difference was the formulation temperature: 42ºC using AstraZeneca's process and 70ºC using CKD's process.

Despite these differences, the District Court found the CKD patent application to be invalidating.  The District Court's basis for finding anticipation was the disclosure in the CKD application of all the limitations of Claim 1 of the '281 patent except the phrase "forming in situ a separating layer."  AstraZeneca contended that this phrase implicated the process steps recited in the '281 specification, specifically the 42ºC inlet air temperature, which was not disclosed in CKD's application.  The District Court declined to import the temperature limitation into the claim, discerning no basis for doing so.  Instead, the District Court determined whether the limitation in the disputed phrase was inherently disclosed in CKD's application not from the reference itself, but using AstraZeneca's assertions made in the Korean infringement action.  Specifically, the District Court relied upon expert testimony by AstraZeneca's witnesses in the Korean action, that CKD's formulation contained a separating layer that was inherently produced by its formulation.  These admissions were coupled by the District Court with testimony from Andrx's expert that a separating layer would form in CKD's formulation "each and every time," and the absence of contrary experimental evidence from AstraZeneca at trial.  Moreover, AstraZeneca's trial expert's contrary testimony was proffered in the absence of his consideration of AstraZeneca's earlier testimony and other evidence from the Korean action, permitting the District Court to discount his testimony.

The Federal Circuit affirmed, applying its clear error standard of review for the factual findings made by the District Court.  The presence of a separating layer in the CKD formulation was deemed inherent from the combination of the ingredients specified in CKD's Korean patent application, and thus the absence of any disclosure of the process by which CKD made its formulation was determined to be without any significance.  The CAFC also affirmed the District Court's obviousness determination for AstraZeneca's dependent claim 9, which recited different ARC species than were disclosed in the CKD patent application.  According to the CAFC, the District Court was correct in holding that there was no patentable difference between the ARC disclosed by CKD (arginine) and the ARC's recited in AstraZeneca's dependent claim 9 (alkaline salts of phosphoric acid, carbonic acid, or silicic acid).

Judge Newman was strenuous in her dissent.  For her, the fact that the CKD Korean application does not disclose formulation conditions, much less describe AstraZeneca's conditions, and that it is "undisputed" that the practice of the disclosed CKD formulation does not produce a separating layer, was dispositive.  The mere possibility that the cited art could produce the claimed product or that the skilled worker might be able to arrive at the claimed process from the teachings of the reference is not enough.  While Judge Newman focused on whether the CKD patent application disclosed the process (which she determined did not), the majority agreed with the District Court that the presence of the recited ingredients was sufficient to produce a separating layer "each and every time" according to unrefuted (or at least insufficiently refuted) trial testimony.  Curiously, the affirmative statements by Andrx's expert that formulations made according to CKD's patent specification would inherently produce a separating layer were unverified by experimental evidence, and as Judge Newman points out, were contrary to the conclusions of the Korean tribunal and CKD's own expert.  Judge Newman also argued that the CKD application is not enabling, since it does not disclose the conditions necessary for preparing its formulations.  Finally, Judge Newman was troubled by the majority's use of "secret information," i.e., the formulation conditions admittedly not disclosed in the CKD patent application.

Judge Newman has the better legal argument, but it is clear that AstraZeneca was defeated by a combination of poor claim drafting, its own prior inconsistent admissions, and the CAFC's standard of review.  The fact that AstraZeneca's inventors were "spurred on" in their own developmental work by their belief that CKD inherently produced a separating layer in situ may also have been a consideration.  AstraZeneca did not prevail, however, at least in part because the process limitations it relied upon at trial, including the inlet air temperature, were not recited even in a dependent claim.  Under these circumstances, the clear lesson is to include process limitations in at least some dependent claims to a process, if a patentee intends to rely upon these limitations to distinguish over the prior art.

In re Omeprazole Patent Litigation (Fed. Cir. 2007)
Panel: Circuit Judges Newman, Rader, and Bryson
Opinion by Circuit Judge Rader
Opinion concurring in part and dissenting in part by Circuit Judge Newman

Additional information regarding this case can be found at the Orange Book Blog and Patently-O.

Cargill, Inc. v. Canbra Foods, Ltd. (Fed. Cir. 2007)

Extreme Caution Needed When Overcoming Inherent Anticipation Rejections

    By Robert Dailey

Last week the Federal Circuit affirmed a District Court finding of inequitable conduct against Cargill in its prosecution of U.S. Patent Nos. 5,969,169 and 6,201,145.  The case highlights the continuing instability in the Federal Circuit's inequitable conduct jurisprudence.

At the broadest level, Cargill's patents cover:

A non-hydrogenated canola oil having a polyunsaturated fatty acid content of from about 7% to about 17%, an oleic acid content of about 74% to about 80% and an oxidative stability of from about 35 AOM to about 40 AOM hours in the absence of added antioxidants.

The Examiner initially rejected the claim as being anticipated by an oil composition disclosed in a European patent.  Since the prior art oil had a composition similar to that of one of Cargill's examples (IMC-30), the Examiner reasoned that the two oils must also have a similar oxidative stability.  Hence, the Examiner's anticipation rejection rested on the proposition that one can predict the oxidative stability of an oil simply based on its fatty acid composition (i.e., that fatty acid composition necessarily determines oxidative stability).

Cargill sought to demonstrate that the Examiner's scientific proposition is false.  This could have been done through a variety of means.  Cargill decided to point to data disclosed in its own application.  Another example (IMC-29) showed another oil which also had a similar composition to the prior art oil, but whose oxidative stability differed strikingly from that of IMC-30.  Cargill pointed to IMC-29 for one specific purpose: to demonstrate that fatty acid composition does not necessarily determine oxidative stability.  The Examiner eventually accepted this argument, and allowed the claims.

All would seem to be well.  The inherency rejection was unwarranted, the applicant pointed out the flaw in the Examiner's scientific logic, and the PTO allowed the claims.  But the Federal Circuit's analysis went further.  Cargill had done extensive testing on IMC-29.  In some of these tests, chemists had simply refined the oil at the lab bench - a process that yields oil with a higher oxidative stability than oil refined commercially.  Although the data were sketchy, some of the bench-refined IMC-29 had oxidative stability values comparable to commercially refined IMC-30.

The Court held that the "reasonable examiner" might have wanted to have access to the data of these bench tests.  Thus, they are material to patentability under this malleable "reasonable examiner" standard.  But would a reasonable examiner find these data material to patentability?  In the case at bar, the Examiner was making an inherent anticipation rejection, not an obviousness rejection.  Hence, the applicant would appear to be under no burden to show that IMC-30 is patentably better than IMC-29.  Rather, the applicant simply needs to show that the Examiner's scientific proposition regarding composition and oxidative stability is untenable.  Cargill did that.  In fact, these bench tests appear to bolster Cargill's inherency argument: two batches of the same IMC-29 refined in two different ways yielded oils having very different oxidative stability values.

The case illustrates the continued problems with the "reasonable examiner" approach for determining materiality.  What would a reasonable examiner want?  Is candor in responding to the Examiner's rejections not sufficient?  In this instance, Cargill exercised complete candor in responding to the inherent anticipation rejection.  The situation would be different if the IMC-29 data in the application had been doctored.  But it wasn't.

What's the moral, then?  Be careful when referring to your own data to defeat an inherency rejection!  Point to treatises or other scientists' work, or use inventor and/or expert declarations.  Or bury the examiner under a weight of case law.  Just don't appeal to your own experimental data.  Otherwise, the court may hold you responsible for knowing every experiment that any technician ever performed in your client's labs on a given composition.

In short, the Court seems to be saying: "Deal with examiners as lawyers, and not at all as scientists."  But is that really what the "reasonable examiner" desires?

    Cargill, Inc. v. Canbra Foods, Ltd. (Fed. Cir. 2007).

    Additional information regarding this case can be found at Patently-O.

    Robert Dailey, Ph.D., is a physical chemist and a third-year law student at the University of North Carolina at Chapel Hill.  Dr. Dailey was a member of MBHB's 2006 class of summer associates, and is a regular Patent Docs contributor.

Innogenetics v. Abbott Labs. (W.D. Wis. 2007)

Innogenetics Wins $7 Million Judgment Against Abbott for Infringing HCV Genotyping Method

    By Robert Dailey --

Judge Barbara Crabb, in an opinion issued last week, rejected all of Abbott's post-trial motions and upheld an earlier $7 million verdict against its diagnostics division for infringing an Innogenetics patent.

Innogenetics owns U.S. Patent Number 5,846,704 (the '704 patent), which is directed to methods of genotyping the hepatitis C virus (HCV) by hybridizing probes to a particular region of the HCV genome.  Claim 1 covers:

1.  A method of genotyping HCV present in a biological sample comprising hybridizing nucleic acids in a biological sample with at least one probe and detecting a complex as formed with said probe and said nucleic acids of HCV, using a probe that specifically hybridizes to the domain extending from the nucleotides at positions -291 to -66 of the 5' untranslated region of HCV.

Abbott sells HCV genotyping assays that perform the claimed method using Realtime PCR.

Abbott argued that its assay does not infringe the patent because Realtime PCR is an after-arising technology that was not known when Innogenetics filed its initial parent application in 1992.  The court provides several reasons for rejecting this argument.  First, SuperGuide Corp. v. DirectTV Enterprises, Inc., 358 F.3d 870 (Fed. Cir. 2004), holds that "[t]he law does not require that the applicant describe in his specification every conceivable and possible future embodiment of his invention."  Nevertheless, the court provides no basis for distinguishing SuperGuide from cases in which the Federal Circuit has held that a claim fails the written description requirement when the patentee attempts to sweep after-arising technology into the claim's scope.  See Chiron Corp. v. Genentech, Inc., 363 F.3d 1247 (Fed. Cir. 2004).  Second, Realtime PCR was already known in the art by 1992 and, therefore, does not qualify as after-arising technology.  Third, Abbott made this argument for the first time at 9:30 p.m. on the eve of the trial while submitting its proposed jury instructions.  This contradicted Abbott's earlier averments that it had no further theories of non-infringement.  (Consequently, Judge Crabb prevented Abbott from presenting this argument at trial.)

Abbott also argued that the '704 patent was invalid because it was anticipated by and obvious in light of prior art directed to detecting HCV in the 5' untranslated region (UTR).  But the Innogenetics method had not merely dealt with detecting HCV in the 5' UTR; their patent also taught how to distinguish among (i.e., classify) different types and subtypes of HCV in the 5' UTR.

Abbott's obviousness argument rested on a combination of prior art references.  Yet Abbott offered the court nothing more than an expert's conclusory statements of obviousness.  The court held that an expert must at least explain how and why the asserted combination of references renders the patent obviousness.

Abbott's anticipation argument was rejected by a jury, whose verdict has now been upheld.  This portion of Abbott's case seems to have failed in part because Abbott refused to offer its primary witness (a trained expert and the author of the asserted prior art reference) as an expert.  As a mere fact witness, he was prevented from giving any opinion-related testimony in court connected to the technology at issue.  Relying on Day v. Consolidated Rail Corp., 1996 WL 257654 (S.D.N.Y. 1996), the court held that Abbott's decision to offer its "expert" as a non-expert did not exempt the witness from the report requirement of Rule 26(a)(2)(B).  (The Rule requires witnesses who give opinion-related testimony on scientific or technical matters to submit reports to the court during pre-trial discovery.)  This left Abbott with little evidence to bring before the jury.

The jury's damage award of $7 million was upheld and the plaintiff's motion for treble damages was denied.  Judge Crabb will issue a subsequent opinion regarding the plaintiff's request for a permanent injunction.

Innogenetics v. Abbott Labs., No. 05-C-0575-C (W.D. Wis.).

Robert Dailey, Ph.D., is a physical chemist and a third-year law student at the University of North Carolina at Chapel Hill.  Dr. Dailey was a member of MBHB's 2006 class of summer associates.