Patent Docs

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.

Eli Lilly & Co. v. Zenith Goldline Pharm., Inc. (Fed. Cir. 2006)

    By Donald Zuhn --

In an appeal from a District Court judgment of validity and infringement, the Federal Circuit affirmed the District Court's finding of validity, holding that U.S. Patent No. 5,229,382 (the '382 patent) was not anticipated by Chakrabati et al., 1980, J. Med. Chem. 23:878-84 (Chakrabati) or the patentee's clinical trials, or rendered obvious by the prior art.

Plaintiffs-Appellees Eli Lilly and Co. and Lilly Industries Ltd. (Lilly) own the '382 patent, which relates to olanzapine (sold under the trademark Zyprexa®) and the use of olanzapine to treat schizophrenia.  Prior to discovering olanzapine, Lilly had identified a number of drugs in the same family of compounds, including clozapine, flumezapine, ethyl flumezapine, and ethyl olanzapine.  Of these prior art compounds, clozapine had been shown to be effective in treating some forms of schizophrenia - but not without potentially fatal side-effects as one percent of patients treated with clozapine would suffer from the blood disorder agranulocytosis.

Until the discovery of olanzapine, the efficacy of clozapine (and other antipsychotics) had been attributed to the presence of an electron-withdrawing group such as a fluorine or chlorine atom.  However, while clozapine has a chlorine atom on its benzene ring, olanzapine has a hydrogen atom, which is not an electron-withdrawing group.

Seeking approval to market generic olanzapine, Defendants-Appellants Zenith Goldline Pharmaceuticals, Inc. (now known as IVAX Pharmaceuticals, Inc.), Dr. Reddy's Laboratories, Ltd., and Teva Pharmaceuticals USA, Inc. (IVAX) filed an Abbreviated New Drug Application (ANDA) with the FDA.  In response, Lilly filed suit against IVAX, alleging that the filing of the ANDA infringed the '382 patent.  Following a bench trial, the District Court determined that the '382 patent was valid and infringed, and found no inequitable conduct.  IVAX appealed the District Court's determinations of validity and no inequitable conduct.

With regard to its anticipation defense, IVAX argued that Chakrabati anticipated claim 1 of the '382 patent because that reference identified compounds from the family of compounds - thienobenzodiazepines - to which olanzapine belonged.  IVAX 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 this argument.

In distinguishing Petering, the Federal Circuit noted that "in contrast to this case, the prior art in Petering did more than make a broad disclosure.  In Petering, the prior art disclosed a limited number of specific preferences from a specifically defined group of [compounds]."  With respect to Schaumann, the Court observed that "the prior art patent [in that case] embraced a very limited number of closely related compounds and specifically described the claimed compound."  The Court also noted that while "the prior art in both Petering and Schaumann expressly spelled out a definite and limited class of compounds that enabled a person of ordinary skill in the art to at once envisage each member of this limited class . . . , the number of compounds actually disclosed by [Chakrabati] numbers in the millions."

The Federal Circuit further noted that while Chakrabati discloses several preferred compounds, none of these preferred compounds resembles olanzapine.  In addition, the Court observed that because Chakrabati "always expressed a preference for halogen-containing compounds (fluorine or chlorine), [and] not hydrogen," one of ordinary skill in the art "would have to depart from the teaching of the article and recombine the components of the specific illustrative compounds with hindsight."  The Federal Circuit, therefore, concluded that Chakrabati did not place olanzapine in the public's possession, and thus, the District Court did not err in finding no anticipation.

With regard to IVAX's argument that Lilly's clinical trials of olanzapine constituted a public use, the Federal Circuit cited TP Labs., Inc. v. Prof'l Positioners, Inc., 724 F.2d 965 (Fed. Cir. 1984), as standing for the proposition that "[e]ven a use that occurs in the open may not invoke a bar when undertaken to experiment on or with the claimed invention."  The Federal Circuit noted that the instant case satisfied several indicia of experimental use set forth in TP Labs., and therefore concluded that the District Court did not err in finding no public use.

Eli Lilly & Co. v. Zenith Goldline Pharm., Inc. (Fed. Cir. 2006)
Panel: Circuit Judges Rader, Schall, and Gajarsa
Opinion by Circuit Judge Rader

For a discussion of the Federal Circuit's decision on the issue of obviousness, readers are encouraged to turn to Kevin Noonan's article on the Lilly case.

Sanofi-Synthelabo v. Apotex, Inc. (Fed. Cir. 2006)

    By Donald Zuhn --

In an appeal from a District Court decision granting a preliminary injunction in favor of Plaintiffs-Appellees Sanofi-Synthelabo, Sanofi-Synthelabo, Inc., and Bristol-Myers Squibb Sanofi Pharmaceuticals Holding Partnership (Sanofi), the Federal Circuit concluded that the District Court did not abuse its discretion in granting preliminary injunctive relief, and thus, affirmed the District Court's grant of the preliminary injunction.

Sanofi owns U.S. Patent No. 4,847,265 (the '265 patent), which relates to clopidogrel bisulfate, the active ingredient in Plavix®, a platelet aggregation inhibiting agent marketed by Sanofi for use in reducing thrombotic events such as heart attacks and strokes.  Clopidogrel is the dextrorotatory enantiomer (d-enantiomer) of the free base methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)-(2-chlorophenyl) acetate (MATTPCA).

Seeking approval to market generic clopidogrel bisulfate, Defendants-Appellants Apotex, Inc. and Apotex Corp. (Apotex) filed an Abbreviated New Drug Application (ANDA) with the FDA.  In response, Sanofi filed suit against Apotex, alleging that the filing of the ANDA infringed the '265 patent.  Apotex counterclaimed asserting that the '265 patent was invalid and unenforceable.  Shortly before the FDA approved Apotex's ANDA, the parties began settlement negotiations.  However, after failing to receive regulatory approval for either of two settlement agreements, Apotex launched its generic clopidogrel bisulfate product.  In response, Sanofi filed a motion for a preliminary injunction.

Following an evidentiary hearing, the District Court granted Sanofi's motion for injunctive relief, finding that Apotex failed to establish a likelihood of proving invalidity at trial.  In particular, the District Court rejected Apotex's anticipation, obviousness, and obviousness-type double patenting defenses, and determined that Apotex failed to raise a substantial question with regard to the enforceability of the '265 patent.  Apotex then appealed the District Court's grant of the preliminary injunction.

With regard to its anticipation defense, Apotex argued on appeal that because a skilled artisan would interpret claim 2 of U.S. Patent No. 4,529,596 (the '596 patent) as disclosing not only the racemate free base of clopidogrel, but also its dextrorotatory and levorotatory enantiomers and pharmaceutically acceptable salts, the '596 patent anticipated the '265 patent.  Apotex also argued that the holdings in In re May, 574 F.2d 1082 (C.C.P.A. 1978), 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) mandated a finding of anticipation in the instant case.

Finding that the '596 patent discloses only the free base of clopidogrel, and does not expressly describe the dextrorotatory and levorotatory enantiomers or any salt, the Federal Circuit determined that the '596 patent fails to describe each and every limitation of claim 3 of the '265 patent.  The Federal Circuit also rejected Apotex's argument that the '596 patent inherently discloses the bisulfate salt of clopidogrel, determining that the District Court did not clearly err in finding that a skilled artisan reading the '596 patent would believe that the hydrochloride salt, rather than the bisulfate salt, was the preferred salt of clopidogrel.

The Federal Circuit also found that the facts in the instant case could be distinguished from those in May, Petering, and Schaumann.  In contrast with May, the Federal Circuit noted that in the instant case, the '596 patent contained no clear statement that the bisulfate salt is "especially suitable" for administering compounds of the genus including clopidogrel.  Unlike in Petering, where "specific preferences" in an anticipatory reference were found to narrow a broad generic formula to a more limited class of twenty compounds, the Federal Circuit determined that no such "pattern of preferences" could be found in the '596 patent that limited the broad generic formula to a limited class including clopidogrel bisulfate.  Finding no error in the District Court's determination that the '596 patent does not inherently disclose clopidogrel bisulfate or its determination that clopidogrel bisulfate is not a species of the genus disclosed in the '596 patent, the Federal Circuit concluded that the District Court did not clearly err in finding that Apotex's anticipation defense lacked substantial merit.

With regard to its obviousness defense, Apotex argued on appeal that it would have been obvious to one of ordinary skill in the art to prepare clopidogrel bisulfate based on the disclosure of the '596 patent.  Apotex also argued that the unexpected results upon which Sanofi relied to establish clopidogrel bisulfate's nonobviousness would not have been unexpected to a skilled artisan.  Apotex further argued that the District Court erred by failing to consider In re Adamson, 275 F.2d 952 (C.C.P.A. 1960), in its obviousness analysis.

Noting that a party alleging invalidity due to obviousness cannot "merely identify each element in the prior art to establish unpatentability of the combined subject matter as a whole," but rather, "must articulate the reasons one of ordinary skill in the art would have been motivated to select the references and to combine them to render the claimed invention obvious," the Federal Circuit concluded that "nothing [in the '596 patent] directed a chemist to the particular enantiomer and salt, clopidogrel bisulfate, which is the limited subject matter of claim 3 [of the '265 patent]."  The Federal Circuit also concluded that the District Court had not clearly erred in evaluating the evidence relating to the unexpected results obtained with clopidogrel bisulfate.  Finally, the Federal Circuit determined that the instant case could be distinguished from Adamson since the '596 patent does not disclose the bisulfate salt of the d-enantiomer of MATTPCA, resolution of MATTPCA would not yield the unnamed bisulfate salt, and it was unexpected that the desirable activity of clopidogrel would be found only in the d-enantiomer.  The Federal Circuit, therefore, concluded that the District Court did not clearly err in finding that Apotex failed to raise a substantial question in its obviousness defense.

Sanofi-Synthelabo v. Apotex, Inc. (Fed. Cir. 2006)
Panel: Circuit Judge Lourie, Senior Circuit Judge Clevenger, and Circuit Judge Bryson
Opinion by Circuit Judge Lourie