Orange Book Blog

Federal Circuit Affirms Validity of Pfizer's Lyrica (Pregabalin) Patent

Pfizer Inc. et al. v. Teva Pharms. USA et al., No. 2012-1576 (Fed. Cir.)

Teva and several other generic pharmaceutical companies each submitted an ANDA seeking approval to market a generic version of Lyrica, for treating seizures and pain. In a unanimous decision last Thursday, the Federal Circuit affirmed the judgment of the U.S. District Court for the District of Delaware by finding claim 2 of U.S. Patent Nos. 6,197,819, covering the active ingredient of Lyrica, pregabalin, infringed and not invalid for lack of enablement, written description, or obviousness.

Pfizer and Northwestern University initally asserted four Orange Book-listed patents against the ANDA filers, but the case ultimately hinged on claim 2 of the '819 patent, which reads quite simply:

2. 4-amino-3-(2-methylpropyl) butanoic acid, or a pharmaceutically acceptable salt thereof.

The compound of claim 2 contains a single chiral center, and may exist, for example, in enantiomerically pure (R)- or (S)- forms or a racemic form, the latter containing equal quantities of both enantiomers. Lyrica and the proposed generic products each contain pregabalin, which is only the S-enantiomer of 4-amino-3-(2-methylpropyl) butanoic acid. Before the district court, the defendants asserted that claim 2 of the '819 patent should be interpreted to cover only the racemic form of 4-amino-3-(2-methylpropyl) butanoic acid (also "3-isobutyl-gamma-aminobutyric acid" or "3-isobutylGABA"). If so construed, the proposed products would not literally infringe the claim. Further, the defendants alleged that claim 2 is invalid for failing the enablement and written description requirements of 35 U.S.C. 112(a) and for obviousness under 35 U.S.C. 103 in view of three asserted prior art references.

The district court's Markman order construed claim 2 of the '819 patent to encompass all stereochemical forms of 3-isobutylGABA. The parties stipulated to infringment by the defendants' proposed products if claim 2 was found valid and enforceable, as interpreted by the district court. This appeal followed the district court's finding that claim 2 of the '819 patent was enforceable and not invalid for the reasons offered by the defendants. On appeal, the defendants asserted that the district court erred in claim construction and its findings with respect to enablement, written description, and obviousness. The Federal Circuit affirmed the district court on all issues.

With respect to claim construction and infringement, the Federal Circuit declined to read limitations into claim 2 that were not present in the claim text. After noting that the defendants' expert admitted that claim 2 covers "3-isobutylGABA in any isomeric form," the court stated that the '819 patent made clear that the patent applicants were capable of indicating when individual enantiomers and when racemic forms of compounds were intended, by using the appropriate (R,S)- or (R)- or (S)- prefixes. Nor could the court find any clear disavowal in the '819 patent that would indicate that a lack of stereochemical indication was intended to limit the disclosure to only the racemic form. In view of the lack of any stereochemical limitation within claim 2, the court upheld the district court's interpretation and finding of infringement of claim 2 of the '819 patent.

On enablement, the ANDA filers asserted that if claim 2 were interpreted to cover all compositions of 3-isobutylGABA, regardless of enantiomeric form, then the specification failed to "teach a skilled artisan how to prepare every conceivable mixture of 3-isobutylGABA’s enantiomer." However, the defendants failed to convince the court that such mixtures were anything other than routine to one of ordinary skill in the art. The court noted that the '819 patent disclosed the method for synthesizing the compound and states that the compound's "enantiomers may be prepared or isolated by methods already well known in the art." Citing In re Hogan, 559 F.2d 595, 606 (CCPA 1977), the court declined to require an applicant to disclose "a detailed recipe for preparing every conceivable permutation of the compound they invented to be entitled to a claim covering that compound."

For written description, Appellant Sun Pharmaceuticals (only) focused on a lack of disclosure by the '819 patent regarding isolation of the individual enantiomers. Sun proposed that since later application filings by the patentee indicated that enantiomer separation for 3-isobutylGABA may have been less than routine, and that the inventors admitted that at the time of filing of their original applications, they had not yet actually separated the 3-isobutylGABA enantiomers, then the applicants were not in possession of the broader claim scope. However, the court found Sun's focus on the enantiomers to be unpersuasive. Rather, the court focused on whether "relevant identifying characteristics" were provided such that "persons of ordinary skill in the art [] recognize that the inventor invented what is claimed." Here, the court noted that disclosure of the claimed structure (in the absence of stereochemical definition), in vitro and in vivo data for the compound, and a method of synthesizing the compound satisfied the statutory requirements.

Finally, the ANDA applicants argued that the district court erred in finding claim 2 of the '819 patent not obvious in view of three proffered prior art references. The references were alleged to disclose that 3-isopropylGABA and other homologous compounds may have anticonvulsant activity, that 3-isobutylGABA would have been expected to have similar activity because of its close structural simlarity to the former, and that the anti-convulsant gabapentin, another 3-substituted gamma-amino butyric acid (GABA) derivative, provided motivation to try other substitutions as the 3-position of GABA.

The court applied the two-part test for obviousness of a chemical compound outlined in Eisai and Takeda by reviewing for (1) whether the asserted prior art compound would have been selected as a lead compound for further modification and (2) whether the prior art would have taught a skilled artisan to make the "specific molecular modifications" necessary to the selected lead compound to yield the claimed compound with a reasonable expectation of success.

As to the first prong, the court reiterated that more than "mere structural similarity" is necessary for a prior art compound to serve as a lead compound. Rather, other properties, such as chemical activity or potency, inform the lead compound selection. Here, the court was unmoved by the offer of either 3-isopropylGABA or gabapentin as a lead compound. The court found insufficient details in the cited art regarding properties of either compound that would have lead to their selection for further research. With respect to gabapentin, the prior art was vague as to whether the compound was in the prior art at all, and if so, whether any of its relevant properties, such as anticonvulsant activities in the context of other anticonvulsants known at the time would have highlighted the compound for further modification. For 3-isopropylGABA, the court noted that the prior art failed to teach its "mechanisms of action, including whether it has anticonvulsive properties."

Moving to the second prong, the court noted that even if either compound were selected as a lead compound, the proffered art failed to teach the precise modifications necessary to yield 3-isobutylGABA. Rather, the court noted that the cited art merely suggest "trillions" of compounds "without calling out alkyl groups in particular or singling out isobutyl specifically." The court concluded by agreeing with the district court's finding that the appellees had convincingly established the complicated and unpredictable nature of anticonvulsant field at the time of filing, thereby precluding any reasonable expectation of success in achieving anticonvulsant in 3-isobutylGABA "even if Appellants were able to establish that the prior art taught the substitution of isobutyl at GABA’s 3-position."

PTAB Institutes Inter Partes Review of Oracea (doxycycline) Formulation Patents

Amneal Pharmaceuticals, LLC v. Supernus Pharmaceuticals, Inc., IPR2013-00368, IPR2013-00371, IPR2013-00372 (PTAB)

    by Robert F. Kappers

The U.S. Patent Trial and Appeal Board issued a trio of related decisions on December 17, 2013, each instituting inter partes review of one of three related patents on once-daily formulations of tetracycline. 

On June 20, 2013, Amneal Pharmaceuticals filed three petitions for inter partes review, seeking to invalidate a family of patents owned by Supernus Pharmaceuticals.  Each of the challenged patents--U.S. Patent Nos. 8,206,740; 8,394,405; and 8,394,406--relates to once-daily, sub-antimicrobial formulations of doxycycline used to inhibit collagen destruction enzymes without provoking undesired side effects attendant to an antibacterial dose.

Claim 1 of the '740 patent is illustrative of the claimed subject matter: 

1. An oral pharmaceutical composition of doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 μg/ml and a maximum of 1.0 μg/ml, the composition consisting of

(i) an immediate release (IR) portion comprising 30 mg doxycycline;

(ii) a delayed release (DR) portion comprising 10 mg doxycycline; and optionally,

(iii) one or more pharmaceutically acceptable excipients.

Amneal asserted the same four grounds of unpatentability in each petition, but the Board accepted only two.  Amneal first asserted that the challenged claims were unpatentable for obviousness over WO 02/080932 A1 ("Ashley '932") as it incorporates Ser. No. 60/281,854 ("Ashley '854").  Amneal also asserted that the challenged claims were unpatentable for obviousness over Ashley '932 as it incorporates Ashley '854 in combination with U.S. 5,348,748 ("Sheth").  According to the petitions, Ashley '932 discloses administering a tetracycline compound in sub-antibacterial doses to treat acne, and further cites and incorporates Ashley '894 for disclosure of administering by sustained release, while Sheth discloses a once-daily formulation of minocycline with varying proportions of quick-release and delayed release dosage forms.

In each decision (-00368; -00371; -00372), the Board determined that Amneal had failed to demonstrate a reasonable likelihood of unpatentability for obviousness over Ashley '932 alone.  The Board rejected Amneal's argument that a person of ordinary skill would have envisaged the claimed ratios of immediate-release to delayed-release portions from the disclosure in Ashley '854 that at least half of the doxycycline dose be released in the upper GI tract.

The Board was more receptive to Amneal's second proffered ground of unpatentability; namely, that the subject matter of the challenged claims is obvious over the combination of Ashley '932 and Sheth.  Specifically, Amneal argued that Ashley '932 discloses all limitations of the illustrative claims except for the particular ratios of immediate-release and delayed-release portions of the formulation.  Rejecting Supernus’s counterarguments, the Board agreed that Sheth disclosed formulations of minocycline having a range of immediate-release to delayed-release ratios from which a person of ordinary skill could have envisaged the claimed ratios.

In the end, the Board instituted inter partes review of each of the three challenged patents, finding that Amneal had demonstrated a reasonable likelihood that the challenged claims in each patent were unpatentable over the combination of Ashley '932 and Sheth.

The petitions are related to ongoing litigation between the parties (currently stayed by joint stipulation), in which Galderma and Supernus alleged infringement of the '740 patent (the parent of the '405 and '406 patents) by Amneal's ANDA No. 203-278 and proposed generic version of Oracea.  See Galderma Labs. Inc., et al. v. Amneal Pharms., LLC, et al., C.A. No. 11-1106-LPS (D. Del.).

Divided Federal Circuit Panel Strikes Down Galderma’s Patents as Obvious—in Shifting the Burden of Production Regarding Secondary Considerations to the Patentee, Did the Majority in Fact Shift the Burden of Persuasion, Too?

Galderma Labs., L.P. et al. v. Tolmar, Inc., No. 2013-1034 (Fed. Cir.)

    by Dunstan H. Barnes

On December 11, 2013, a three-judge Federal Circuit panel struck down the asserted claims of five patents belonging to Galderma Laboratories for being invalid as obvious.  In Judge Sharon Prost's opinion for the court, joined by Judge William Bryson, she sought to draw a narrow distinction between shifting to the patentee the burden of production rather than the burden of persuasion, once an accused infringer has shown that the claimed invention falls within a range disclosed in the prior art.  Judge Pauline Newman vociferously criticized this burden-shifting in her dissent.

The five patents-in-suit are directed to a topical medication used to treat acne that contains 0.3% adapalene.  Claim 5 of U.S. Patent No. 7,838,558 is representative:

5. A topically applicable pharmaceutical composition comprising 0.3% by weight of [adapalene] relative to the total weight of the composition, effective for the treatment of acne, formulated into a topically applicable, pharmaceutically acceptable medium therefor, said composition being in the form of a topically applicable, pharmaceutically acceptable aqueous gel comprising at least one carbomer gelling agent and wherein the sole anti-acne ingredient is adapalene.

In September 2009, Tolmar filed an ANDA seeking approval to market a generic version of the patented product, Differin Gel, 0.3%.  In response, in January 2010, Galderma sued Tolmar for patent infringement in the United States District Court for the District of Delaware.  After a bench trial, the district court ruled in favor of Galderma on several issues, including validity.  On appeal to the Federal Circuit, the sole issue before the court was invalidity for obviousness under 35 U.S.C. § 103.

The Federal Circuit panel majority held that Tolmar had proven obviousness by clear and convincing evidence, and therefor reversed the district court's decision.  Tolmar's obviousness argument relied primarily on three prior art references:  two prior art patents ("Shroot '720 patent" and "Shroot '440 patent") and Galderma's data sheet for its earlier-marketed 0.1% adapalene gel product ("Data Sheet").  Tolmar further supported its obviousness argument with nine scientific journal articles.

The Shroot '720 patent disclosed several compositions containing a broad range of adapalene concentrations:  0.001%, 0.1%, and 1%.  Similarly, claim 4 of the Shroot '440 patent listed a preferred range of 0.01 to 1% for cosmetic compounds including the inventive compounds, such as adapalene, as the active ingredient.  The majority pointed out that both Shroot patents were listed in the FDA's Orange Book for Galderma's prior art 0.1% adapalene gel product and its 0.3% adapalene gel product.  Although the Data Sheet disclosed simply 0.1% adapalene as an acne treatment and not a range, it also disclosed virtually every inactive ingredient listed in the asserted claims.

In addition to the three primary prior art references, Tolmar supported its obviousness argument with nine scientific journal articles that Tolmar believed showed using 0.3% adapalene for acne treatment would have been obvious to a person of ordinary skill in the art at the time of the invention.  The majority noted that "many skilled artisans believed at the time of the invention that 0.1% was the optimal concentration of adapalene for the treatment of acne," a statement that Judge Newman seized upon in her dissent.

The most interesting aspect of this case involves a legal standard regarding the burdens of production and persuasion.  The majority stated:

where there is a range disclosed in the prior art, and the claimed invention falls within that range, the burden of production falls upon the patentee to come forward with evidence that (1) the prior art taught away from the claimed invention; (2) there were new and unexpected results relative to the prior art; or (3) there are other pertinent secondary considerations. 

To support this burden-shifting standard, the majority cited Novo Nordisk A/S v. Caraco Pharm. Labs. Ltd., 719 F.3d 1346, 1352-54 (Fed. Cir. 2013), a case bearing certain similarities to the present case:  Judge Prost authored the majority opinion and Judge Newman wrote a dissenting opinion.  And even though the issue in Novo Nordisk was not precisely the same—the prior art suggested an allegedly obvious combination of two drugs rather than disclosing a range—the Federal Circuit held that there is a shift to the patentee to bear "the burden of production once the court determined that the challenger has established a prima facie case of obviousness."  Id. at 1354.  The Novo Nordisk majority emphasized that it was not shifting the burden of persuasion, "as long is the [district] court reserved its ultimate conclusion on validity until after it considered the evidence from both sides . . . ."  Id.

In applying this standard, the panel majority examined three secondary consideration factors in reaching its conclusion that the claims are invalid as obvious:  (1) teaching away; (2) unexpected results; and (3) commercial success.  First, the majority held that the district court "clearly erred" by finding that the prior art taught away from a 0.3% concentration, because although the prior art understanding was that 0.1% was the optimal concentration, "[a] teaching that a composition may be optimal . . . does not criticize, discredit, or otherwise discourage investigation into other compositions," and therefore does not qualify as a "teaching away."  Second, the majority found that there were no unexpected results because although "the expected result was an increase . . . in . . . certain side effects[,] [t]he failure of that . . . increase to materialize, though unexpected, constitutes a only a difference in degree from the prior art results."  Third, the majority discounted the commercial success of Galderma's 0.3% gel product because "[t]he now expired Shroot patents blocked the market entry of 0.3% adapalene products until their expiration in 2010," which meant that "no entity other than Galderma could have successfully brought . . . 0.3% to market prior to 2010."

In her dissent, Judge Newman accused her colleagues of "distort[ing] the burdens of proof and production, ignor[ing] the applicable standard of proof and rely[ing] on their own factual determinations and creative theories of law . . . ."  In doing so, she stated, the panel majority "places on the patentee the burden of establishing patentability based on 'secondary considerations.'"  She suggests that the majority's standard, quoted above, does not shift only the burden of production, but the burden of persuasion, too, because the majority held that Tolmar had met its evidentiary burden simply by demonstrating that "the invention fell within a broad range disclosed in the prior art . . . ."  In addition, Judge Newman was clearly bothered by the majority's lack of deference to the district court, which "applied the correct law to a vast body of evidence, most of which is not discussed by the panel majority."

Judge Newman also analyzed the secondary consideration factors of "teaching away" and "unexpected results."  First, she relied upon the district court's finding (based on "prior art" and "expert testimony presented by both sides") that the prior art as a whole taught away from increasing the adapalene concentration above 0.1%.  Second, Judge Newman found no clear error in the district court's holdings that:  (a) it was "unexpected that the tolerability profile of 0.3% adapalene was not statistically different from that of 0.1% adapalene"; and (b) that the difference was "in kind, not in degree," because Galderma's products "violated the trend" of exhibiting "increased adverse side effects with increased concentration."

It will be interesting to see whether Galderma petitions for en banc review of this opinion in light of the potentially controversial burden-shifting standard adopted by the panel majority.

Cadence Prevails Over Exela in OFIRMEV® (Acetaminophen) ANDA Litigation

Cadence Pharms., Inc. v. Exela Scis., LLC, No. 11-733-LPS (D. Del.)

    by Dunstan H. Barnes

On November 22, 2013, the U.S. District Court for the District of Delaware issued a Final Judgment and Permanent Injunction barring Exela from manufacturing a generic version of OFIRMEV®, which is an injectable liquid acetaminophen composition.  Judge Leonard Stark held that all fourteen asserted claims from the two patents in suit were not invalid and would be infringed by Exela's generic product.  Judge Stark's reasoning was revealed in his November 14 Memorandum Opinion which was unsealed on November 22.

Plaintiff Cadence Pharmaceuticals, Inc. ("Cadence") holds approved NDA No. 022450 for OFIRMEV®, which was approved by the U.S. Food and Drug Administration in November 2010.  Plaintiff SCR Pharmatop ("Pharmatop") is a French civil law partnership that owns U.S. Patent Nos. 6,028,222 ("the '222 patent") and 6,992,218 ("the '218 patent"), which are directed to, respectively, a formulation of, and a method for preparing, a liquid acetaminophen (or paracetamol) composition.  Paracetamol is the name used outside of the United States for acetaminophen.  Cadence is a Delaware corporation based in California that has an exclusive license to the '222 and '218 patents.

In 2011, Cadence and Pharmatop sued Exela Pharma Sciences, LLC, Exela Pharmsci, Inc., and Exela Holdings, Inc. (collectively, "Exela") for patent infringement after Exela notified the plaintiffs that it had filed ANDA No. 203092 seeking regulatory approval for a generic version of OFIRMEV®. 

Cadence and Pharmatop had also sued Perrigo Company, and its subsidiaries Paddock Laboratories, Inc. and Paddock Laboratories, LLC.  Each of these three parties were dismissed from the suit by a joint stipulation of the parties after the parties settled and entered into a license agreement.  Cadence announced in November 2012 that, under the license agreement, Perrigo has the exclusive right of first refusal to negotiate an agreement with Cadence to market an authorized generic version of OFIRMEV® in the United States if Cadence elects to launch an authorized generic version of the product.

After construing the claims in August 2012, the Court conducted a seven-day bench trial in May and July of 2013.

At trial, Cadence and Pharmatop successfully proved by a preponderance of the evidence that Exela's generic version of OFIRMEV® literally infringed all ten asserted claims of the '222 patent.  Despite Exela's arguments to the contrary, the plaintiffs successfully proved that in Exela's generic product, sodium ascorbate acted as a "buffering agent" and mannitol acted as a "free radical scavenger" (i.e., an antioxidant).  This meant that Exela's generic product met each of the asserted claim limitations.

Although Cadence and Pharmatop failed to prove literal infringement of any of the four asserted claims of the '218 patent, the plaintiffs succeeded under the doctrine of equivalents.  The court found no literal infringement because independent claim 1 required the solution to have a dissolved oxygen content of greater than 2.0 ppm prior to the deoxygenation step.  Because the evidence at trial showed no substantial difference based on the time at which the oxygen content is reduced to below 2.0 ppm, the court held that Exela infringed under the doctrine of equivalents.

To invalidate the '222 patent, Exela argued that three pieces of prior art—Greek Patent Application No. 870101510, Korean Patent No. 1993-011994, and U.S. Patent No. 5,270,050—rendered the '222 patent anticipated or obvious.  Excela's anticipation argument failed because Exela was unable to convince the court that the prior art disclosed a "stable" liquid formulation, as recited in claim 1, the only independent claim at issue in the '222 patent.  Exela's obviousness argument failed for the same reason and additionally because the court was persuaded that each of the following secondary considerations supported a finding of nonobviousness: (1) unexpected results, (2) satisfaction of an unmet need, (3) failure of others, (4) commercial success, (5) successful licensing, and (6) praise of others.

Exela was similarly unable to win its argument that the '218 patent was invalid as obvious in view of the '222 patent combined with an article from the 1978 Journal of Pharmaceutical Studies.  Importantly, the 1978 article concerned the oxidative degradation of pyrogallol, which is highly sensitive to oxidation, rather than paracetamol, which is not.  The court was unconvinced by Exela's argument for two reasons.  First, the court found independent claim 1 was valid and nonobvious given the technical differences in degradation of paracetamol compared to the degradation of pyrogallol (hydrolysis instead of oxidation), as well as the technical difficulties of deoxygenation.  Second, Cadence and Pharmatop persuaded the court that all six secondary considerations listed above supported the nonobviousness of the '222 patent.

Based on its findings, the court enjoined Exela from producing its generic version of OFIRMEV® until the '222 and '218 patents expire:  August 5, 2017 for the '222 patent and June 6, 2021 for the '218 patent.

PTAB Declines to Institute Inter Partes Review of Alimta (Pemetrexed) Patent

Accord Healthcare v. Eli Lilly and Co., IPR2013-00356 (PTAB)

    by Herbert D. Hart III

On October 1, 2013, the Patent Trial and Appeal Board issued a decision denying the petition for inter partes review filed by Accord Healthcare targeting Eli Lilly's U.S. Patent No. 7,772,209.  The '209 patent is listed in the Orange Book for Alimta (pemetrexed disodium).

The Board denied Accord's petition because it was filed more than one year after the filing date of the complaint in the first of two ANDA lawsuits between the parties (Lilly v. Accord, 1:12-cv-00086-TWP-DKL (S.D. Ind.) ("the '086 action"), filed January 20, 2012 and served January 23, 2012).  Accord had argued that its petition was timely because it was filed within one year of the filing of the complaint in the second of the two lawsuits (Lilly v. Accord, 1:13-cv-00335-TWP-DKL (S.D. Ind.) ("the '335 action"), filed February 28, 2013 and served March 7, 2013).  The first lawsuit concerns Accord's 100 mg/vial and 500 mg/vial pemetrexed products and the second concerns its 1000 mg/vial product.

Specifically, the Board found that the filing of the second complaint did not reset the time for filing a petition for inter partes review:

We reject Accord's implicit argument that the one-year period set forth in § 315(b) should not be measured from the date of service of the complaint in the '086 action.  The plain language of the statute does not indicate or suggest that the filing of a later lawsuit renders the service of a complaint in an earlier lawsuit a nullity.

Accord's petition can be found here, and Lilly's patent owner response can be found here.

Of the eleven petitions for inter partes review so far filed by generic drug companies, six (including Accord's) were filed against patents already in litigation, and five were filed by just two petitioners.  Three trials have been instituted, while no institution decision has been issued in response to the remaining seven petitions.  There have as yet been no final decisions in any inter partes review trials.

Federal Circuit Affirms Obviousness of Novo Nordisk's PRANDIN Patent

Novo Nordisk v. Caraco Pharm. Labs., No. 2011-1223 (Fed. Cir.)

In its third trip to the Federal Circuit, the court on Tuesday affirmed a decision holding claim 4 of Novo's U.S. Patent No. 6,677,358 invalid as obvious.  Claim 4 of the '358 patent, listed in the Orange Book for PRANDIN (repaglinide) tablets, is directed to "[a] method for treating non-insulin dependent diabetes mellitus (NIDDM) comprising administering to a patient in need of such treatment repaglinide in combination with metformin."  This is the same case in which the Supreme Court decided last year that a "delisting counterclaim" may be used to force amendment of an Orange Book use code.

The Federal Circuit's opinion on Tuesday was authored by Judge Prost and joined by Judge Dyk.  Judge Newman dissented in a pointed opinion.  The court also unanimously reversed the district court's finding that the '358 patent is unenforceable due to inequitable conduct.

The case revolved around the three bases that Novo advanced for reversal of the district court's finding of obviousness--two of which (incorrect burden shifting to the patentee and lack of deferral to fact-finding by the USPTO) were quickly dispatched by the court.  But on the third basis for reversal--that Caraco's evidence insufficiently supported the district court's ultimate obviousness finding, the judges divided sharply on their interpretation of the record.

The majority based its affirmance of obviousness on the district court's reasoning that:

1. the closest prior art [to the repaglinide/metformin combination] was combination therapy using metformin and a sulfonylurea;

2. combination therapy using metformin and one of the sulfonylurea class of secretagogues was well known in the art to produce beneficial and even synergistic results in controlling glucose levels in Type II diabetes patients; [and]

3. repaglinide was known as an insulin secretagogue having a similar mechanism of action to the sulfonylurea class of secretagogues.

These findings outweighed Novo's evidence, both before the USPTO and during litigation, that the combination of repaglinide and metformin is, unexpectedly, eight times more effective in reducing fasting plasma glucose ("FPG") levels than metformin alone and despite repaglinide having no impact on FPG.

The majority explained away the allegedly unexpected effect of repaglinide/metformin on FPG by noting that "[r]epaglinide and sulfonylureas are both insulin secretagogues, and they therefore have a 'similar mechanism of action'" and that "the prior art taught that metformin could be combined with certain sulfonylureas which were, like repaglinide, short-acting secretagogues."  In particular, the court noted that prior art proffered by Caraco "report[ed] that metformin/sulfonylurea combinations yielded an 'apparent synergistic effect' and 'appear[ed] to have a synergistic effect'."

The court further picked apart Novo's evidence of unexpected results by noting that (1) the same study that found the reduction in FPG (the "Moses Study"), also showed that the near-term and long-term benefits of repaglinide/metformin "were generally inferior to the results found by prior art studies involving metformin combined with sulfonylureas"; (2) Novo's expert, Dr. Sturis, felt that the Moses Study had not mathematically or scientifically proven the existence of synergy; (3) Dr Sturis' own repaglinide/metformin study only "strongly suggest[ed]" synergy; (4) Novo's final study (Pfeiffer), showing a 35% improvement in insulin sensitivity in repaglinide/metformin combination therapy over metformin alone, had questionable reliability due to its small sample size, or results that were "explained away" by Pfeiffer in a contemporaneous report as predictable in view of the prior art; and (5) certain other tests on drug-naïve patients either did not "consistently" show a synergistic effect on FPG or did not "show statistically better results than the drugs used in monotherapy."

On these bases, the court concluded that "it is reasonable that an artisan seeking to combine a known insulin sensitizer (like metformin) with a new insulin secretagogue (like repaglinide) would base his expectations upon prior art sensitizer/secretagogue combinations."  In fact, the Court found that it was "not erroneous . . . to conclud that the prior art predicted the results" of the combination of repaglinide and metformin on FPG.

Judge Newman begged to differ from her colleagues' "erroneous view of the evidence and incorrect application of the law of obviousness."  In her view, the panel majority's generalization that "earlier metformin/sulfonylurea combinations were generally understood to yield synergy," was inaccurate.  Rather, only some sulfonylureas formed synergistic combinations, but "synergism was not a general property of the combinations."  According to Judge Newman, "it was well-known that not all insulin stimulants form synergistic combinations with metformin."

Focusing on the district court's selection of the combination of metformin-glyburide to invalidate the '358 patent, Judge Newman noted the substantial differences between repaglinide and glyburide, including the substantial structural differences between the two and the fact that the latter is a long-lasting insulin secretagogue while repaglinide is a short-lasting secretagogue.  In order to provide a more equal comparison from which to draw reasonable expectations, Judge Newman suggested that "a more reasonable analysis would consider metformin in combination with nateglinide, which is structurally similar to repaglinide, or a shorter-acting sulfonylurea such as glipizide."  That is, "the 'closest prior art' is the reference having the most 'in common' with the claimed invention, not the reference that happens to describe the most impressive results."

Reacting to the majority's dissection of Novo's evidence of unexpected results, Judge Newman reminded the majority that, "[t]o be patentable, a compound need not excel over prior art compounds in all common properties."  Rather, one must look to whether the claimed combination "would produce results superior to the additive effect of the components separately."  On a record where it was not shown that glyburide was an effective synergist in combination with metformin, Judge Newman could not conclude that repaglinide would be expected to be an effective synergist.  Ultimately, for Judge Newman, "[t]he synergy demonstrated by Novo for the metformin-repaglinide combination therapy was not predicted or predictable, and was not obvious."

District of Delaware Invalidates Entecavir Patent as Obvious

Bristol-Myers Squibb v. Teva Pharms., No. 10-805-CJB (D. Del.)

    by Aaron F. Barkoff

Today, in the District of Delaware, Judge Burke issued a 171-page opinion holding that claim 8 of U.S. Patent No. 5,206,244, covering the entecavir molecule, is invalid as obvious.  Entecavir is the active ingredient in Baraclude tablets, which are indicated for the treatment of chronic hepatitis B virus (HBV) infection.  The 30-month stay of final approval of Teva's ANDA was set to expire tomorrow.

Entecavir is a carbocyclic nucleoside analog that mimics the naturally-occurring nucleoside 2'-deoxyguanosine (dG):

Teva argued successfully that one of ordinary skill in the art seeking to make an anti-HBV compound at the time of the invention (1990) would have selected 2'-CDG, another prior art carbocyclic nucleoside analog, as a "lead compound" and would have modified 2'-CDG at the 5' position by adding an exocyclic methylene:

Judge Burke devoted 140 pages of his opinion to findings and conclusions that entecavir would have been obvious in light of the prior art.  The court held that "the prior art clearly would have directed the skilled artisan to select 2'-CDG, a carbocyclic analog, as a lead compound for further development efforts," finding that "in direct contrast to BMS's arguments in its briefing, the testimony of its own expert at trial repeatedly and conclusively established that researchers were, in fact, treating and using 2'-CDG as a lead compound in the relevant time period."  Similarly, in holding that a person of ordinary skill would have had a reason to modify 2'-CDG by adding a carbon atom at the 5' position, the court found "that the powerful admissions by BMS's expert severely undercut BMS's arguments to the contrary regarding motivation to combine."  The court likewise found BMS's arguments regarding reasonable expectation of success unpersuasive, stating, "notably, BMS's opening brief fails to address this factor of the prima facie case in any great detail."

Before concluding that claim 8 of the '244 patent is invalid as obvious, the court examined the objective evidence of nonobviousness, observing that "all evidence relevant to obviousness or nonobviousness [must] be considered, and be considered collectively."  First, the court, "following the direction of the Federal Circuit and this Court's case law, [found] that Teva's choice to copy entecavir, while not irrelevant to the obviousness analysis, does not amount to compelling evidence of nonobviousness here."  Next, the court found "that Baraclude has been a commercial success, though a less dynamic one than BMS asserts in its briefs."  The court then analyzed the testimony of a BMS expert, Dr. Gish, relating to skepticism of those in the art, but found that "in the absence of additional corroborating evidence . . . [Dr. Gish's] verbal claim of skepticism is simply not enough to weigh in BMS's favor as to this factor regarding nonobviousness."  The court similarly found evidence of failure of others to be weak.

The court ultimately concluded:

Teva has made out a strong prima facie case of obviousness.  The evidence that it put forward at trial in that regard was multi-faceted and compelling.  In addition, as to almost every significant portion of the prima facie case, Teva's position was not only bolstered by the opinion of its expert, Dr. Heathcock, but also by the testimony of BMS's expert, Dr. Schneller.  On cross-examination, Dr. Schneller was forced to concede the accuracy of many significant points that Teva sought to assert as to that prima facie case.  The force of this evidence was clear, and it was convincing.

As noted above, the evidence as to objective considerations was mixed.  Some of those considerations redounded to the benefit of BMS's position as to nonobviousness to a degree, but as to a number of other considerations, the impact of that evidence was not particularly compelling.  The totality of that evidence did not strongly persuade the Court as to entecavir's nonobviousness.

In addition to obviousness, Teva argued that the '244 patent is unenforceable due to inequitable conduct.  Teva based its inequitable conduct allegation on the fact that prior art disclosing 2'-CDG was not cited to the PTO during prosecution (which, incidentally, strengthened Teva's obviousness position).  Here, the court sided with BMS, finding that Teva did not demonstrate "that the single most reasonable inference in this case is that [BMS] had the specific intent to deceive the PTO, nor that the evidence requires a finding of deceitful intent in light of all of the circumstances."

Though successful in the district court, it is unclear when Teva will begin marketing its generic entecavir tablets, as Teva's ANDA has apparently not yet received tentative approval.  In addition, according to the Orange Book, BMS holds a three-year exclusivity on Baraclude that expires in October 2013 and another three-year exclusivity that expires in October 2015.  Meanwhile, BMS will very likely appeal today's decision to the Federal Circuit.

Federal Circuit Affirms Validity of Lilly's Alimta (Pemetrexed) Patent

Eli Lilly & Co. v. Teva Parenteral Medicines , No. 2011-1561 (Fed. Cir.)

    by Aaron F. Barkoff

Lilly's anticancer drug Alimta (pemetrexed) is approved for the treatment of mesothelioma and non-small cell lung cancer.  Teva, Barr and APP filed ANDAs seeking approval to market generic versions of Alimta prior to the expiration of U.S. Patent No. 5,344,932, owned by Princeton University and exclusively licensed to Lilly.

In a unanimous opinion last Friday, the Federal Circuit affirmed a district court decision that the asserted claims of the '932 patent are not invalid for obviousness-type double patenting.

Claim 3 of the '932 patent recites pemetrexed:

Teva asserted that claim 3 of the '932 patent is invalid for obviousness-type double patenting over two patents in the same family as the '932:  U.S. Patent Nos. 5,028,608 and 5,248,775.  The '608 and '775 patents have expired, but the '932 patent remains in effect until July 24, 2016, due to a patent term extension of over four years to compensate for delays in the regulatory approval of Alimta.  Lilly holds a further six months of pediatric exclusivity over pemetrexed.

As the Federal Circuit explained:

The doctrine of obviousness-type double patenting is intended to prevent the extension of the term of a patent by prohibiting the issuance of claims in a second patent not patentably distinct from the claims of the first patent.  A later patent claim is not patentably distinct from an earlier claim if the later claim is obvious over, or anticipated by, the earlier claim.

Teva's first argument was that pemetrexed is not patentably distinct from a compound recited in claim 3 of the '608 patent:

Here, according to the Federal Circuit:

Teva's primary argument concerns the appropriate legal standard for evaluating obviousness-type double patenting.  Relying on our decision in Amgen Inc. v. Hoffman La-Roche Ltd., 580 F.3d 1340 (Fed. Cir. 2009), Teva contends that the correct analysis involves only the differences between the claims at issue, so that any features held in common between the claims--in this case, all but the aryl regions of the '608 Compound and pemetrexed--would be excluded from consideration.  In Amgen, we explained that once the differences between claims are established, the obviousness-type double patenting analysis entails determining "whether the differences in subject matter between the claims render the claims patentably distinct."  But those differences cannot be considered in isolation--the claims must be considered as a whole.

On the merits, the court stated:

In the chemical context, we have held that an analysis of obviousness-type double patenting requires identifying some reason that would have led a chemist to modify the earlier compound to make the later compound with a reasonable expectation of success.  Here, the district court considered the parties' arguments and evidence, particularly their conflicting expert testimony as to how an ordinarily skilled chemist presented with the '608 Compound would have been motivated to proceed at the time.  In its decision, the court credited Lilly's evidence to find that "the ways in which a person of ordinary skill in the art would modify [the '608 Compound] would not result in pemetrexed."  We owe that finding considerable deference on appeal, and we see no clear error based on the record before us.

Teva's second argument was that pemetrexed is not patentably distinct from a compound recited in claim 2 of the '775 patent:

Here, Teva's arguments were based not on the structural similarity of pemetrexed and the '775 Intermediate, but rather on the fact that the '775 patent disclosed that the '775 Intermediate is used to make pemetrexed.  As the court put it, "By later claiming pemetrexed itself, Teva maintains, the '932 patent appropriates a previously disclosed use for previously patented compound, which renders the asserted '932 claims invalid for obviousness-type double patenting under a line of our precedent including . . . Sun Pharm. Indus. v. Eli Lilly & Co. (Fed. Cir. 2010)."

The Federal Circuit explained:

As a general rule, obviousness-type double patenting determinations turn on a comparison between a patentee's earlier and later claims, with the earlier patent's written description considered only to the extent necessary to construe its claims.  . . .  The cases on which Teva relies represent a limited exception to this customary framework.  . . .  In Pfizer v. Teva Pharms. USA (Fed. Cir. 2008), we held claims to methods of administering a particular anti-inflammatory drug invalid for obviousness-type double pateting where th patentee's earlier patent claimed the drug itself and disclosed the same methods of administering the drug.  And in Sun, the patent holder had developed an antiviral compound, gemcitabine, that also proved useful for treating cancer.  . . .  As in Pfizer, we held the patentee's subsequent claims to methods of using gemcitabine to treat cancer invalid for double pateting, looking to the disclosure of anticancer utility in the first patent's specification.

In summary, according to the court, Pfizer and Sun "address the situation in which an earlier patent claims a compound, disclosing the utility of that compound in the specification, and a later patent claims a method of using that compound for a particular use described in the specification of the earlier patent.  Furthermore, in each of those cases, the claims held to be patentably indistinct had in common the same compound or composition."

The court distinguished this case:

Rather than a composition and a previously disclosed use, the claims at issue recite two separate and distinct chemical compounds:  the '775 Intermediate and pemetrexed, differing from each other in four respects.  That alone suffices to undermine Teva's argument regarding the '775 Intermediate, for the asserted claims of the '932 patent do not recite a use of the same compound, but a different compound altogether.

Finally, the Federal Circuit corrected an error made by the district court.  The district court disregarded Lilly's objective evidence of nonobviousness, holding that "secondary considerations are not relevant to the analysis of invalidity for obviousness-type double patenting."  The Federal Circuit took the opportunity to reiterate its recent statement from In re Cyclobenzaprine:  a fact-finder "must withhold judgment on an obviousness challenge until it has considered all relevant evidence, including that relating to the objective considerations."

OBB News Briefs: First-Inventor-to-File Rules; Myriad oral argument; Lyrica decision

• On Friday morning, the USPTO pre-published its proposed rule changes implementing the provisions of the America Invents Act that convert the U.S. patent system from a "first to invent" to a "first inventor to file" system.  The proposed rules (available here) were scheduled to be published in the Federal Register on Monday, but were withdrawn later Friday.  We understand that the proposed rules were withdrawn because there was not enough space in Monday's Federal Register to accomodate both the proposed rules and a companion "guidance document" that the PTO wants published in the same issue of the Federal Register.  We expect that the proposed rules and guidance document will be published together sometime next week, and further that the published proposed rules will be identical to those that were pre-published today.
• Also Friday morning, the Federal Circuit heard oral argument in AMP v. Myriad following remand from the Supreme Court for further consideration in light of Prometheus.  An .mp3 audio recording of the oral argument is available here and also posted on the Federal Circuit's website.
• On Thursday, Judge Sleet of the U.S. District Court for the District of Delaware issued a 133-page opinion holding Pfizer's patents on Lyrica (pregabilin) valid and infringed by eight generic drug companies who filed ANDAs with paragraph IV certifications to the patents.  The ANDA applicants are now enjoined from marketing their generic versions of Lyrica until at least December 30, 2018, when, according to the Orange Book, the last of the patents-in-suit will expire.  The issues in the case included obviousness, anticipation, priority, written description, inventorship, literal and DOE infringement, and finally whether two patent term extensions, stemming from two separate NDAs for Lyrica that were approved on the same day, were valid.

Federal Circuit Again Vacates Preliminary Injunction in Metformin Case

Sciele Pharma v. Lupin, No. 2012-1228 (Fed. Cir.)

In a precedential decision today, the Federal Circuit vacated a preliminary injunction that had been entered against Lupin in the ANDA litigation over Lupin's generic version of FORTAMET (metformin extended-release tablets).  This is the second preliminary injunction against Lupin that the Federal Circuit has vacated in the litigation.

The U.S. District Court for the District of Delware entered the first preliminary injunction against Lupin in December 2011.  The Federal Circuit vacated the injunction on February 6, 2012, because the "district court's order imposing the preliminary injunction failed to even address Lupin's obviousness arguments."  On remand shortly therafter, the district court again entered a preliminary injunction against Lupin.  Lupin then moved for a stay, which the district court denied.  Lupin appealed again to the Federal Circuit, which ordered expedited briefing, held oral arguments on April 18, 2012, and, later the same day, granted Lupin's request to stay the second preliminary injunction.

Lupin argued in the appeal that the presumption of validity should not apply because the PTO erroneously granted the asserted claims of the patent-in-suit, U.S. Patent No. 6,866,866.  Sciele argued, on the other hand, that there should be a heightened presumption of validity because the prior art references relied upon by Lupin (Cheng and Timmins) were before the PTO during prosecution.  The Federal Circuit explained that, while new evidence not considered by the PTO "may carry more weight than evidence previously considered," the burden of proof required to prove invalidity, clear and convincing evidence, never changes:

The burden does not suddenly change to something higher--"extremely clear and convincing evidence" or "crystal clear and convincing evidence"--simply because the prior art references [relied on to prove invalidity] were considered by the PTO.  In short, there is no heightened or added burden that applies to invalidity defenses that are based upon references that were before the Patent Office.  The burden is always the same, clear and convincing evidence.

The Federal Circuit next addressed the merits of Lupin's invalidity argument, i.e., that the asserted claims of the '866 patent are invalid as obvious over Cheng and Timmins.  The asserted claims are directed to controlled-release dosage forms of metformin providing a mean time to maximum plasma concentration (Tmax) of between 5.5 and 7.5 hours.  According to the Federal Circuit, Cheng discloses all of the limitations of the asserted claims except for the Tmax range of 5.5 to 7.5 hours (instead disclosing a Tmax of 8-12 hours).  In addition, while Timmins discloses a median Tmax and not the claimed mean Tmax, Timmins, according to the Federal Circuit, "also provides the raw data from which one skilled in the art could compute the range of possible mean Tmax values."  According to the court, "[b]ased on this data, one skilled in the art would understand that the mean Tmax in Timmins must fall between 4.67 and 6.33 hours."  Thus, according to the court, Timmins "teaches one skilled in the art to lower the Tmax of Cheng."  This, in the Federal Circuit's view, was sufficient to raise a substantial question of validity that should have precluded a preliminary injunction.

To buttress its findings on the issue of obviousness, the Federal Circuit cited statements that the patentee made during prosecution in support of enablement:

During prosecution the applicant indicated "that one skilled in the art would be able to manipulate the processes and formulations of the [prior art] by other methods to obtain the claimed pharmacokinetic parameters of the present invention by routine experimentation.  While [Sciele] argued, and the district court seemed to accept, that this statement applies only to enablement, we are hard pressed to understand this distinction.  Coupled with the motivation to lower the Tmax, as disclosed in Timmins, the applicant's characterization of the predictability and skill in the art during prosecution provides further evidence that it would have been a routine and obvious design choice to make an extended-release dosage form with a lower Tmax.

Quoting KSR, the Federal Circuit concluded, "After all, 'if a person of ordinary skill can implement a predictable variation, section 103 likely bars its patentability.'"

Accordingly, the court vacated the preliminary injunction and remanded the case to the district court for further proceedings.