Patent Docs: Enablement

Enablement

February 14, 2013

Cephalon, Inc. v. Watson Pharmaceuticals, Inc. (Fed. Cir. 2013)

Whether ANDA litigation has had a positive or negative impact on generic drug availability is an open question, in view of several recent reports looking at the effects such litigation has had on both branded and generic drugs over the past thirty years. Indeed, the current squabble over "reverse payment" settlement agreements of lawsuits under the ANDA provisions of the Hatch-Waxman Act (codified at 35 U.S.C. § 271(e)(2)) involves many of these same issues, revolving around the question of whether it is prudent for both branded and generic parties of ANDA lawsuits to settle rather than wage protracted, often pyrrhic, patent litigation (see "FTC Releases Another Report on Reverse Payment Settlement Agreements in ANDA Litigation"). Occasionally, of course, both parties get an outcome they can live with, and one such occasion occurred today in Cephalon v. Watson Pharmaceuticals, where the Federal Circuit affirmed a District Court decision that the generic drug did not infringe the patent-in-suit but reversed the District Court on the issue of whether the patents were invalid for lack of enablement.

The case involved a formulation of fentanyl, an opioid sold by NDA holder Cephalon under the brand name FENTORA®. Cephalon listed U.S. Patent Nos. 6,200,604 and 6,974,590 in the Orange Book and asserted both patents in response to Watson's ANDA filing; claim 1 of the '604 patent:

1. A method of administering at least one systemically distributable pharmaceutical agent across the oral mucosa comprising:
    a) providing a solid oral dosage form including a pharmaceutically effective amount of an orally administerable medicament; and at least one effervescent agent in an amount sufficient to increase absorption of said orally administerable medicament across the oral mucosa; wherein said orally administerable medicament is not substantially encompassed by or dispersed in a material that prevents absorption of said medicament across the oral mucosa;
    b) placing said solid oral dosage form in the mouth of a patient so that saliva in said patient's mouth activates said at least one effervescent agent in said tablet; and
    c) holding said solid oral dosage form and the dissolving contents of said solid oral dosage form in the mouth of a patient whereby said at least one effervescent agent promotes absorption of said orally administerable medicament across the oral mucosa.

and claim 1 of the '590 patent:

1. A method of administration of fentanyl to a mammal across the oral mucosa thereof, said method comprising:
providing a solid oral dosage form comprising fentanyl or a pharmaceutically acceptable salt thereof and at least one saliva activated effervescent agent in an amount sufficient to increase absorption of said fentanyl or pharmaceutically acceptable salt thereof across said oral mucosa, at least one pH adjusting substance, and wherein said amount of said at least one effervescent agent is between about 5% by weight and about 80% by weight; and buccally, sublingually or gingivally administrating said solid oral dosage form to said mammal.

are representative (emphases in original opinion).

The formulation involved orally administered fentanyl designed to use the mucosal membranes of the mouth and oral cavity to introduce the drug into the body (thus avoiding the gastrointestinal tract). The claims of the patents-in-suit were directed to the use of effervescent agents as penetration enhancers to promote uptake of fentanyl (or other drugs) into the oral mucous membranes. In addition, the patent claims included in the formulation a "pH adjusting substance" that worked together with the effervescent agent in promoting drug uptake. As explained in the Federal Circuit opinion, effervescence agents falling within the scope of the patent claims included "at least one compound that evolves a gas," typically via a chemical reaction between the agent and water (saliva) in the mouth. These agents included an acid source, such as citric acid, and a carbon dioxide source (such as carbonate or bicarbonate), wherein the reaction resulted in carbon dioxide production. The pH adjusting substance was included because the effervescence reaction reduces the pH of saliva in the mouth, which can affect the solubility of fentanyl or other drug in the formulation.

The District Court found that Watson's ANDA product did not infringe, based on its construction of the claim term "at least one [saliva activated] effervescent agent in an amount sufficient to increase absorption . . . across [the] oral mucosa." In the District Court's construction, the effervescent agent was required to be activated by contact with saliva, which raised the question of whether the potassium bicarbonate and mannitol components of Watson's accused infringing generic drug reacted to have this effect. (Cephalon's Fentora® product contained fentanyl citrate, mannitol, sodium starch glycolate, magenesium stearate, citric acid, sodium bicarbonate, and sodium carbonate, wherein the sodium bicarbonate and citric acid are an effervescent couple that react to evolve carbon dioxide, whereas Watson's generic version contained fentanyl citrate and mannitol, sodium starch glycolate, potassium bicarbonate, and magnesium stearate.) The District Court did not credit Cephalon's expert's testimony that mannitol was the acidic component of an effervescent agent, despite testimony that the higher the mannitol concentration levels the more acidic a water solution containing it, in part because Cephalon provided no evidence of the effect of mannitol on saliva. Rather, the Court determined that Watson's expert was more persuasive when he testified that "the important piece of information that is missing [in this case] is what the potential or alleged acidity of mannitol in either artificial saliva or, even more important, in the human mouth . . . and there is no evidence that mannitol would be acidic under those conditions."

Regarding invalidity, the District Court construed the term "effervescent agent" to require that "at least one compound that evolves gas by means of an effervescent reaction" (emphasis in original opinion) and further determined that the claim language required the "effervescent agent" to be a single compound. Watson argued that the "effervescent agent" is disclosed in the Cephalon patents as comprising a "couple" (the acidic compound and the carbon dioxide-releasing compound) and thus that the term should require "a combination of two or more compounds that evolve gas." Under the District Court's construction, the soluble acid source must be in a separate dosage form from the effervescent agent itself and that these separate dosage forms be co-administered. Using this construction, the District Court found that the patents-in-suit were not enabling, being devoid of any disclosure relating to co-administration of two separate dosage forms and thus requiring undue experimentation.

The Federal Circuit reversed in part and affirmed in part, in an opinion by Judge Wallach joined by Judges Bryson and Reyna. The opinion affirmed the finding of no infringement on the grounds that there was no clear error by the District Court in deciding in Watson's favor on this issue. With regard to invalidity, the panel noted that the District Court erred by reasoning that Watson had raised a prima facie case of non-enablement against Cephalon's claims, which Cephalon did not rebut at trial. The panel, citing Morton Int'l, Inc. v. Cardinal Chem. Co., 5 F.3d 1464, 1469–70 (Fed. Cir. 1993), invoked the statutory presumption of validity in asserting that this was error, and that the challenger (Watson) bore the burden of proving invalidity by clear and convincing evidence. Turning to this question, the panel considered the District Court's reliance on Watson's proffered expert testimony that amounted (according to the Federal Circuit) to mere "ipse dixit" opinion that did not rise to the level of clear and convincing evidence. And the District Court's interpretation of Cephalon's expert's testimony regarding whether experimentation per se would be required to satisfy the enablement portion of the statute in view of the District Court's claim construction was also improper, according to the opinion, because the mere fact of experimentation is not the standard; the question is whether whatever experimentation that may be required is undue. Here, the Federal Circuit considered Watson's showing that the extent of experimentation that might be required was undue to be insufficient to arise to the level of clear and convincing evidence. Specifically, the panel stated that "[u]nsubstantiated statements indicating that experimentation would be 'difficult' and 'complicated are not sufficient" to establish undue experimentation. Thus, Watson had failed to establish non-enablement as a matter of law and the panel reversed.

Cephalon, Inc. v. Watson Pharmaceuticals, Inc. (Fed. Cir. 2013)
Panel: Circuit Judges Reyna, Bryson, and Wallach
Opinion by Circuit Judge Wallach

Posted at 11:59 PM in Enablement, Federal Circuit, Infringement - Literal or DOE | Permalink | Comments (0) | TrackBack (0)

December 31, 2012

January 25, 2012

Streck, Inc. v. Research & Diagnostic Systems, Inc. (Fed. Cir. 2012)

By Andrew Williams --

In a sequel of sorts to the hugely popular Streck, Inc. v. Research & Diagnostic Systems, Inc. (Fed. Cir. 2011), the Federal Circuit released Streck II (Streck, Inc. v. Research & Diagnostic Systems, Inc. (Fed. Cir. 2012)) earlier this month. Not to be upstaged by the original, this ambitious follow-up leaves the priority determination behind, and instead focuses on the infringement proceeding appeal. Notably, Streck II clocks in at over twice the length of its predecessor. However, if you have ever asked yourself whether a counterclaimant could maintain the full scope of a declaratory judgment challenge if a plaintiff narrows the scope of asserted claims early on in litigation, then Streck II could keep you on the edge of your seat. Spoiler alert -- the answer is "no."

The background and cast of characters was basically the same for both opinions. For those unfamiliar with the original Streck, the technology at issue in both cases was integrated controls for hematology analyzers. Prior to 1996, such instruments measured reticulocytes and white blood cells separately, because the various blood components would interfere with each other, causing error in counting or classifying. Such stand-alone controls using either true reticulocytes (also referred to as natural reticulocytes) or reticulocytes analogs were known before the filing dates of the patents-at-issue. As the instrument makers began attempting to develop an integrated analyzer that could measure the different blood components in the same sample, both Streck and Research & Diagnostic Systems (R&D) sought to create an integrated control. As we learned in Streck, one of the difficulties to overcome was the stability of the controls over extended periods of time. Streck obtained a patent to such controls, U.S. Patent No. 6,221,668, and sued R&D in the U.S. District Court for the District of Nebraska for infringement of three patents. Claim 1 of the '668 patent is representative:

1. A hematology control composition comprising:
a) a stabilized reticulocyte component; and
b) a fixed and stabilized white blood cell component capable of exhibiting a five-part differential.

The District Court construed the claims to encompass both true reticulocytes and reticulocyte analogs. Streck's inventor, however, only actually reduced his invention to practice with his previous developed reticulocyte analogs, while R&D's commercial product used true reticulocytes.

At this point, the plot of Streck II gets a bit convoluted. As previously mentioned, Streck filed its lawsuit in Nebraska. However, both parties agreed to be bound by the local patent rules of the United States District Court for the Northern District of California. As a result, Streck served a Disclosure of Asserted Claims and Preliminary Infringement Contentions shortly after the initial case management conference. In this disclosure, Streck narrowed the scope of asserted claims. R&D followed up with preliminary invalidity contentions narrowly drawn to the asserted claims, but later expanded the contentions to include all but one of the claims in the patents-at-issue. Streck further narrowed its asserted claims to ten, and then to nine, prior to the Court's Summary Judgment decision. On September 9, 2009, the Court held that Streck's patents satisfied the Written Description requirement with respect to integrated controls with true reticulocytes, and denied R&D's motion for summary judgment on enablement. The Court also dismissed the counterclaims with respect to Claim 3 of two of the patents, because there was "no reasonable apprehension of suit," and found that, as a matter of law, R&D infringed the asserted claims (and that there was evidence from which a jury could find willfulness). Subsequently, just before trial, the Court sided with Streck and excluded the evidence related to the validity of all unasserted claims, stating that the validity of these claims would not go to the jury. After an eight-day jury trial, the Court granted JMOL for Streck on enablement. The only issues submitted to the jury were priority, damages, and willfulness. The jury did not find R&D's infringement to be willful and awarded damages of 12.5%. As the priority issue was covered in Streck, it will not be addressed here. The procedural background concluded with the District Court entering an injunction against R&D.

Declaratory Judgment Jurisdiction over Counterclaims

The first issue on appeal was whether R&D could maintain invalidity counterclaims against claims that Streck was no longer asserting. Steck originally filed suit in June 2006 alleging infringement of all claims in the patents-in-suit, but within six months, it had narrowed the asserted claims to fifteen specific claims. R&D, in turn, responded with preliminary invalidity contentions against those fifteen claims, but expanded the scope of its invalidity contentions in the next two years to all but one claim of the patents-in-suit. Streck subsequently narrowed the asserted claims to ten, and then to nine. As a result, the District Court dismissed R&D's invalidity counterclaims against two claims because it had "no reasonable apprehension" it would face an infringement suit on any claim other than the claims asserted by Streck. Moreover, prior to trial, the Court excluded R&D's evidence with regard to the unasserted claims, because of these same jurisdictional concerns.

The Federal Circuit agreed with the District Court that there was no jurisdiction, even though it used the outdated "reasonable apprehension" test. As the Federal Circuit pointed out, even though MedImmune rejected strict reliance on the "reasonable apprehension of suit" test, it did not do away with the relevance of this test. The Federal Circuit looked favorably on a New Jersey District Court case as persuasive authority, Hoffman-La Roche Inc. v. Mylan Inc., No. 2:09cv1692, 2009 U.S. Dist. LEXIS 114784, at *17-18 (D.N.J. Dec. 9, 2009). In that case, like here, the patentee narrowed the scope of the asserted claims when it served infringement contentions. That court noted that jurisdiction exists on a claim-by-claim basis at every stage of the litigation, and that even though the plaintiff's decision to change the scope of the suit did not automatically divest the court of jurisdiction, the counterclaimant must show why jurisdiction continues to exist. Applying the same reasoning, the Federal Circuit found that "there was no evidence that R&D met its burden of showing a continuing case or controversy with respect to the unasserted claims." In fact, the Court noted that R&D relied too heavily on the District Court's use of the "reasonable apprehension" test, and pointed out that MedImmune doesn't stand for the proposition that jurisdiction automatically exists whenever a competitor wants to mount a validity challenge.

Interestingly, the Federal Circuit cited favorably to Streck's narrowing of the scope of the claims at the outset of the litigation, prior to any dispositive rulings. In fact, it appears that neither party cited to the preliminary infringement and invalidity contentions, but instead the Court itself identified the early nature of the narrowing of scope of the litigation. This begs the question, therefore, of when is it advisable to narrow the scope of the claims in an infringement suit? Should it be done as soon as possible, thereby possibly foreclosing the ability to assert relevant claims before fact discovery is completed (or perhaps has even begun)? Or can a patentee wait until the eve of filing of Summary Judgment motions? Of course, after MedImmune, courts must look to "all the circumstances," and therefore the answer will be fact specific. Nevertheless, it would be advisable to monitor the claims one is asserting in an infringement suit during all stages of the litigation, especially if it is desirable to move some of those claims out of harm's way, or if the validity of those claims is in such question that taking them to the jury could have prejudicial affect.

Written Description

The second issue on appeal was whether Streck's patents satisfied the written description requirement of 35 U.S.C. § 112, ¶ 1. Specifically, R&D alleged that the patents failed to provide sufficient details to establish that Streck was in possession of a true reticulocyte integrated control. The test, according to Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010) (en banc), is whether the disclosure "conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Id. at 1351. The Federal Circuit implicitly noted that there are generally two situations where written description can be found lacking: (1) when newly added claim language is not supported by the specification as filed, and (2) when patentees attempt to claim a broad genus without providing adequate support for enough species within that genus. The Court found that neither of these situations applied, because the patents-in-suit specifically referred to several types of true reticulocytes, i.e., several species, as possible embodiments of the claimed invention. And, even though it was more relevant to the enablement requirement, the Court did note that because analogs are designed to mimic true reticulocytes, and because stand-alone true reticulocytes were known in the art, it was not difficult to conclude that one skilled in the art would have recognized that the claimed integrated controls could be made with either true reticulocytes or analogs.

R&D did not appear to take its written description challenge very seriously. Indeed, the District Court noted that the R&D focused primarily on enablement, and the Federal Circuit argument centered almost exclusively on the enablement issue. Instead, R&D appeared to rely mainly on the testimony of a Streck inventor to establish a lack of written description. However, R&D apparently mischaracterized the testimony. The inventor did testified to the commercial practicalities of the use of true reticulocytes, but such evidence does not speak to the feasibility or viability of the use of true reticulocytes in a control. Instead, it merely reflects the inventor's personal preference. Also, R&D pointed to the inventor's difficulty in identifying support in the specification for true reticulocytes. However, he later clarified that the patent covers both kinds of reticulocytes, and cited to the language referenced above. Finally, R&D cited the lack of any reduction to practice by Streck of true reticulocytes. However, actual reduction to practice is not necessary because the filed specification constitutes a constructive reduction to practice. Therefore, such an allegation is without merit.

Enablement

R&D's lack of enablement assertions appeared to have more credibility, but they also ultimately fell short. In fact, the Federal Circuit held that the evidence clearly supported a finding of enablement, and therefore met the exacting standard of taking this fact-laden inquiry away from the jury. The District Court had granted JMOL after the close of evidence but before the case went to the jury, and the Federal Circuit affirmed that decision.

Much like with the written description challenge, R&D alleged that the patents-in-suit do not enable true reticulocyte integrated controls. Of course, to satisfy the enablement requirement, the specification must enable one skilled in the art how to make and use the claimed invention without undue experimentation. And, even though the specification need not disclose what is well known in the art, this rule is not a substitute for a basic enabling disclosure.

The question in this case appeared to center around what the novel aspects of the invention were. R&D relied on Automotive Technologies Int'l, Inc. v. BMW of North America, Inc., 501 F.3d 1274 (Fed. Cir. 2007), which held that a patent that disclosed mechanical side-impact crash sensors for automobile airbags did not, without more, enable the use of electronic side-impact crash sensors. In that case, the Court determined that the electronic sensors were novel, and distinctly different than mechanical sensors. Moreover, the knowledge of one of skill in the art could not supply the missing information, especially when that missing information constituted the novel aspect of the invention. In contrast, in the present case, the novel aspect of the invention was the integrated reticulocyte control, and the use of true reticulocyte in the invention is virtually indistinguishable from analogs. Moreover, even though the burden was on R&D to establish lack of enablement by clear and convincing evidence, R&D failed to submit sufficient evidence to submit the case to a jury. R&D relied heavily on its expert, but the expert provided conclusory assertions which do not give rise to a genuine issue of fact. In fact, R&D's expert admitted on cross-examination that he had never been involved in developing controls. Finally, R&D pointed to the testimony of the Streck inventors that the quantity of experimentation to make and use a true reticulocyte integrated control would be high. However, this testimony was referring to the difficulties of using such a control prior to the patent disclosure.

Overbreadth of Injunction

After a quick flashback to Streck, in which the Court dismissed R&D's appeal of priority and evidentiary ruling as controlled by the outcome of the first case, Streck II concluded rather anticlimactically. R&D argued that the permanent injunction entered by the District Court was over broad because it prohibited R&D "from otherwise infringing the asserted claims of [the Patents-in-Suit] until the expiration of the last to expire of the Patents-in-Suit." Specifically, R&D wanted the injunction limited to the adjudicated products, and products not more than colorably different therefrom. However, the Federal Circuit noted that the injunction as a whole did specifically refer to the products at issue in the case. Therefore, because the injunction already contained the limitation sought, the Federal Circuit affirmed the permanent injunction entered by the District Court.

In conclusion, even though it had its slow points, we would give Streck II two thumbs up, and would recommend it to most patent practitioners, especially those embroiled in litigation, trying to determine whether it is advantageous to narrow the scope of asserted claims.

Streck, Inc. v. Research & Diagnostic Systems, Inc. (Fed. Cir. 2012)
Panel: Circuit Judges Newman, O'Malley, and Reyna
Opinion by Circuit Judge O'Malley

Posted at 11:00 PM in Enablement, Federal Circuit, Injunction, Written Description | Permalink | Comments (0) | TrackBack (0)

August 10, 2011

Eli Lilly & Co. v. Actavis Elizabeth LLC (Fed. Cir. 2011)

By Kevin E. Noonan --

On the same day the Federal Circuit rendered its opinion in AMP v. USPTO (the Myriad case), the Court also handed down its opinion in Eli Lilly & Co. v. Activis Elizabeth LLC. In an opinion by Judge Newman, joined by Judge Lourie (Judge Friedman was on the panel, but died before the court reached its decision), the Federal Circuit reversed a District Court finding of invalidity based on the patentee's failure to satisfy the utility aspect of the enablement requirement of § 112, 1st paragraph ("The specification shall contain a written description of the invention . . . in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same. . ."), reversed the District Court's holding that, if held valid, defendants would be liable for inducing infringement but not contributory infringement, and affirmed in all other respects.

The defendants (Actavis Elizabeth LLC, Sun Pharmaceuticals Ltd., Sandoz Inc., Mylan Pharmaceuticals Inc., Apotex, Inc., Aurobindo Pharma, Ltd., and Teva Pharmaceuticals USA Inc.) each filed an Abbreviated New Drug Application (ANDA) on atomoxetine ((R)-(–)-N-methyl-3- (2-methylphenoxy)-3-phenylpropylamine), sold by Eli Lilly as Strattera® to treat attention deficit/hyperactivity disorder (ADHD). The patent-in-suit was U.S. Patent No. 5,658,590; specifically at issue was claim 1:

A method of treating attention- deficit/hyperactivity disorder comprising administering to a patient in need of such treatment an effective amount of tomoxetine.

Atomoxetine itself was known and patented by Eli Lilly & Co. in U.S. Patent No. 4,314,081, which expired in 1999. That patent disclosed urinary incontinence and depression as two uses for the drug; it was only in 1993 that Eli Lilly scientists suggested that atomoxetine could be used to treat ADHD. In this regard, the District Court found that "occurrence of ADHD is wide, the cause is unknown, and the mechanism of drug treatment unclear," all of which is exacerbated by the lack of an animal model. In addition, the '590 patent specification taught that treatments current at the time the invention was made were inadequate and "exhibited deficiencies" (including sudden death in children). Despite these deficiencies, testimony established that the Lilly scientists' suggestion that the drug be used to treat ADHD was "met with skepticism" and FDA approval took approximately 7 years.

The ANDAs filed by the defendants contained Paragraph IV certifications of invalidity (for obviousness, and lack of enablement based on scope and utility), unenforceability, and non-infringement (under both inducement to infringe and contributory infringement). The District Court held that none of the defendants had established invalidity for obviousness or lack of enablement based on scope, but that claim 1 of the '590 patent was invalid for failure to provide evidence that the claim was operable, i.e., the specification failed to satisfy the utility aspect of the enablement requirement. The basis for the District Court's decision was that the "utility [of the claimed method] was not established because experimental data showing the results of treatment of ADHD were not included in the specification." The question addressed by the Federal Circuit was the extent of disclosure required to satisfy this requirement of the statute. Lilly contended that disclosing the use of atomoxetine to treat ADHD was enough, while defendants contended (and the District Court agreed) that the claimed utility must be established by experimental evidence in the application as filed.

The Federal Circuit reversed, based on its determination that the District Court's finding that experimental data was required to be in the application as filed was error. Provided priority between inventors is not involved, the Court's opinion said that applicants are able to submit data "either before or after the patent application was filed," where after-filed evidence "can be used to substantiate any doubts as to the asserted utility since this pertains to the accuracy of a statement already in the specification." The Court's opinion reversing the District Court's finding of invalidity was based on the requirement that an assertion of utility must be accepted as sufficient to satisfy the utility requirement unless there is "some reason" for the skilled worker to question the "objective truth" of the asserted utility, citing In re Langer, 503 F.2d 1380, 1391 (CCPA 1974), In re Brana, 51 F.3d 1560 (Fed. Cir. 1995), and In re Marzocchi, 439 F.2d 220, 223 (CCPA 1971). From Brana, the Court quoted the requirement that "[o]nly after the PTO provides evidence showing that one of ordinary skill in the art would reasonably doubt the asserted utility does the burden shift to the applicant to provide rebuttal evidence sufficient to convince such a person of the invention's asserted utility," citing In re Bundy, 642 F.2d 430, 433 (CCPA 1981).

The Federal Circuit noted that the accuracy of the disclosed utility had not been questioned by the defendants, and that it was also undisputed that Lilly performed successful clinical trials after the patent application that resulted from the '590 patent was filed. And during prosecution, the examiner "did not require the submission of data" that ADHD could be treated with atomoxetine.

In assessing the adequacy of the disclosure of in the specification, the Federal Circuit opinion also noted that "[t]he utility of this product to treat ADHD is not so incredible as to warrant the special procedures that are authorized for use when the examiner doubts the described utility" or "for subject matter in once notoriously intractable areas such as cures for baldness or cancer." Here, "deference is owed to the 'qualified agency presumed to have done its job,'" citing Am. Hoist & Derrick Co. v. Sowa & Sons, Inc., 725 F.2d 1350, 1359 (Fed. Cir. 1984).

The opinion appears to restore to its traditional moorings the requirements for enablement that were called into question by the Court's decision in Janssen Pharmaceutica N.V. v. Teva Pharmaceuticals USA, Inc., 583 F.3d 1317 (Fed. Cir. 2009) (aka In re '318 Patent Litigation). In that case, the teachings that a specific compound, galantamine, could be used to treat Alzheimer's disease were found insufficient because "animal tests were 'not finished . . . by the time the '318 patent was allowed.'" The panel here distinguished the purported lack of an enabling disclosure in Janssen with the instant case, where the specification "contained a full description of the utility, experimental verification had been obtained before the patent was granted, and the examiner had not requested additional information." Here, the Court's opinion seems to be based on the existence of after-filing evidence sufficient for Lilly to rebut an assertion that the "objective truth of the asserted utility" would be doubted by the skilled worker.

Regarding the other asserted grounds of invalidity, the Federal Circuit affirmed the District Court finding that defendants had not established that the claimed invention was obvious. Defendants' obviousness argument was based on prior art that another compound -- desipramine, a norepinephrine inhibitor -- was used to treat ADHD and that atomoxetine was also to be a norepinephrine inhibitor. Thus, defendants argued that it would have been obvious to test atomoxetine for the treatment of ADHD. The District Court found this argument to be insufficient, because it is not permissible to "pick and choose" from references to find evidence supporting obviousness, while excluding other evidence (including serious side-effects from despiramine use) that would be necessary to appreciate what a reference "fairly suggests," citing In re Wesslau, 353 F.2d 238, 241 (CCPA 1965). The District Court also rejected defendants' argument that atomaxetine would have been "obvious to try" for treating ADHD; this determination was based on the Supreme Court's decision in KSR Int'l Co. v. Teleflex Inc. to the effect that "there was no evidence . . . the exercise of common sense would have led a person of ordinary skill to test atomoxetine for treatment of ADHD" (a conclusion supported by testimony from experts on both sides).

Defendants also argued that the specification did not enable the claimed method throughout its full scope, relating to the claim limitation directed to "administering to the patient an effective amount" of the drug for treating ADHD, because this limitation was not directed to the expressly disclosed formulations. Defendants presented expert testimony that undue experimentation would be required to determine particular formulations and effective amounts to be administered. The specification disclosed that oral formulations were preferred and contained generic disclosure of oral formulations, as well as ranges of preferred doses. Applying the rubrics of In re Wands, the District Court found that a person skilled in the art would be able to make formulations throughout the full scope of the claimed limitation through the exercise of no more than routine experimentation. In affirming this result, the Federal Circuit rejected defendants' argument based on ALZA Corp. v. Andrx Pharmaceuticals, LLC, 603 F.3d 935 (Fed. Cir. 2010) (where the claimed formulations were "a breakaway from the prior art"), and asserted the principle from Spectra-Physics, Inc. v. Coherent, Inc., 827 F.2d 1524, 1534 (Fed. Cir. 1987) that "a patent need not teach, and preferably omits, what is well known in the art."

Finally, the Federal Circuit reversed the District Court's finding that if claim 1 of the '590 patent was valid, the defendants were liable for inducing infringement under 35 U.S.C. § 271(b), but not contributory infringement under § 271(c). According to the Court, the possibility of "off-label" uses were irrelevant to the issue, since each defendant would be selling the generic product with an FDA-approved label directed to Lilly's claimed method. Moreover, since the only use for which the ANDA filers could sell the drug was the FDA-approved use, atomoxetine had no "substantial non-infringing use" and thus its sale also constituted contributory infringement under § 271(c).

Eli Lilly & Co. v. Actavis Elizabeth LLC (Fed. Cir. 2011)
Nonprecedential disposition
Panel: Circuit Judges Newman, Friedman, and Lourie
Opinion by Circuit Judge Newman
(The opinion notes that Circuit Judge Friedman heard oral argument in the appeal, but died on July 6, 2011, and did not participate in the final decision. The case was decided by the remaining judges on the panel, in accordance with Fed. Cir. Rule 47.11.)

Posted at 11:59 PM in Enablement, Federal Circuit, Infringement - Contributory or Induced | Permalink | Comments (0) | TrackBack (0)

September 07, 2010

Goeddel v. Sugano (Fed. Cir. 2010)

By Kevin E. Noonan --

Today the Federal Circuit reversed a priority determination in an interference over claims to human beta-interferon, in an opinion teeming with irony, déjà vu, anachronism, and the peculiar effects on outcome caused by the form of interference counts.

Two interferences, Nos. 105,334 and 105,337 between Junior Party David Goeddel and Robert Crea and Senior Party Haruo Sugano, Masami Muramatsu, and Tadatsigi Tanaguchi, were directed towards claims to isolated human DNA encoding beta-interferon (also termed "human fibroblast interferon" or hFIF in the opinion) as well as the isolated interferon protein itself. The "DNA Interference" was declared between Goeddel patent application No. 07/374,311 and Sugano patent Nos. 5,326,859 and 5,514,567 and contained one count:

A DNA encoding a mature human fibroblast interferon having a total of 166 amino acids of the sequence

Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu Thr Gly Tyr Leu Arg Asn

and unaccompanied by a human fibroblast interferon presequence.

The "Protein Interference" was declared between Sugano's application No. 08/463,757 and Goeddel's patent No. 5,460,811. The sole count of the "Protein Interference" is:

A composition comprising water and a nonglycosylated mature human fibroblast interferon polypeptide having a total of 166 amino acids and the following amino acid sequence

said composition being free of any glycosylated human fibroblast interferon.

In each interference, Junior Party Goeddel was given the benefit of priority to U.S. patent application Serial No. 06/190,799, filed September 25, 1980. Senior Party Sugano was given priority to a Japanese application, No. 33931/80, filed March 19, 1980. The Board of Patent Appeals and Interferences decided the priority question in favor of Sugano in each interference, based on its determination that the Japanese application constituted a constructive reduction to practice of an invention within the scope of each interference count.

On appeal, Goeddel argued that Sugano's Japanese priority application did not satisfy the enablement or written description requirements of 35 U.S.C. § 112, first paragraph; interference practice permits a party to rely on a prior, foreign filed application only if that application satisfies the requirement of § 112, first paragraph (Hyatt v. Boone, 146 F.3d 1348, 1351 (Fed. Cir. 1998)). The basis of Goeddel's argument is that both counts were directed to nucleic acids encoding or an isolated protein having the amino acid sequence of the "mature" (active) form of human beta-interferon. The mature form has the 166 amino acid sequence set forth in each of the interference counts, but beta-interferon DNA encodes a 187 amino acid (inactive) form that is produced in human cells and then specifically cleaved to produce the mature, active, 166 amino acid form (i.e., the first 21 amino acids of the immature form are removed from the protein to produce the mature form). The Sugano priority Japanese application disclosed this immature, 187 amino acid form (both the nucleic acid and protein) but did not disclose the mature, 166 amino acid form. Instead, the application referenced a scientific publication by Knight, entitled "Human Fibroblast Interferon: Amino Acid Sequence Analysis and Amino Terminal Amino Acid Sequence," which disclosed amino terminal protein sequencing that identified the first 13 amino acids of the mature form. The Sugano Japanese priority application disclosed production of human beta-interferon in bacteria, which do not specifically cleave the immature, 187 amino acid form into the mature, 166 amino acid form, and also does not disclose either the mature form nor the specific cleavage site that could be used to produce the mature form of human beta-interferon. (As quoted in the Federal Circuit's opinion, the Board found that "[t]he sequences of mature hFIF DNA or polypeptide are not explicitly disclosed.") Because of these deficiencies, Goeddel argued that Sugano's Japanese priority application did not satisfy the requirements of 35 U.S.C. § 112, first paragraph, was not a competent priority document, did not provide Sugano with an earlier priority date for either of the interference counts and thus that Goeddel should be awarded priority in both interferences.

The Board found (correctly, Sugano argued on appeal) that its disclosure in the Japanese priority application satisfied the enablement and written description requirements. For enablement, Sugano argued that the determination of whether a priority document satisfied the statutory requirements must take into consideration the knowledge of the person of ordinary skill in the art. ("[P]atent applications are 'written for a person of skill in the art, and such a person comes to the patent with the knowledge of what has come before,' [argued Sugano], and thus 'it is unnecessary to spell out every detail of the invention in the specification,'" citing Lizard Tech, Inc. v. Earth). Supplementing the express disclosure of the Japanese priority application with the knowledge from the art, including the disclosure of the Knight reference, would have been sufficient to enable the skilled worker to produce the mature form of beta-interferon, according to Sugano. The Board relied on testimony from a Goeddel expert, to the effect that "no new technology" would have been required for the skilled worker to produce the mature form in view of the disclosure of the Japanese priority application disclosing the immature, 187 amino acid form and the identification in the Knight reference of the "line of demarcation" between the 21 amino-terminal presequence and the amino terminus of the mature, 166 amino acid form. Regarding the written description requirement, the Board found, and Sugano argued, that the combination of the complete 187 amino acid immature sequence expressly disclosed in the Japanese priority application, and the disclosure by Knight of the amino terminal amino acids of the mature, 166 amino acid form of beta-interferon would permit the skilled worker to "envision" the mature form and thus satisfy the written description requirement. The Board stated that "although not explicitly described in the Japanese Application, 'the amino acid of, and DNA sequence encoding, mature hFIF would be readily apparent,'" and that "a person of skill in the field of the invention, reading the Japanese Application, would conclude that Sugano was in possession of the invention of the interference counts" (despite an admission by Sugano's expert that the Japanese priority application "does not state where the presequence ends and where the mature hFIF sequence begins").

The Federal Circuit disagreed with the Board and Sugano, in an opinion written by Judge Newman and joined by Judge Lourie and Judge Bryson. The Court rejected the standard that an application merely enable the skilled worker to "envision" the claimed invention to satisfy the requirement for constructive reduction to practice in an interference proceeding. "[C]onstructive reduction to practice 'is "not a question of whether one skilled in the art might be able to construct the patentee's device from the teachings of the disclosure. . . . Rather, it is a question whether the application necessarily discloses that particular device," according to the Federal Circuit opinion, citing Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326-27 (Fed. Cir. 2000) (quoting Jepson v. Coleman, 314 F.2d 533, 536 (CCPA 1963). "[I]n the context of interference priority, [Section 112] requires that the subject matter of the counts be described sufficiently to show that the applicant was in possession of the invention," said the Court, which in this case meant possession of the 166 amino acid, mature and active form of beta-interferon.

That a modified gene encoding the 166 amino acid protein could have been "envisioned" does not establish constructive reduction to practice of the modified gene. The question is not whether one skilled in this field of science might have been able to produce mature hFIF by building upon the teachings of the Japanese Application, but rather whether that application "convey[ed] to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) . . . The Japanese application does not describe a bacterial expression vector that directly produces the mature hFIF, nor does it suggest producing a modified gene to directly encode the 166 amino acid mature hFIF.

And thus, the Board erred in granting priority to Party Sugano, the Federal Circuit concluded. Sugano's attempts to support its claims with reference to the Court's decisions in Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 968 (Fed. Cir. 2002), and University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 923 (Fed. Cir. 2004), were similarly unavailing, the Court stating that "these cases do not hold that envisioning an invention not yet made is a constructive reduction to practice of that invention." The panel aded that "[p]recedent in evolving science is attuned to the state of the science, but remains bound by the requirement of showing 'that the inventor actually invented the invention claimed,'" citing Bradford Co. v. Conteyor North Am., Inc., 603 F.3d 1262, 1269 (Fed. Cir. 2010), and Fiers v. Revel, 984 F.2d 1164, 1170 (Fed. Cir. 1993).

Hence the irony, since "Fiers v. Revel" is the caption of an interference decision that is more properly styled "Fiers v. Revel v. Sugano," also involving an interference between Sugano and different parties almost twenty years ago. The Fiers v. Revel case is arguably the first case in the line of written description jurisprudence that goes through University of California v. Eli Lilly, Enzo Biochem., Rochester, and Ariad. Sugano prevailed in that interference, precisely because its priority document contained the nucleotide sequence of human beta-interferon where the other two parties' applications did not. Perhaps fittingly. Sugano lost this interference because its priority application could not satisfy the standards that its earlier interference helped to establish.

Goeddel v. Sugano (Fed. Cir. 2010)
Panel: Circuit Judges Newman, Lourie, and Bryson
Opinion by Circuit Judge Newman

Image of beta-interferon (above) by AJC1, from flickr under the Creative Commons license.

Posted at 11:59 PM in Enablement, Federal Circuit, Written Description | Permalink | Comments (0) | TrackBack (0)

September 06, 2010

Eli Lilly & Co. v. Teva Pharmaceuticals USA, Inc. (Fed. Cir. 2010)

By Kevin E. Noonan --

The old proverb "success has many fathers, while failure is an orphan" comes to mind when considering the Federal Circuit's decision in Eli Lilly & Co. v. Teva Pharmaceuticals USA, Inc. In the Court's decision, repeated failures, even by Lilly scientists in developing its osteoporosis drug Evista® (raloxifene hydrochloride), were sufficient to defeat Teva's counterclaim that patent claims related to methods of use were obvious.

The action arose following Teva's ANDA filing containing a Paragraph IV certification that the patents-in-suit were invalid (there was no discussion in the opinion of any inequitable conduct allegations below). The patents fell within three broad categories, and included the Bone Loss patents (U.S. Patent No. 6,906,086 and Reissue Patents Nos. RE39,049; and RE38,968), the Low Dose patent (Reissue Patent No. RE39,050) and the Particle Size patents (U.S. Patents Nos. 6,458,811 and 6,894,064). Specific claims representative of the patents-in-suit include the following:

Claim 1 of the '086 patent (Bone Loss patent):

A method of inhibiting post-menopausal bone loss in a post-menopausal woman in need of treatment to prevent or treat post-menopausal osteoporosis comprising administering a single daily oral dose to said woman of an effective amount of [raloxifene] hydrochloride.

Claim 14 of the '050 reissue patent (Low Dose patent):

A method of preventing post-menopausal osteoporosis in a post-menopausal woman in need of treatment to prevent post-menopausal osteoporosis comprising administering to said woman a hydrochloride salt of . . . [raloxifene] in an amount of 60 mg/day.

Claim 1 of the '811 patent (Particle Size patent; emphasis added):

A compound of formula I . . . [raloxifene] and pharmaceutically acceptable salts and solvates thereof, characterized in that the compound is in particulate form, said particles having a mean particle size of less than about 25 microns, at least about 90% of said particles have a size of less than about 50 microns.

The District Court (Judge Sarah Evans Parker) found the Bone Loss and Low Dose patents not invalid under §§ 103 and 112, 1st paragraph (enablement), but that the Particle patents were invalid for failing to satisfy the written description requirement under 112, 1st paragraph, and granted a permanent injunction keeping generic raloxifene hydrochloride off the market until Lilly's patents expire.

Relevant to the Federal Circuit's analysis was the developmental history of raloxifene. Originally pursued as an "antiestrogen" breast cancer treatment (similar in mode of action to tamoxifen), clinical experience with the drug showed low bioavailability in humans (despite significant bioavailability in experimental animals). This result appeared to be related to the presence of free hydroxyl groups in raloxifene that were modified by conjugation with glucaronide as part of the detoxification and elimination pathways in humans. The Court cited several prior art references disclosing low bioavailability and that raloxifene underwent "rapid metabolic conversion." These included the Buzdar reference (1988) that disclosed results showing that raloxifene elicited no complete or partial responses for breast cancer patients resistant to tamoxifen (although the reference did not directly attribute these results to low bioavailability). These bioavailability concerns regarding raloxifene were an express ground for the District Court to find that Lilly's claims for its Bone Loss and Low Dose patents were non-obvious, since the known low bioavailability for raloxifene would have precluded the skilled worker from having a reasonable expectation that the drug would be clinically useful for treating osteoporosis.

In its opinion, written by Chief Judge Rader joined by Judge Linn and Judge Prost, the Court affirmed the District Court's determination that Teva had not provided clear and convincing evidence that the claims of the Bone Loss or Low Dose patents were obvious. On appeal, Teva argued three prior art references in support of its obviousness arguments. U.S. Patent No. 5,075,321 (Schreiber patent) disclosed the use of raloxifene for treating autoimmune disorders (and according to the opinion was the basis for Lilly reissuing three of the patents-in-suit). The Court found that this reference did not provide clear and convincing evidence of obviousness, because osteoporosis is not an autoimmune disease, and the evidence suggested different mechanisms of action. "Without a closer relationship, Teva cannot show that an ordinarily skilled artisan would have expected Dr. Schrieber's article to have relevance for the treatment of postmenopausal osteoporosis," the Court said. The opinion also rejected Teva's argument that the reference is relevant for showing clinically-significant bioavailability for raloxifene, based on the different uses (osteoporosis versus autoimmune disorders) as well as the fact that what was prior art in the Schrieber reference was based on animal studies that did not address the bioavailability issue in humans.

The second reference, a scientific journal article by Jordan, disclosed rat studies on the effects of tamoxifen and raloxifene on bone density. According to the Court's opinion, "Dr. Jordan concluded that these results 'may have important implications for the clinical [human] applications of antiestrogens'" and that "'[i]t is possible . . . that in the future, tamoxifen could be considered to be used as a substitute for estrogen [for the prevention of osteoporosis in postmenopausal women]'" (emphasis added). The reference also contained an assertion calling for clinical investigation of the use of tamoxifen for treating osteoporosis. Unfortunately for Teva's argument, the Federal Circuit did not consider these teachings relevant for the use of raloxifene, because the reference suggested that tamoxifen, not raloxifene, be explored for use as an osteoporosis treatment. In addition, not only was the reference silent as to the bioavailability issue, but the opinion cited the District Court's reasoning that the Jordan reference "exemplified" the bioavailability concerns with raloxifene and that the skilled worker "'would not have had a reasonable expectation of success in using raloxifene to treat human postmenopausal osteoporosis.'" The Federal Circuit particularly faulted the portion of Teva's arguments relying on how Lilly scientists interpreted the Jordan results in support of its case for obviousness, since these inventors have greater than ordinary skill. In addition, the Lilly scientists possessed internal information relating to the capacity for conjugation of raloxifene to be reversed in vivo (resulting in improved bioavailability), but this knowledge was also unavailing in support of Teva's arguments the court held, relying on KSR Int'l. Co. v. Teleflex Inc. ("The question is not whether the combination was obvious to the patentee but whether the combination was obvious to a person of ordinary skill in the art.") Not expressly stated in the Court's opinion was the extent to which its determination was affected by Lilly scientists possessing information not within the knowledge of the worker of ordinary skill.

Finally, with regard to the Jones patent (which disclosed raloxifene), the opinion relied on this patent having been filed before any of the bioavailability results were obtained or concerns were raised, and that "[t]he record does not contain any reason that a person of ordinary skill would have ignored those later publications." The Court also said that further evidence, specifically the results of the "failed" Buzdar study, would have precluded the skilled worker from having a reasonable expectation of success using raloxifene. The Court rejected Teva's arguments that the Buzdar reference did not attribute its results to bioavailability issues, saying the skilled worker could draw that inference.

The Court came to the same conclusions and affirmed the lower court's non-obviousness determination for the claims of the Low Dose patent. On appeal, Teva also argued that these claims were invalid under the doctrine of obviousness-type double patenting, based in part on the District Court's finding that the nature of the experiments to determine a clinically-effective low dose were routine (in its analysis addressing Teva's enablement challenge to these claims). The Federal Circuit noted that this challenge was not raised below, and that the "record is insufficiently clear for it to conclude that the proper resolution is beyond any doubt." Possibly significant (in view of the several recent instances of claims being invalidated for obviousness-type double patenting), the Court expressly stated that the policy rationales raised by Teva (that these patents extended Lilly's exclusivity term for Evista®) were not great enough to overcome the procedural deficiencies.

Teva also challenged the Bone Loss and Low Dose patents in the District Court on enablement grounds, and the Federal Circuit also affirmed the District Court's determination that the claims of these patents were enabled. Teva's enablement challenge sounded in operability under 35 U.S.C. § 112, 1st paragraph (which the Court has held has its own utility requirement distinct from the utility requirement under § 101; In re Brana). Here, the opinion cites the Manual of Patent Examining Procedure for its provisions relating to the effect of human clinical trials on the question of operability raised under 35 U.S.C. § 112, 1st paragraph (i.e., that having an on-going clinical trial is evidence that the invention is sufficiently operable for patenting purposes):

Before a drug can enter human clinical trials, the sponsor, often the applicant, must provide a convincing rationale to those especially skilled in the art (e.g., the Food and Drug Administration) that the investigation may be successful. Such a rational would provide a basis for the sponsor's expectation that the investigation may be successful. In order to determine a protocol for phase I testing, the first phase of the clinical investigation, some credible rationale of how the drug might be effective or could be effective would be necessary. Thus, as a general rule, if an applicant has initiated human clinical trials for a therapeutic product or process, Office personnel should presume that the applicant has established that the subject matter of that trial is reasonably predictive of having the asserted therapeutic utility. MPEP (2008) § 2107.03 at IV (emphasis added).

The Court's opinion recognized that Teva's arguments relate to an inherent "Catch 22" regarding the relationship between the enablement requirement and the lack of a reasonable expectation of success in an obviousness determination:

To the extent that Teva revisits this [obviousness] argument in the enablement context, it appears to contend that Lilly's actions provide circumstantial evidence that an ordinarily skilled artisan would not have found helpful the facts on which the district court relied to hold that the patents are enabled. This court rejects that argument as well, and for essentially the same reason: it conflates the expertise of Lilly scientists with the knowledge of one of ordinary skill in the art. . . . Indeed, Lilly appears to have had many advantages that a person of ordinary skill would not have had, not the least of which was the FDA's prior approval of Lilly's IND application. Lilly's reliance on those advantages rather than its knowledge of Black's conjugate studies [relating to greater than expected bioavailability] to proceed with human trials does not create clear and convincing evidence that a person of ordinary skill would fail to find comfort in the latter.

The Federal Circuit also affirmed the District Court's finding that the asserted claims of the Particle Size patents were invalid for failure to satisfy the written description requirement of 35 U.S.C. § 112, 1st paragraph. These patents disclosed a range of particle sizes that increased bioavailability, wherein "within the claimed particle size range, the raloxifene particles provide 'surprisingly consistent in vivo absorption/bioavailability characteristics.'" The District Court construed the relevant claim language, "in particulate form," to include the size of the particles either in the pure active pharmaceutical ingredient (API) or in the tablet after formulation (which construction benefited Lilly's contention that the API had been prepared with easily-dissociated particles so that the API, but not the formulated tablet, would fall outside the scope of the Particle Size patent claims). Unfortunately for Lilly, however, the District Court found that the patent specifications did not disclose or describe determining particle size in the formulated tablet, and the Federal Circuit agreed:

[A]fter reading the patent, a person of ordinary skill in the art would not understand how to extract raloxifene particles from a formulation in order to determine whether they fall within the claimed particle size range and, in fact, would have no indication that size measurements on anything other than unformulated raloxifene would bear any relevance to the invention.

The Court affirmed, because since satisfaction of the written description requirement is a question of fact, it could not find that the District Court's decision was clearly erroneous, in particular due to admissions by Lilly's own expert regarding whether these embodiments were disclosed.

Since the Federal Circuit affirmed the District Court's decision that neither the Bone Loss nor the Low Dose patents are invalid, the injunction preventing Teva from providing generic raloxifene hydrochloride stands until expiration of the last expiring of these patents (March 2, 2014).

Eli Lilly & Co. v. Teva Pharmaceuticals USA, Inc. (Fed. Cir. 2010)
Panel: Chief Judge Rader and Circuit Judges Linn and Prost
Opinion by Chief Judge Rader

Posted at 11:48 PM in Double Patenting, Enablement, Federal Circuit, Obviousness, Written Description | Permalink | Comments (1) | TrackBack (0)

May 03, 2010

ALZA Corp. v. Andrx Pharmaceuticals, LLC (Fed. Cir. 2010)

By Andrew Williams --

Last week, in ALZA Corp. v. Andrx Pharms., LLC, the Federal Circuit affirmed the U.S. District Court for the District of Delaware's decision that ALZA's patent related to treating Attention Deficit and Hyperactivity Disorder ("ADHD") was invalid for lack of enablement. ALZA markets the drug Concerta® for the treatment of ADHD, which releases methylphenidate after ingestion at an ascending rate over an extended period of time. Methylphenidate is the same active ingredient as found in Ritalin®. However, because Ritalin® is an immediate-release formulation, it had to be administered two to three times a day. And, as many of the patients that took Ritalin® were children, at least one of these doses had to be administered during the school day. As a result, there was a desire to create a once-a-day method of treating ADHD by developing a sustained or controlled-release dosage form, also known as an extended-release formulation.

ALZA undertook to create such a dosage form. It discovered after a series of clinical trials that MPH plasma concentrations that had ascending patterns had greater efficacy than when concentrations were constant. ALZA was able to use this information to develop a safe and effective once-a-day extended release oral dosage form. Subsequently, ALZA obtained U.S. Patent No. 6,919,373 ("the '373 patent"), whose only independent claim reads: "A method for treating ADD or ADHD comprising administering a dosage form comprising methylphenidate that provides a release of methylphenidate at an ascending release rate over an extending period of time." ALZA spent most of its effort developing an osmotic dosage form, and therefore the '373 patent specification focused on adapting osmotic systems to create ascending release dosage forms. However, the '373 patent did mention non-osmotic dosage forms.

Andrx filed an Abbreviated New Drug Application ("ANDA") to sell a generic version of Concerta®. However, Andrx asserted that its product did not infringe the '373 patent. It is likely that Andrx believed that its ANDA product was a non-osmotic dosage form, because it attempted to limit the scope of the claims to osmotic dosage forms. Nevertheless, the District Court construed the claims to include both osmotic and non-osmotic dosage forms. ALZA successfully argued for the broader claim interpretation, but ultimately it was because the claims were construed broadly that they were found to be invalid. The District Court held that the asserted claims were invalid for lack of enablement because the specification did not enable the full scope of the claims, namely non-osmotic dosages forms.

The issue presented to the Federal Circuit was whether the specification would have enabled a person of ordinary skill in the art to create non-osmotic oral dosage forms (such as tablets and capsules) with ascending release rates without undue experimentation at the time of filing. As with all cases dealing with undue experimentation, the Court looked at the Wands factors, and agreed with the District Court that seven of the eight factors weighed in favor of undue experimentation. One of the most significant reasons identified by the Federal Circuit was that the specification did not contain "such full, clear, concise, and exact terms as to enable any person skilled in the art" to make and use such non-osmotic oral dosage forms. ALZA pointed to the specification that contained a ten-line disclosure of various non-osmotic forms with a reference to a textbook that discusses how to make and use these forms. The problem, however, was not that the claims encompassed non-osmotic forms themselves, but that the claims included a functional limitation -- the non-osmotic oral dosage forms were required to have ascending release rates. And, ALZA was trying to rely on the knowledge of a person of ordinary skill to serve as a substitute for missing information in the specification. Interestingly, ALZA argued that a person skilled in the art could derive this functional limitation if they engaged in an iterative, trial-and-error process. Apparently, however, according to the Federal Circuit, iterative, trial-and-error is undue experimentation.

ALZA also challenged the District Court's reliance on the testimony of the fact and expert witnesses. ALZA's expert witness, Dr. Martyn Davies, testified that the experimentation required to obtain non-osmotic dosage forms was routine. However, the level of skill upon which his analysis was based was at a level higher than the one the District Court adopted. In addition, ALZA challenged the testimony of its own employees, who explained that ALZA had been unable to develop these "routine" non-osmotic dosage forms. Specifically, ALZA argued that at least one of these employees was not skilled in the art. However, the Federal Circuit found the level of the employees' knowledge to be irrelevant, because their testimony related to ALZA's difficulty in creating a non-osmotic form, not to the knowledge of one skilled in the art.

The Federal Circuit commented on the irony that it was precisely because ALZA argued for broader claim construction that its claims were found to be invalid. The Court failed, however, to mention that ALZA may have been required to argue for the broader construction in order for the claims to cover Andrx's ANDA product. Nevertheless, one lesson to be learned from this case is that you better be careful what you ask for, because you might not like what you get.

ALZA Corp. v. Andrx Pharmaceuticals, LLC (Fed. Cir. 2010)
Panel: Circuit Judges Dyk, Schall, and Prost
Opinion by Circuit Judge Prost

Posted at 11:25 PM in Enablement, Federal Circuit | Permalink | Comments (2) | TrackBack (0)

September 29, 2009

In re '318 Patent Infringement Litigation (Fed. Cir. 2009)

By Donald Zuhn --

Last week, a divided panel of the Federal Circuit affirmed a determination by the District Court for the District of Delaware that the claims of U.S. Patent No. 4,663,318 were invalid for lack of enablement. The '318 patent, which issued on May 5, 1987 from U.S. Application No. 06/819,141, is directed to a method for treating Alzheimer’s disease with galanthamine. The lone independent claim of the '318 patent recites:

1. A method of treating Alzheimer's disease and related dementias which comprises administering to a patient suffering from such a disease a therapeutically effective amount of galanthamine or a pharmaceutically-acceptable acid addition salt thereof.

The majority opinion notes that at the time the '141 application was filed (January 1986), researchers had observed a correlation between Alzheimer’s disease symptoms and a reduced level of the neurotransmitter acetylcholine in the brain (acetylcholine is released by a transmitting neuron and binds to nicotinic receptors and muscarinic receptors on a receiving neuron). The majority opinion also notes that at the time the '141 application was filed, the small molecule galanthamine (at right; also known as galantamine) was known to inhibit acetylcholinesterase, an enzyme that breaks down acetylcholine. The majority opinion states that the specification for the '318 patent is "only just over one page in length" and provides "almost no basis for its stated conclusion that it was possible to administer 'an effective Alzheimer's disease cognitively-enhancing amount of galanthamine.'" The majority opinion also states that the specification provides "short summaries" of six scientific papers in which galanthamine had been administered to humans or animals, but "did not provide analysis or insight connecting the results of any of these six studies to galanthamine's potential to treat Alzheimer's disease in humans" or "refer to any then-existing animal test results involving the administration of galantamine in connection with this animal model of Alzheimer's disease."

During prosecution of the '318 patent, the examiner rejected the claims for indefiniteness and obviousness. In attempting to overcome the rejection, the inventor, Dr. Bonnie Davis, informed the Patent Office that "experiments [are] underway using animal models which are expected to show that treatment with galanthamine does result in an improvement in the condition of those suffering from Alzheimer's disease," and that it was "expected that data from this experimental work will be available in two to three months and will be submitted to the Examiner promptly thereafter." The majority opinion notes that the results of these experiments were not known until July 1987, after the '318 patent issued, that the studies "required several months and considerable effort by researchers at the Johns Hopkins University," and that the results were never submitted to the Patent Office. In November 1995, Dr. Davis licensed the '318 patent to Plaintiffs-Appellants Janssen Pharmaceutica N.V., Janssen L.P., and Synaptech, Inc. (Janssen).

Seeking approval to market a generic version of Janssen's galanthamine-based therapeutic for treating mild to moderate Alzheimer's disease, several generic drug manufacturers filed Abbreviated New Drug Applications (ANDAs) with the FDA. In response, Janssen filed infringement suits against each ANDA filer. These infringement suits were consolidated.

Following a bench trial, the District Court determined that the '318 patent was invalid for lack of enablement. The District Court based its determination on two grounds: (1) the specification of the '318 patent did not demonstrate utility because relevant animal testing experiments were "not finished . . . by the time the '318 patent was allowed" and the specification provided only "minimal disclosure" of utility, and (2) the specification and claims did not "teach one of skill in the art how to use the claimed method" because the application "only surmise[d] how the claimed method could be used" without providing sufficient galanthamine dosage information.

Writing for the majority, Judge Dyk, joined by Judge Mayer, cites Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1358 (Fed. Cir. 1999), for the proposition that "a patent claim [that] fails to meet the utility requirement because it is not useful or operative, . . . also fails to meet the how-to-use aspect of the enablement requirement." Judge Dyk observes that "[t]ypically, patent applications claiming new methods of treatment are supported by test results," adding that "[o]ur predecessor court held in Krimmel [292 F.2d 948, 954 (CCPA 1961)] that animal tests showing that a new nonobvious compound 'exhibits some useful pharmaceutical property' are sufficient to demonstrate utility" and that "under appropriate circumstances, . . . the first link in the screening chain, in vitro testing, may establish a practical utility for the [pharmaceutical] compound in question," citing Cross v. Iizuka, 753 F.2d 1040, 1051 (Fed. Cir. 1985).

In affirming the District Court's judgment of invalidity for lack of enablement, Judge Dyk states that:

In this case, however, neither in vitro test results nor animal test results involving the use of galantamine to treat Alzheimer's-like conditions were provided. The results from the '318 patent's proposed animal tests of galantamine for treating symptoms of Alzheimer's disease were not available at the time of the application, and the district court properly held that they could not be used to establish enablement.

In addition, Judge Dyk notes that Janssen did not contend, either during prosecution or at trial, that the six scientific papers discussed in the specification of the '318 patent established utility. Instead, Janssen argued on appeal that utility may be established by analytic reasoning. In particular, Janssen argued that the specification "set[] forth the evidence from existing studies demonstrating galantamine's effects on central nicotinic as well as muscarinic receptors and connect[ed] it to a model for Alzheimer's therapy rendering those effects therapeutically relevant." Judge Dyk, however, states that "[t]hese insights . . . are nowhere described in the specification." He also states that "at the end of the day, the specification, even read in the light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis," which is "not sufficient." Judge Dyk, therefore, concludes that "[t]he '318 patent's description of using galantamine to treat Alzheimer’s disease thus does not satisfy the enablement requirement because the '318 patent's application did not establish utility."

Writing in dissent, Judge Gajarsa contends that District Court's determination of non-enablement should have been vacated because the lower court "did not undertake the required legal analysis to determine whether an ordinarily skilled artisan reading the patent would understand it to reveal a credible utility for the invention," and further, "failed to make the factual findings necessary to support the ultimate legal conclusion regarding enablement." Noting that "[t]he parties do not dispute that Dr. Davis's insight regarding galantamine's utility for treating Alzheimer's Disease (AD) was correct," Judge Gajarsa states that "[t]he relevant question here is whether, at the time Dr. Davis filed her application, the patent's written description would have credibly revealed to an ordinarily skilled artisan galantamine's utility for AD treatment."

With respect to the issues of obviousness and enablement, Judge Gajarsa argues that:

In terms of the present case, if Dr. Davis used her unique neuroendocrine perspective to examine the prior art and arrive at a novel insight about galantamine based on selected prior art findings, then the invention may be nonobvious; and if her patent disclosed those selected findings in such a manner that a person of ordinary skill would credit her insight regarding galantamine's utility, then the invention is enabled.

However, in the instant case:

[T]he district court committed error . . . by focusing generally on what the prior art does or does not teach -- the primary factual consideration underlying obviousness -- while neglecting to consider what the patent text discloses to an ordinarily skilled artisan -- the primary factual consideration underlying enablement.

In particular, Judge Gajarsa contends that the District Court failed to "determine how one of ordinary skill would understand [the findings of the six prior art studies described in the specification], either independently or in combination with one another."

Judge Gajarsa also finds fault with "the majority opinion's emphasis on the sufficiency of the evidence presented by Janssen." Stating that "the majority fails to establish the defendants' burden and instead focuses almost exclusively on the sufficiency of Janssen's showing and the merit of Janssen's arguments," Judge Gajarsa argues that such focus is improper. Moreover, "[b]ecause the district court erred as a matter of law and failed to make certain required factual findings," Judge Gajarsa contends that "we cannot defer to the district court's legal conclusion or fact-findings, and thus, it is particularly problematic for the majority to require Janssen to demonstrate on appeal that its patent is valid."

In re '318 Patent Infringement Litigation (Fed. Cir. 2009)
Panel: Circuit Judges Mayer, Gajarsa, and Dyk
Opinion by Circuit Judge Dyk; dissenting opinion by Circuit Judge Gajarsa

Posted at 11:59 PM in Enablement, Federal Circuit | Permalink | Comments (10) | TrackBack (0)

October 07, 2008

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.

Aventis_pharmaceuticals 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.

Impax_laboratories 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.

Rilutek 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."

Federal_circuit_seal_2 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.

Posted at 11:56 PM in Enablement, Federal Circuit, Novelty | Permalink | Comments (0) | TrackBack (0)

April 06, 2008

Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc. (Fed. Cir. 2008)

By Donald Zuhn --

Orthomcneil Last week, the Federal Circuit determined that the District Court for the District of New Jersey properly construed claim 1 of U.S. Patent No. 4,513,006 to encompass Plaintiff-Appellee Ortho-McNeil Pharmaceutical, Inc.'s epilepsy drug topiramate, and affirmed the District Court's decision to (1) permanently enjoin Defendants-Appellees Mylan Laboratories, Inc. and Mylan Pharmaceuticals, Inc. (Mylan) from infringing the '006 patent, (2) dismiss Mylan's invalidity defenses based on inequitable conduct, obviousness, and non-enablement, and (3) reset the effective date of Mylan's Abbreviated New Drug Application (ANDA).

Topiramate_pills Ortho-McNeil manufactures and sells TOPAMAX®, which is used to treat epilepsy and which comprises the active ingredient topiramate. Ortho-McNeil researcher Dr. Bruce Maryanoff invented topiramate during a search for new antidiabetic drugs, discovering that the reaction intermediate topiramate had unexpected anticonvulsant properties.

Mylan Seeking approval to market generic topiramate, Mylan filed an Abbreviated New Drug Application (ANDA) with the FDA. In response, Ortho-McNeil filed an infringement suit under 35 U.S.C. § 271(e)(2) in the District Court of New Jersey.

Following a Markman hearing, the District Court rejected Mylan's construction of claim 1 as excluding topiramate. On summary judgment, the District Court also rejected Mylan's affirmative defenses of invalidity based on obviousness and non-enablement and unenforceability due to inequitable conduct. As a result of these determinations, the District Court enjoined Mylan from infringing the '006 patent and reset the effective date of Mylan's ANDA.

On appeal, Mylan argued that the District Court improperly construed the word "and" in claim 1 of the '006 patent, which recites:

According to Mylan, the phrase "R2, R3, R4 and R5 are independently hydrogen or lower alkyl and R2 and R3 and/or R4 and R5 together may be a group of formula (II)" in claim 1 specifies two independent limitations:

[1] R2, R3, R4 and R5 are independently hydrogen or lower alkyl and
[2] R2 and R3 and/or R4 and R5 together may be a group of formula (II),

both of which must be met for a compound to infringe the claim. In topiramate (at left), R2 and R3 and R4 and R5 together are a group of formula (II), and therefore, none of R2, R3, R4 and R5 are hydrogen or lower alkyl. Mylan argues that when claim 1 is properly construed, it does not encompass topiramate.

The Federal Circuit disagreed with Mylan's construction, finding that the District Court properly interpreted claim 1. According to the CAFC, the term "and appears in conjunction with the adverbs independently and together," and therefore, "links alternatives that occur under the different conditions of independence or togetherness." In other words, R2, R3, R4 and R5 need not always be hydrogen or lower alkyl.

In support of this construction, the Federal Circuit noted that if the term "and" were construed to require a conjunctive meaning, dependent claims 2, 5, 9, and 10 would be rendered meaningless. The CAFC also noted that the specification supported the above construction. Finally, while stating that it need not consult extrinsic evidence, given the plain language of claim 1, the dependent claims, and the specification, the Federal Circuit pointed out that "dictionary definitions of [the term] and, while most often listing the additive sense as the most common usage of the term, also show usage of the term to connote alternatives."

With respect to the issue of unenforceability, the Federal Circuit rejected Mylan's argument that during prosecution of the '006 patent, Ortho-McNeil made statements about prior art compounds that were inconsistent with its own testing of those compounds. Instead, the CAFC agreed with the District Court that Ortho-McNeil "merely accurately characterizes the references as claiming limited utility."

The Federal Circuit also rejected Mylan's arguments for invalidity. As to obviousness, the CAFC stated that "this invention, contrary to Mylan's characterization, does not present a finite (and small in the context of the art) number of options easily traversed." Moreover, "the ordinary artisan in this field would have had to (at the time of invention without any clue of potential utility of topiramate) stop at that intermediate and test it for properties far afield from the purpose for the development in the first place (epilepsy rather than diabetes)." As to Mylan's assertion that claims 6-8 are not enabled, the Federal Circuit again agreed with the District Court, stating that it would not require undue experimentation to determine an "anticonvulsively effective amount" of topiramate.

Finally, with respect to Mylan's argument that the District Court's order resetting the effective date of Mylan's ANDA was inconsistent with 21 U.S.C. § 355(j)(5)(B)(iii), the Federal Circuit determined inter alia that 21 U.S.C. § 355 is directed to the FDA and does not limit a court's authority to reset the effective date of an ANDA that is approved before the court grants a preliminary injunction or finds infringement, as in the instant case.

Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc. (Fed. Cir. 2008)
Panel: Chief Judge Michel and Circuit Judges Rader and Linn
Opinion by Circuit Judge Rader

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

Posted at 11:15 PM in Claim Construction, Enablement, Federal Circuit, Obviousness | Permalink | Comments (0) | TrackBack (0)

November 04, 2007

Pharmaceutical Res., Inc. v. Roxane Labs., Inc. (Fed. Cir. 2007)

By Donald Zuhn --

On October 26th, the Federal Circuit affirmed a District Court's finding on summary judgment that certain claims of U.S. Patent Nos. 6,593,318 (the '318 patent) and 6,593,320 (the '320 patent) were invalid under 35 U.S.C. § 112, first paragraph, for lack of enablement.

Par_pharmaceutical The '318 and '320 patents are directed to stable flocculated suspensions of megestrol acetate (see below) and methods for making such suspensions. Seeking to design around a patent owned by Bristol-Myers Squibb (BMS) and directed to stable suspensions of megestrol acetate, Plaintiffs-Appellants Pharmaceutical Resources, Inc. and Par Pharmaceuticals, Inc. (Par) discovered that flocculated suspensions of megestrol acetate could be formed using a wider array of ingredients (i.e., surfactants and wetting agents) and concentrations than disclosed in the BMS patent (the BMS patent discloses only one stable flocculated megestrol acetate suspension). Par received a number of patents for its flocculated megestrol acetate suspensions, including the '318 and '320 patents.

Roxanelogo Par brought suit against Defendant-Appellee Roxane Laboratories, Inc. (Roxane) in 2003, asserting that Roxane infringes certain claims of the '318 and '320 patents. Following the District Court's Markman order, Roxane moved for summary judgment of invalidity, arguing that the '318 and '320 patent were invalid for lack of enablement. The District Court granted Roxane's motion for summary judgment of invalidity, finding that "as a matter of law Par is not entitled to the broad claims it asserts in this action."

Megacees1 On appeal, the Federal Circuit determined that "[t]he scintilla of evidence put forward by Par to suggest that the claims are enabled, most of which actually conflicts with the intrinsic evidence in this case, does not raise a genuine issue of material fact." In particular, the Federal Circuit noted that both the '318 and '320 patents disclosed that "[t]he surfactants in a stable flocculated suspension need to be selected carefully and be used within a critical concentration range because even minor changes can have an effect on the properties of such a stable formulation." However, the Federal Circuit found that while Par's patents describe the unpredictability of flocculated megestrol acetate suspensions, the patents disclose only three working examples, utilizing only one surfactant not described in the BMS patent.

The Federal Circuit also noted that the extrinsic evidence supported a conclusion that the preparation of flocculated megestrol acetate suspensions is unpredictable. For example, "Dr. Chao, a named inventor of the '318 and '320 patents, testified that predictions could not be made regarding whether or not particular combinations of ingredients including megestrol acetate would form a stable flocculated compound, but rather, this required actual experimentation."

In rejecting Par's argument that its own experiments with megestrol acetate are sufficient to create a genuine issue of material fact regarding enablement, the Federal Circuit concluded that given the teachings in the patent about the criticality of the choice of surfactant and concentration:

the extraordinarily broad scope of the claims, which encompasses hundreds of surfactants, the high degree of unpredictability of the art, and the minimal guidance provided by the three working examples in the specification, the mere fact that Par's inventors were able to create successfully a stable flocculated megestrol acetate suspension with seven surfactants does not create a genuine issue of material fact regarding enablement.

Thus, the Federal Circuit determined that the asserted claims of the '318 and '320 patents were invalid under 35 U.S.C. § 112, first paragraph, for lack of enablement.

Pharmaceutical Res., Inc. v. Roxane Labs., Inc. (Fed. Cir. 2007)
Nonprecedential disposition
Panel: Chief Judge Michel, Circuit Judge Moore, and District Judge Cote
Opinion by Circuit Judge Moore

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

Posted at 11:48 PM in Enablement, Federal Circuit | Permalink | Comments (0) | TrackBack (0)

October 07, 2007

Monsanto Co. v. Syngenta Seeds, Inc. (Fed. Cir. 2007)

By Kevin E. Noonan --

Monsanto_2 The Federal Circuit last week clarified two frequently-disputed areas of patent prosecution: how to claim progeny of inventions that inherently self-replicate, and how to appropriately fulfill both the written description and enablement requirements of 35 U.S.C. § 112, first paragraph, and at the same time disclose broadly enough to support claims of appropriate breadth.

Logo_dekalb Monsanto Co. and its wholly-owned subsidiary, DeKalb Genetics Corp., sued Syngenta Seed Co. for infringing patents relating to transgenic corn seed, specifically corn resistant to Monsanto's RoundUp®-brand insecticide (glyphosate) by expressing Agrobacterium 5-enolpyruvoyl-shikimate-3- phosphate synthetase (EPSPS). The patents at issue were U.S. Patent No. 4,940,835, claiming a chimeric plant gene that confers glyphosate resistance; U.S. Patent No. 5,538,880, claiming methods for producing herbicide-resistant and insect-resistant corn (Zea mays) plants; and U.S. Patent No. 6,013,863, claiming methods for producing glyphosate-resistant transgenic corn using a screenable marker gene. The alleged infringing acts were producing transgenic corn using seed harvested from transgenic corn obtained from Monsanto under a license that precluded harvesting seed for replanting (said licenses were to Monsanto licensee companies acquired by Syngenta, at least some of whom were named as defendants).

Claim 1 of the '835 patent reads:

1. A chimeric plant gene which comprises:
(a) a promoter sequence which functions in plant cells;
(b) a coding sequence which causes the production of RNA, encoding a chloroplast transit peptide/5-enolpyruvylshikimate-3- phosphate synthase fusion polypeptide, which chloroplast transit peptide permits the fusion polypeptide to be imported into a chloroplast of a plant cell; and
(c) a 3' non-translated region which encodes a polyadenylation signal which functions in plant cells to cause the addition of polyadenylate nucleotides to the 3' end of the RNA;
the promoter being heterologous with respect to the coding sequence and adapted to cause sufficient expression of the fusion polypeptide to enhance the glyphosate resistance of a plant cell transformed with the gene.

Claim 4 of the '880 patent reads:

4. A process comprising obtaining progeny from a fertile transgenic plant obtained by the process of claim 1 which comprise said DNA.

Claim 5 of the '863 patent reads:

5. The process of claim 1 further comprising obtaining transgenic glyphosate resistant progeny plants of subsequent generations from said fertile transgenic plant.

The District Court granted summary judgment to Syngenta on invalidity of the '835 patent and non-infringement of the '880 and '863 patents. The District Court found the '835 invalid for failing to satisfy the enablement requirement, because the asserted claims encompassed all plant cells, and while the patent enabled genetic transformation of dicotyledonous plants it was filed prior to the time that methods were known in the art for genetically-transforming monocots. The patent specification not providing methods for transforming monocots, while the claims encompassed monocots, rendered the specification non-enabling throughout the scope of the asserted claims.

With regard to infringement, the District Court found that the asserted claims of the '880 and '863 patents required not merely the step of obtaining transgenic progeny but also the process of producing the transgenic plant in the first place, based on the dependent-claim structure of the asserted claims of these patents. It was undisputed that DeKalb had produced the transgenic plants initially and had thus performed these steps recited by the claims. In addition, the District Court found that Syngenta had lawfully obtained the disputed seed through acquisition of the named defendant subsidiaries, and that part of that right included the right to further produce progeny transgenic plants comprising the resistance gene.

Federal_circuit_seal The Federal Circuit unanimously affirmed in an opinion by Judge Rader. The CAFC rejected both of Monsanto's theories of infringement: first, that claim 4 of the '880 patent was an independent claim and did not require performance of the steps recited in earlier claims; or second, that performance of the transgenic plant production steps by DeKalb did not preclude a finding of Syngenta's infringement by performing the ultimate step of obtaining the progeny transgenic plants. Regarding Monsanto's first theory, the Federal Circuit stated that claim 4 of the '880 patent and claim 5 of the '863 patent were cast in the conventional form of dependent claims. This is not sufficient, according to the Federal Circuit, and the CAFC analyzed these claims with regard to whether they not only referenced at least one earlier claim but further limited the referent claim (pursuant to 35 U.S.C. § 112, fourth paragraph). In this analysis, the Federal Circuit held that claim 4 fulfilled the statutory requirements of a dependent claim, and further stated that while Monsanto could have presented claim 4 as merely requiring the product of process claim 1 as a starting material, it had not. The prosecution history supported this interpretation, as the claim as originally presented was "unquestionably" a dependent claim, and the patentees had asserted that amendments made to cast the claim into the form that issued as claim 4 were "directed to matters of form not affecting the scope of the invention" and did not introduce new matter. The Federal Circuit also rejected Monsanto's contention, made during oral argument, that claim 1 was a product-by-process claim and thus merely provided a starting material for the process of claim 4.

Having affirmed the District Court's determination that claims 4 (of the '880 patent) and 5 (of the '863 patent) were dependent claims, the Federal Circuit held that Syngenta's performance merely of the ultimate step of the properly-construed process claim was not infringement as a matter of law. The principle is simple: although an independent claim may be infringed while its dependent claim is not, the converse is not true. Wahpeton Canvas Co., Inc. v. Frontier, Inc., 870 F.2d 1546, 1552 (Fed. Cir. 1989). Here, it was undisputed that the steps comprising the independent claims of both asserted patents were performed not by the accused infringer Syngenta, but by Monsanto or DeKalb. Thus, since Syngenta did not infringe these independent claims, it could not infringe the asserted dependent claims. Moreover, the steps of the corresponding independent claims were practiced by Monsanto or DeKalb prior to grant of either of the asserted patents. Accordingly, this activity did not support Monsanto's infringement claims (made under both § 271(a) and § 271(g)).

Turning to the District Court's invalidity decision, the Federal Circuit focused, as had the District Court, on the term "plant cells" in claim 1 of the '835 patent. The CAFC adopted the lower court's construction of this term to include both monocots and dicots as "plant cells." Analogizing to the factual circumstances of In re Vaeck, the Federal Circuit agreed with the District Court that there was no basis in the patent specification to limit the term "plant cells" and thus both monocots and dicots properly fell within the scope of the claims. Unfortunately for Monsanto, however, it was undisputed that genetic transformation of monocotyledonous plants was not known in the art, nor disclosed in the patent specification, at the '835 patent's filing date. Thus, the practice of the invention claimed in the '835 patent throughout its entire scope, as required by the statute, would require undue experimentation. The Federal Circuit affirmed this conclusion despite the fact that the claims in dispute were not directed to plant cells per se, but to chimeric genes and constructs comprising them. The CAFC stated that this distinction was not dispositive, since the capacity to be expressed in "plant cells" was a required feature of the claimed chimeric genes.

What lessons can the biotechnology patent practitioner take from this decision? First, it is evident that extreme caution should accompany claim drafting dependent on process steps, even should those process steps be necessary to overcome prior art or to fulfill the requirements of § 112. As noted by the Federal Circuit, the outcome might have been different had claim 4 of the '880 patent recited a claim such as: "A process comprising obtaining progeny from a fertile transgenic plant comprising a chimeric gene encoding a chloroplast transit peptide/5-enolpyruvylshikimate-3-phosphate synthase fusion polypeptide expressed at a level sufficient to increase the plant's resistance to glyphosate," or even better, "Progeny of a fertile transgenic plant comprising a chimeric gene encoding a chloroplast transit peptide/5-enolpyruvylshikimate-3- phosphate synthase fusion polypeptide expressed at a level sufficient to increase the plant's resistance to glyphosate." Either of these claims would be free of any process steps that could raise issues with regard to performance of any steps other than the steps Syngenta certainly performed in this case, i.e., producing progeny of Monsanto's transgenic plants.

Second, attempts made during claim drafting to accommodate the Federal Circuit's focus on the written description requirement over the past decade, coupled with the desire to provide a sufficiently broad disclosure to encompass the broadest scope of the invention, must be balanced by a consideration of whether such scope is enabled either explicitly in the specification or by the skill of one having ordinary skill in the art. In the Monsanto case the issue was one of technique: monocots could not be genetically transformed, so claims not limited to dicots could not be enabled. It is foreseeable that in other instances unknown reagents or genes could be implicated, particularly for unrecognized members of known multigene families. In any event, it behooves patent claim drafters to consider carefully the relationship between what is described and what is enabled to avoid the outcome suffered by Monsanto.

Monsanto Co. v. Syngenta Seeds, Inc. (Fed. Cir. 2007)
Panel: Circuit Judges Rader and Gajarsa and District Judge O'Malley
Opinion by Circuit Judge Rader

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

Posted at 11:35 PM in Enablement, Infringement - Literal or DOE | Permalink | Comments (0) | TrackBack (0)

October 27, 2006

Ex parte Bandman (B.P.A.I. 2004)

By Donald Zuhn --

In an appeal from a final rejection of claims 3, 6, 7, 9, and 12 of U.S. Application No. 09/915,694, the Board of Patent Appeals and Interferences reversed the rejection of the claims under both the written description and enablement requirements of 35 U.S.C. § 112, first paragraph, and entered a new ground of rejection under 35 U.S.C. § 112, second paragraph, for claim 12.

Claims 3 and 12 of the '694 application, which were representative of the subject matter on appeal, recite, inter alia, an isolated polynucleotide encoding a polypeptide comprising a naturally occurring amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 1 (claim 3) and an isolated polynucleotide comprising a naturally occurring polynucleotide sequence at least 95% identical to the polynucleotide sequence of SEQ ID NO: 2 (claim 12).

The Examiner had rejected claims 3, 6, 7, 9, and 12 for failing to comply with the written description requirement, asserting that the specification provides only a single representative species -- the polynucleotide of SEQ ID NO: 2, and fails to disclose any structure-function relationship in this species. The Examiner had also rejected claims 3, 6, 7, 9, and 12 for failing to comply with the enablement requirement, asserting that because the specification does not teach the specific amino acids and structural motifs in the proteins encoded by the claimed polynucleotides that are essential for protein activity (specifically, malate dehydrogenase activity), the amount of experimentation required to make the claimed polynucleotides was undue. Appellants contended that because the claims at issue recite polynucleotides having a naturally occurring polynucleotide sequence, or that encode a polypeptide having a naturally occurring amino acid sequence, "through the process of natural selection, nature will have determined the appropriate amino acid sequences [i.e., those retaining malate dehydrogenase activity]."

With regard to the written description rejection, the Board noted that "[t]he written description requirement . . . does not require a description of the complete structure of every species with a chemical genus" (Ex parte Bandman, No. 2004-2319, slip op. at 3 (B.P.A.I. January 6, 2005)). The Board also compared the circumstances of the instant case with those faced by the Federal Circuit in Enzo Biochem, Inc. v. Gen-Probe Inc., 296 F.3d 1316 (Fed. Cir. 2002). In Enzo Biochem, the Federal Circuit determined that an "[a]dequate written description may be present for a genus of nucleic acids based on their hybridization properties, 'if they hybridize under highly stringent conditions to known sequences because such conditions dictate that all species within the genus will be structurally similar'" (Ex parte Bandman, No. 2004-2319, slip op. at 4 (B.P.A.I. January 6, 2005) (citing Enzo Biochem, Inc., 296 F.3d at 1327)). In the instant case, the Board determined that the genus of molecules defined by the claims was similarly limited and reversed the Examiner's written description rejection.

With regard to the enablement rejection, the Board disagreed with the Examiner's assertion that in order to satisfy this requirement, the specification must provide guidance regarding the specific amino acid residues that are tolerant to change without affecting malate dehydrogenase activity. Instead, the Board deemed persuasive Appellants' argument that because the claims were limited to naturally occurring sequences, nature will have determined the amino acid residues that are tolerant to change (i.e., naturally occurring variants will presumably retain malate dehydrogenase activity). In particular, in reversing the Examiner's enablement rejection, the Board determined that the Examiner had not provided sufficient evidence that a naturally occurring polypeptide that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1 or a polypeptide encoded by a naturally occurring polynucleotide sequence that is at least 95% identical to the polynucleotide sequence of SEQ ID NO: 2 would not retain malate dehydrogenase activity.

Although the Board reversed both the written description and enablement rejections, it also entered a new ground of rejection for claim 12 under 35 U.S.C. § 112, second paragraph. The Board found that the specification provided no guidance that would allow one of ordinary skill in the art to determine, with a reasonable degree of confidence, whether a polynucleotide sequence that is at least 95% identical to the polynucleotide sequence of SEQ ID NO: 2 occurs naturally. The Board concluded that the metes and bounds of claim 12 were unclear, and therefore, that the claim was indefinite.

Ex parte Bandman (B.P.A.I. 2004)
Panel: Administrative Patent Judges Smith, Grimes, and Green
Opinion by Administrative Patent Judge Green

This article was originally published on Patently-O on June 14, 2005.

Posted at 10:19 AM in Board of Patent Appeals and Interferences, Definiteness, Enablement, Written Description | Permalink | Comments (1) | TrackBack (0)

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