Orange Book Blog

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

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  The proposed rules (available here) were scheduled to be published in the Federal Register on Monday, but were withdrawn later Friday.  We understand that the proposed rules were withdrawn because there was not enough space in Monday's Federal Register to accomodate both the proposed rules and a companion "guidance document" that the PTO wants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

Federal Circuit Again Vacates Preliminary Injunction in Metformin Case

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

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

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

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

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

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

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

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

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

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

District Court Finds Inducement of Infringement in Doxercalciferol Case

Bone Care Int'l v. Roxane Labs., No. 09-cv-285 (GMS) (D. Del.)

In an opinion this past Monday, the U.S. District Court for the District of Delaware found in favor of Genzyme and against ANDA applicants Roxane, Sandoz, and Anchen in the paragraph IV litigation concerning HECTOROL (doxercalciferol), Genzyme's drug for the treatment of secondary hyperparathyroidism (SHPT) in patients with end-stage renal disease (ESRD).  The court ruled that defendants' ANDA products would induce infringement of claim 7 of U.S. Patent No. 5,602,116; that claim 7 is entitled to a 1988 priority date; and that claim 7 is not invalid as "inoperative" or obvious.  This post focuses on the inducement issue.

Claim 7 of the '116 patent is directed to:

A method for lowering or maintaining lowered serum parathyroid hormone [PTH] in patients suffering from hyperparathyroidism secondary to end stage renal disease, comprising: administering to said patients an effective amount of [doxercalciferol] to lower and maintain lowered serum parathyroid hormone levels.

After a Markman hearing, the court construed the term "effective amount of doxercalciferol to lower and maintain lowered serum parathyroid hormone levels" to mean "an amount of doxercalciferol sufficient to lower and maintain lowered blood concentrations of PTH with a lower incidence of hypercalcemia than would result from using calcitriol or alfacalcidol to achieve the same level of PTH suppression."

After concluding that claim 7 would be directly infringed by the defendants' ANDA products (a predicate to finding inducement of infringement), the court addressed whether the defendants have the required intent to induce infringement.  The key issue here was whether the defendants intend to induce infringement of claim 7 notwithstanding that their proposed labeling says nothing about the incidence of hypercalcemia resulting from doxercalciferol relative to the incidence resulting from calcitriol or alfacalcidol.

The court began its analysis by stating:

As noted, the "pertinent question" in ANDA cases, with respect to induced infringement, is "whether the proposed label instructs users to perform the patented method," and "promotes" or "encourages" others to practice that method.  Here, the court has found, for the reasons stated above, that the defendants' proposed product labels would instruct users to perform each element of the patented method detailed in claim 7.  The Federal Circuit has clarified, however, that satisfaction of this element, without more, is insufficient to prove inducement.  Instead, the patentee must also present evidence that the defendant "knew or should have known that his actions would induce actual infringement" and "that the induced acts constitute patent infringement."

The court continued:

As noted, in the Hatch-Waxman context, "statements in a package insert that encourage infringing use of drug product are alone sufficient to establish intent to encourage direct infringement" for purposes of induced infringement under 35 USC 271(b).  The Federal Circuit has stated, however, that inducement in the ANDA context should not be decided according to the tenets of strict liability action.  Instead, a court assessing an inducement claim should determine whether the proposed label "instructs users to perform the patented method" and "teaches an infringing use . . . such that we are willing to infer from those instructions an affirmative intent to infringe the patent."  Here, each of these requirements is met.

For these statements of law, the court cited AstraZeneca v. Apotex (Fed. Cir. 2010), DSU Medical v. JMS (Fed. Cir. 2006), and Vita-Mix v. Basic Holdings (Fed. Cir. 2009).

The court thus concluded:

With respect to the specific intent element of inducement, the court concludes that the plaintiffs have sufficiently shown that the defendants "knew or should have known their actions would induce actual infringements."  In this case, all defendants filed ANDAs with the FDA seeking approval to market a doxercalciferol product that would be sold accompanied by information instructing physicians and medical professionals to administer doxercalciferol according to the method explained in claim 7 for treating SHPT in patients with ESRD.  This FDA-approved indication is the same use set forth in claim 7 of the patent-in-suit . . . .

The court concludes that, based on the clinical trials and literature available, the defendants knew or should have known that doxercalciferol has been shown to lower and maintain lowered PTH levels with a lower incidence of hypercalcemia than would result from using calcitriol or alfacalcidol at the same level of PTH suppression.  Thus, the court concludes that the defendants, in submitting their ANDAs, knew or should have known that their proposed products would induce actual infringement of claim 7.  The court finds this level of intent sufficient for inducement purposes.

The defendants are certain to appeal the decision to the Federal Circuit.

Federal Circuit Affirms Unenforceability of TAXOTERE Patents

Aventis Pharma S.A. et al. v. Hospira, Inc. et al., No. 2011-1018 (Fed. Cir.)

In a precedential decision earlier this week, the Federal Circuit affirmed a district court decision holding two patents on TAXOTERE (docetaxel), U.S. Patent Nos. 5,750,561 and 5,714,512, unenforceable for inequitable conduct.  The Federal Circuit also affirmed findings that claim 5 of the '561 patent and claim 7 of the '512 patent are invalid for obviousness and that claim 7 of the '512 patent is not infringed.

The decision is notable as one of the few cases--and the first Hatch-Waxman case--involving inequitable conduct that the Federal Circuit has decided since Therasense, which raised the bar for proving inequitable conduct.  In addition, the decision illustrates how losing a claim construction argument can lead to losing on validity, which in turn can lead to losing on inequitable conduct.

Claim 5 of the '561 patent recites:

5.  A perfusion, which contains approximately 1 mg/ml or less of [docetaxel], and which contains less than 35 ml/l of ethanol and less than 35 ml/l of polysorbate, wherein said perfusion is capable of being injected without anaphylactic or alcohol intoxication manifestations being associated therewith.

Claim 7 of the '512 patent depends from claims 1 and 6.  When the claims are considered together, claim 7 effectively recites:

7.  A composition comprising docetaxel, said composition being dissolved in polysorbate, said composition being essentially free or free of ethanol.

On appeal, Sanofi argued that the term "perfusion" in claim 5 of the '561 patent should have been construed to mean that the composition is effective for treatment, safe, and stable for at least eight hours.  Citing its recent decision in Thorner v. Sony Computer, the Federal Circuit refused to read those limitations into the claim.  And, because Sanofi's counsel conceded at oral argument that under the district court's construction of "perfusion," claim 5 was obvious over the prior art (the "GV reference" and the "Vidal reference"), the Federal Circuit affirmed the district court's judgment that claim 5 is invalid as obvious.

With respect to claim 7 of the '512 patent, Sanofi disputed the district court's construction of "essentially free or free of ethanol."  But the Federal Circuit ignored that dispute because the parties agreed that the "composition" of claim 7 encompassed both stock solutions and perfusions and, according to the Federal Circuit, "Sanofi has not addressed the district court's obviousness finding with respect to stock solutions in its opening brief."  The Federal Circuit therefore held that Sanofi waived any argument that the claimed stock solutions were not obvious over the prior art.

Turning to inequitable conduct, the Federal Circuit described the issues as follows:

The district court found that the Vidal and GV references were material to patentability and that inventor Fabre intentionally withheld them with the intent to deceive the U.S. Patent and Trademark Office.  Based on these findings, the court concluded that the '512 patents were unenforceable for inequitable conduct.  Sanofi argues that we should reverse the court's inequitable conduct judgment because Fabre explained why he did not disclose these references to the PTO and, thus, the court's finding that he acted with the intent to deceive was not the single most reasonable inference that could be drawn from the evidence.  Additionally, Sanofi contends that these references were not material to patentability because they were duplicative of references that were before the PTO.

The Federal Circuit addressed materiality first, quoting from Therasense:  "when a 'claim is properly invalidated in district court based on the deliberately withheld reference, then that reference is necessarily material' for purposes of the inequitable conduct inquiry."  The court stated:

Here, we have affirmed the district court's finding that the '561 and '512 patents were invalid based on, inter alia, the withheld GV and Vidal references.  Because such references are necessarily material to patentiablity, the district court did not err in finding that the materiality requirement was established.

Thus, a claim-construction loss led to a validity loss, which led to an inequitable-conduct loss.

Of course, inequitable conduct also requires intent to deceive, which, according to the Federal Circuit (quoting Therasense again), is shown by proving "by clear and convincing evidence that the applicant knew of the reference, knew that it was material, and made a deliberate decision to withhold it."  Here, the court concluded that, even though the district court reached its decision before Therasense, "Based on the district court's thorough discussion of its factual findings and its well-reasoned analysis that is consistent with Therasense, this determination was not an abuse of discretion."

Federal Circuit Affirms Dismissal of Factor VIII Priority Case for Lack of Interfering Subject Matter

Genetics Institute, LLC v. Novartis Vaccines & Diagnostics, Inc., No. 2010-1264 (Fed. Cir. 2011)

    by Scott P. McBride

In 2000, Genetics Institute obtained a patent term extension under 35 U.S.C. § 156 on U.S. Patent No. 4,868,112, based on the time consumed by testing and regulatory review of its commercial recombinant Factor VIII product, ReFacto®, which is indicated for the treatment of hemophilia A.  The PTO extended the term of the '112 patent approximately 3.5 years, to February 28, 2010.

In May 2008, during the extended term of the '112 patent, Genetics Institute sued Novartis Vaccines and Diagnostics, Inc. under 35 U.S.C. § 291 to determine priority of invention between claims 1, 5, 9 and 10 of the '112 patent and certain claims of Novartis's U.S. Patent Nos. 6,228,620 and 6,060,447.  Genetics Institute asserted that the claims at issue were all directed to the same subject matter, namely truncated Factor VIII proteins lacking all or part of the B domain while retaining procoagulant activity.

Novartis moved to dismiss the suit on two grounds: (1) lack of subject matter jurisdiction because the extension of the '112 patent under 35 U.S.C. § 156 applied only to certain claims, and not to the entire patent; and (2) lack of interference in fact.

Last year, the U.S. District Court for the District of Delaware granted Novartis's motion to dismiss, concluding that there was no interference in fact as to any of the allegedly interfering claims.  In an opinion last week, the Federal Circuit affirmed the dismissal on the same grounds.

Claim 1 of the '112 patent recites:

A recombinant DNA which upon expression results in a truncated Factor VIII protein which is an active procoagulant wherein the recombinant DNA encodes for a protein having the amino acid sequence of a human Factor VIII:C except for having a deletion corresponding to at least 581 amino acids within the region between Arg-759 and Ser-1709, wherein the amino acid numbering is with reference to Met-1 of the human Factor VIII:C leader sequence.

In the appeal, Novartis first argued that the Federal Circuit lacked appellate jurisdiction because the '112 patent's extended term expired in 2010.  Novartis argued that an interference between patents under 35 U.S.C. § 291 requires that the allegedly interfering patents be unexpired.  Novartis relied on case law interpreting 35 U.S.C. § 291, specifically Albert v. Kevex Corp., 729 F.2d 757 (Fed. Cir. 1984).  In Albert, the defendant statutorily disclaimed the allegedly interfering claims under 35 U.S.C. § 253, which divested the district court of subject matter jurisdiction.

The Federal Circuit rejected Novartis's argument that the expiration of the patent term extension had the same effect as a disclaimer, because statutory disclaimers are retroactively considered part of the original patent such that the disclaimed claims are treated as though they "never existed."  In contrast, an expired patent may form the basis of an action for past damages, subject to a defense raising the six-year time limitation on damages.  Moreover, unlike 35 U.S.C. § 135, which relates to interferences between applications or a pending application and an "unexpired patent," Section 291 for interferences between patents is not limited to "unexpired" patents.

Novartis next argued that the district court lacked subject matter jurisdiction because the extended term allegedly applied to less than all claims of the '112 patent.  Specifically, Genetics Institute’s application to extend the patent term identified only claims 9 and 10 of the '112 patent as relating to its commercial product ReFacto® and claim 10 was allegedly construed by the district court such that it could not cover ReFacto®.

The Federal Circuit rejected Novartis's arguments based on its conclusions that (1) the language of Section 156 makes clear that the extension applies to the entire patent, not merely on a claim-by-claim basis; (2) the legislative history states that "all provisions of the patent law apply to the patent during the period of extension"; (3) the "rights derived" provision of Section 156(b) was intended to limit the effect of an extension, not to restrict the extension to particular claims (for patents that claim a product, rights in the extended term are "limited to any use approved for the product"); (4) because claim 9 depended from claims 1 and 5, and Novartis conceded that claim 9 covered ReFacto®, Novartis thus conceded that claims 1 and 5 also covered ReFacto®; and (5) the district court did not make any findings of fact that claim 10 did not encompass ReFacto®, but merely stated that claim 10 "may not" encompass ReFacto®.

Finally, Novartis argued there was no interference in fact between the claims at issue.  An interference in fact under § 291 requires that the two patents claim "the same or substantially the same subject matter," using a "two-way test."  Under the two-way test, an interference exists between two claims if each claim anticipates or renders obvious the other.  The majority opinion (authored by J. Lourie and joined by J. Plager) concluded that the first part of the two-way test (obviousness of Novartis's invention in view of Genetics Institute's invention) was not met.  In reaching this conclusion, the majority held that evidence of unexpected results may be used to rebut a case of prima facie obviousness, even if that evidence was obtained after the patent's filing or issue date.

Judge Dyk dissented.  Judge Dyk would have held that unexpected results must be disclosed in the junior party's specification or known by the junior party's inventor(s) prior to filing, for such results to be used in determining nonobviousness.  For purposes of the first part of the two-way test, Judge Dyk would have held that unknown and unexpected results would not be usable to (1) show that there was there some reason why the junior inventor would have modified the senior party's invention to arrive at the junior party's invention, and (2) overcome a prima facie case of obviousness.

It remains to be seen whether and how the court's decision will impact future obviousness cases.

Federal Circuit Affirms Summary Judgment of Nonobviousness of FORTICAL Formulation

Unigene Labs and Upsher-Smith v. Apotex, No. 2010-1006 (Fed. Cir. 2011)

In a decision yesterday, the Federal Circuit affirmed a district court opinion granting Unigene's motion for summary judgment that claim 19 of U.S. Patent No. RE40,812 is not invalid for obviousness.  Claim 19 of the '812 patent covers the pharmaceutical formulation of FORTICAL (calcitonin nasal spray).  The Federal Circuit also affirmed the district court's denial of Apotex's motion to breach the attorney-client privilege under the crime-fraud exception and the district court's determination that Apotex had waived certain counterclaims, but the validity decision is the most interesting.

Claim 19 of the '812 patent recites:

A liquid pharmaceutical composition for nasal administration comprising about 2,200 MRC units of salmon calcitonin, about 20 mM citric acid, about 0.2% phenylethyl alcohol, about 0.5% benzyl alcohol, and about 0.1% polyoxyethylene(2) sorbitan monooleate.

Unigene filed its NDA for FORTICAL under section 505(b)(2), naming Novartis's MIACALCIN as the reference listed drug.  Whereas MIACALCIN contains benzalkonium chloride ("BZK"), an absorption enhancer, preservative and surfactant, FORTICAL contains citric acid (absorption enhancer), phenylethyl- and benzyl-alcohol (preservatives) and polysorbate 80 (surfactant).  Unigene also filed a patent application on its formulation, which issued as the '812 patent.

Apotex filed an ANDA for a generic version of FORTICAL, alleging that claim 19 of the '812 patent is invalid for obviousness.  Apotex argued that the formulation of claim 19 would have been obvious in light of MIACALCIN, a prior art patent (disclosing solid formulations of salmon calcitonin) and a prior art publication authored by Day.  The district court granted summary judgment of nonobviousness, which is relatively rare in Hatch-Waxman cases.

On appeal, the Federal Circuit began its obviousness analysis with an extensive discussion of KSR, in which the Supreme Court held that the teaching-suggestion-motivation (TSM) test is not a required part of the obviousness analysis.  The Federal Circuit acknowledges this, quoting from KSR:  "The obviousness analysis cannot be confined by a formalistic conception of the words, teachings, suggestion, and motivation . . . ."  But in the next paragraph, the Federal Circuit seems to rely on the TSM test, quoting from its 2006 decision in Eli Lilly v. Zenith Goldline:

to establish a prima facie case of obviousness based on a combination of elements in the prior art, the law requires a motivation to select the references and to combine them in the particular claimed manner to reach the claimed invention.

The Federal Circuit then explained how KSR should be applied in cases involving pharmaceutical formulation patents.  The court compared the obviousness analysis in pharmaceutical compound cases to that in pharmaceutical formulation cases:

A prima facie case of obviousness in the chemical arts is often based on a known compound, called a "lead compound," which serves as a starting point for a person of ordinary skll developing the claimed invention.  Where the patent at issue claims a chemical compound, a lead compound is often used to show structural similarities between the claimed compound and prior art.  In the context of a composition or formulation patent where the patented formulation was made to mimic a previously FDA-approved formulation, the functional and pharmaceutical properties of the "lead compound" can be more relevant than the actual chemical structure (though not always mutually exclusive).  Thus, the term "reference composition" is more appropriate than "lead compound" when considering obviousness for a chemical composition. . . .

Addressing Apotex's obviousness position specifically, the Federal Circuit stated:  "To a person of ordinary skill in the art, citric acid would not be an obvious substitute for BZK's functions as an absorption enhancer and as a surfactant because citric acid has a vague role in even the closest prior art."  The court further found that the prior art actually teaches away from using citrict acid "as an absorption enhancing agent or stabilizing agent in a liquid formulation with a salmon cacitonin active ingredient."

The court concluded:  "There is no genuine dispute of material fact that a person of ordinary skill attempting to make a liquid composition to deliver salmon calcitonin into a human body through nasal administration, would not have considered using about 20 mM citric acid with the narrowly claimed amounts of benzyl alcohol, phenylethyl alcohol, and polysorbate 80, because the formulation would not be expected to perform properly to meet the specificity of a pharmaceutical use."

Federal Circuit Affirms Validity of Argatroban Patent

Mitsubishi Chemical Corp. v. Barr Labs., No. 2010-1432 (Fed. Cir. 2011)

Mitsubishi Chemical owns U.S. Patent No. 5,214,052, which claims a "method for dissolving an arginineamide, comprising dissolving [argatroban] and/or its salt in a solvent containing ethanol, water and a saccharide"; and a "pharmaceutical composition for injection, comprising [argatroban] and/or its salt together with ethanol, water and a saccharide."  Barr filed an ANDA for a generic version of argatroban, alleging that each claim of the '052 patent is invalid due to anticipation and/or obviousness.

[As an aside, process patents may not be listed in the Orange Book.  In this case, however, the '052 patent also claims pharmaceutical formulations, which makes the patent eligible for listing.  Mitsubishi asserted both the process claims and composition claims in the litigation, and it appears that was just fine with Barr.]

Last year, the U.S. District Court for the Southern District of New York held following a trial that the claims of the '052 patent are not invalid, and enjoined Barr from marketing a generic version of argatroban until the '052 patent expires (in 2014).  Earlier this week, the Federal Circuit affirmed that decision.

Barr's primary invalidity argument was that the claims of the '052 patent were anticipated by a Japanese article published in 1986 by a Mitsubishi employee, Toshihiro Yamamoto.  The key dispute concerned the English translation of a single sentence in the Yamamoto article describing the preparation of an argatroban solution that was administered to laboratory rats.

The district court agreed with Mitsubishi's translation of that sentence: "In 7.5% D-sorbitol-4% ethanol, an argipidine solution dissoved under hydrochloric acid acidity (pH 1.5 to 1.7) was intraperitoneally administered at a dosage of 1 ml/kg, 15 minutes before common carotid artery occlusion."  The court further credited corroborating testimony that Yamamoto teaches dissolution of argatroban in hydrochloric acid, followed by formulation of the dissolved argatroban with D-sorbitol and ethanol.  Barr, on the other hand, argued that the Yamamoto reference taught dissolution of argatroban in a solution containing HCl, D-sorbitol and ethanol, thereby anticipating the process claims of the '052 patent.

Addressing the district court's findings regarding the correct translation of Yamamoto, the Federal Circuit stated:

The fact-finder's selection of a particular translation as the best translation of a foreign language reference raises pure questions of fact.  The district court's selection of the appropriate translation in this case was based in large part on a credibility determination, and such determinations are "virtually never" overturned for clear error.  Although Barr contends that [Mitsubishi's] translation should be disregarded because it was prepared for purposes of litigation, that is not a sufficient reason to conclude that the district court's choice of [that] translation was clearly erroneous.

The Federal Circuit further observed that "the district court took note of the fact that Yamamoto's description of the argatroban solution was quite cryptic because, as both experts agreed, Yamamoto focused on the pharmacological activity of the argatroban molecule, rather than on argatroban's solubility or on treating the rats."  According to the Federal Circuit, "In order to anticipate, the teaching of a reference must be clear and unambiguous."

With respect to the formulation claims, the district court found that the solution disclosed in Yamamoto is not a "pharmaceutical composition for injection"--i.e., "a composition that is suitable for treating medical conditions by injection"--because to be suitable for injection into human patients a pharmaceutical composition must have a pH above 3, and the Yamamoto solution has a pH between 1.5 and 1.7.  The key dispute here concerned the proper construction of "pharmaceutical composition for injection."  The Federal Circuit affirmed the district court's construction, and thus affirmed the validity of the formulation claims.

Federal Circuit Affirms Summary Judgment of Invalidity for Obviousness in Temazepam Case

Tyco Healthcare Group LP v. Mutual Pharm. Co., No. 2010-1513 (Fed. Cir. 2011)

   by Scott P. McBride

RESTORIL (temazepam) is a hypnotic (sleep-inducing) drug marketed for the treatment of insomnia.  In a decision last month, the Federal Circuit affirmed the invalidity of two claims of U.S. Patent No. 5,211,954 directed to temazepam formulations.  Claim 1 recites:

A hard gelatin capsule containing a temazepam formulation consisting essentially of 6 to 8 milligrams of crystalline temazepam having a surface area of from 0.65 to 1.1 m2/g and 95% of the temazepam having a particle size of less than 65 microns in admixture with a pharmaceutically acceptable carrier therefor.

Claim 2 "is identical except that it recites a composition containing 7.5 milligrams of crystalline temazepam."

In 2006, Mutual filed an ANDA for a generic version of 7.5 mg temazepam capsules, after which Tyco filed suit for infringement of the '954 patent.  In 2009, after Mutual received tentative FDA approval of its ANDA, Tyco moved for a preliminary injunction, which was denied due to "uncontroverted evidence" of no literal infringement due to the "surface area" limitation.

In an opinion last year, District Judge Chesler (D.N.J.) concluded on summary judgment that the two asserted composition claims were invalid for obviousness.  Judge Chesler noted that (1) RESTORIL capsules had been sold in the United States in 15 mg and 30 mg dosages more than a year before the 1986 priority date of the '954 patent, (2) a 1983 volume of the British National Formulary, a UK medical reference book, directed physicians to the use of temazepam at a dosage between 5 and 15 mg for the treatment of insomnia in the elderly, and (3) it was undisputed that "physicians always seek to prescribe the lowest effective dose of any medication, particularly hypnotics such as temazepam."

In affirming, the Federal Circuit noted that, when Tyco's predecessor filed a Supplemental NDA with the FDA for manufacture and sale of 7.5 mg temazepam capsules within the scope of both '954 claims, the application stated that:

[t]he formulation and manufacture of RESTORIL Capsules, 7.5 mg are similar to that used for the 15 and 30 milligram capsules . . . .  The [7.5 mg] formulation differs only in the reduction of the dose.  . . .  The capsule manufacturing method is exactly the same as has been described for the currently marketed doses.

The Federal Circuit stated, "[g]iven that uncontested description, the only limitation of the two '954 claims that was not fully disclosed by the prior art RESTORIL capsules is the lower dosage of temazepam."

The district court and the Federal Circuit relied on, among other things, the 1983 British National Formulary book.  The British National Formulary book stated that, for temazepam, the dose for "elderly patients [could be] 5-15 mg."  According to the district court, "[t]his entry plainly tells one of skill in the art to treat insomnia in the elderly by administering a dose in the range of 5 to 15 mg."  Moreover, the summary judgment record included evidence of a 1984 statement by an FDA representative to a group that included the named inventor of the 954 patent, that "the doses proposed in [certain] studies may be too high, [given] that in Great Britain, temazepam doses from 5-15 mg are recommended for geriatrics."

The Federal Circuit stated that where there is a range disclosed in the prior art, and the claimed invention falls within that range, the claim is presumed obvious.  That presumption is rebuttable either by a showing that the prior art taught away from the invention or by a showing of new and unexpected results. 

The Federal Circuit did not accept Tyco's arguments that the prior art taught away from the claimed invention or that secondary considerations of new and unexpected results and commercial success permitted a conclusion of non-obviousness.  The Federal Circuit also rejected, as "silly," one assertion made by Tyco's counsel at oral argument that the language "5-15 mg" did not actually disclose a range of doses (even though Tyco's expert had called it a "range").

Regarding that same range, the Federal Circuit also concluded that even if some of the references in the record taught away from the claimed dose generally, those teachings did not undermine the teachings in the British National Formulary book that related to the dosage in elderly patients. 

Finally, the Federal Circuit acknowledged, as correct, Tyco's expert's statements that the British National Formulary book (1) "nowhere states that a temazepam dose of 5 mg, 6 to 8 mg, or 7.5 mg, is effective in treating insomnia," (2) nor does it "state that 7.5 mg was effective," and (3) the British National Formulary book provides "[n]o clinical or statistical evidence . . . demonstrating that a dose within a range of 5-15 mg would work" in treating insomnia.  But the Federal Circuit also concluded that these observations do not undermine the district court's conclusions as to obviousness because the 954 patent's composition claims do not discuss the intended use of the capsules in a particular treatment regimen.

District Court Grants TRO Against Mylan's Generic Amrix--After Finding Patents Invalid

In Re: Cyclobenzaprine Hyldrochloride Extended-Release Capsule Patent Litigation, No. 09-md-2118-SLR (D. Del. 2011)

In a strange turn of events, the district court that just eight days earlier found the asserted claims of the patents on Amrix invalid, granted a motion for a temporary restraining order against Mylan.

As we previously reported, on May 12, following a seven-day bench trial conducted last September and October, the U.S. District Court for the District of Delaware held that the asserted claims of U.S. Patent Nos. 7,387,793 and 7,544,372 are invalid due to obviousness.  This decision cleared the way for Mylan, the first paragraph IV filer, to launch its generic version of Amrix.  As we reported, Mylan did so on May 13, triggering its 180-day exclusivity period.

Notwithstanding that they lost after trial, on May 15 the plaintiffs filed a motion for a temporary restraining order.  This was followed by three rounds of briefs by each side--including briefs filed each day last week--until the district court granted the motion last Friday.

Given that one of the legal requirements for granting a TRO is a "likelihood of success on the merits," and the district court previously found after a full trial that the plaintiffs lost on the merits, it is very surprising that the court granted the TRO.  Did the court, after reconsideration, find that its decision was wrong on the merits?  No--in its Memorandum Order, the court defended each of the findings that plaintiffs asserted to be erroneous.  But inexplicably, the court concluded that "plaintiffs' success on appeal is just as likely as not," and therefore "this factor marginally supports a temporary restraining order."

Later on Friday, Mylan filed an Emergency Motion for Reconsideration, stating that the court "committed fundamental, material errors of law."  Specifically, according to Mylan, the court "did not find that Plaintiffs were likely to succeed on the merits but rather that 'plaintiffs' success on appeal is just as likely as not.'  As a matter of law, this sort of 50-50 assessment is insufficient to establish a likelihood of success and destroys the basis for the TRO."  Mylan, of course, is concerned that its 180-day exclusivity period will tick away while it's prevented from marketing.

While the court granted the plaintiffs' motion, it has not yet entered an order enjoining Mylan.  The court has scheduled a hearing for tomorrow at 9:00 am, and presumably will hear argument on Mylan's emergency motion.

UPDATES:

• On May 24, Mylan filed a supplemental brief in support of its Emergency Motion for Reconsideration
• Later on May 24, in this Order, the district court denied Mylan's Emergency Motion for Reconsideration
• Also on May 24, in this Order, the district court entered an injunction against Mylan
• Still later on May 24, Mylan filed a Notice of Appeal to the Federal Circuit
• On May 25, in this Order, the Federal Circuit stayed the district court's May 24 injunction

District Court Decides Amrix (Cyclobenzaprine) Litigation in Favor of ANDA Filers, Finding Claims of Patents-in-Suit Invalid for Obviousness

In Re: Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, No. 09-md-2118-SLR (D. Del. 2011)

In an Opinion and Order issued today, the U.S. District Court for the District of Delaware found in favor of ANDA applicants Mylan, Barr and Anchen in the Amrix (Cyclobenzaprine HCl extended-release capsules) Paragraph IV litigation.  The decision follows a bench trial that took place last autumn.  The decision is somewhat surprising, because on April 8th, just before the 30-month stay was set to expire and while the parties were still waiting for an opinion from the court, the court enjoined the defendants from lauching generic versions of Amrix until the court issued its opinion.

The patents-in-suit were U.S. Patent Nos. 7,387,793, which claims extended-release formulations of cyclobenzaprine HCl, and 7,544,372, which claims methods of relieving muscle spasms by administering the formulations.  The defendants argued that the asserted claims of the patents-in-suit are invalid for obviousness over prior art multiparticulate extended-release drug formulations, "when combined with the known PK parameters of immediate-release cyclobenzaprine as disclosed in the prior art."  The plaintiffs, Eurand, Cephalon and Anesta AG, argued that "before the patents-in-suit, no dosage form of cyclobenzaprine existed that provided a therapeutically effective plasma concentration over a period of 24 hours, nor did PK values for said formulation exist."  They further argued that not every element of the asserted claims was described in the prior art and, thus, the patents could not be obvious.

The court, however, disagreed, noting that "not every limitation of a claimed invention need be found in the prior art," but instead gaps can be filled by the knowledge of a person of ordinary skill in the art.  Moreover, the court found that the claimed PK profile was disclosed in the prior art, "and optimization of this immediate release profile into an extended release form was routine for one of ordinary skill in the art."

The court concluded:

It would have been obvious to one of skill in the art at the time of the invention to try and create an extended release formulation of cyclobenzaprine mirroring the PK properties of the immediate release formulation.  If an extended release formulation matches the AUC and C_max of the already approved immediate release formulation, a person of ordinary skill in the art can generally expect that the extended release formulation will have approximately the same effect in the body as the immediate release formulation.  Such a motivation is taught by the FDA, in its direction that an extended release dosage form should have the same AUC and C_max of an already approved immediate release formulation.  Additionally, it would have been obvious to one of skill in the art to use the invention's claimed drug delivery system, as it had already proven effective with a drug that was related to cyclobenzaprine and shared many of its properties.

Therefore, a person or ordinary skill in the art would have been motivated to take a group of known elements to create an extended release version of cyclobenzaprine, and to have a reasonable expectation of success in doing so.  The patents-in-suit "claim a structure already known in the art that is altered by the mere substitution of one element for another known in the field, and the combination did no more than yield a predictable result."  KSR.  Therefore, the invention was obvious.

In addition to finding the asserted claims invalid for obviousness, the court found the claims not invalid for failure to comply with the best mode requirement; and found the patents not unenforceable due to inequitable conduct.  The court also found that Mylan and Barr infringe the claims, but Anchen does not.

Mylan previously announced in a press release that it was the first to file a patent challenge relating to Amrix, and thus believes that it is entitled to 180-day exclusivity.  Mylan's ANDA was granted final approval on April 18th, following expiration of the 30-month stay.  It remains to be seen when Mylan will launch its generic Amrix product.

RELATED READING:

• Mylan Tentative Approval Letter