Orange Book Blog

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

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

    by Dunstan H. Barnes

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

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

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

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

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

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

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

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

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

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

Invalidity Due to Public Use in ANDA Cases

Pronova Biopharma Norge v. Teva Pharms., No. 2012-1498 (Fed. Cir.)

    by Aaron F. Barkoff

It is not unusual for a defendant in an ANDA case to assert invalidity due to prior public use, but it is rare that such a defense succeeds.  In a unanimous decision last week, the Federal Circuit held the asserted claims of Pronova's U.S. Patent No. 5,656,667 invalid as anticipated by prior public use, reversing a District of Delaware trial decision in the process.

Pronova's '667 patent protects Lovaza capsules, a drug product derived from fish oil and indicated to reduce triglyceride levels.  The asserted claims of the '667 patent were directed to pharmaceutical compositions comprising specific concentrations of different omega fatty acids.

The parties agreed that more than one year before the priority date of the '667 patent, Pronova's predecessor shipped two vials of a composition that met all of the limitations of the asserted claims to a third-party researcher, Dr. Skrinska.  Evidence at trial showed that Skrinska "tested the two samples to confirm (and did confirm) their content."  There was no evidence, however, that Skrinska used the samples to reduce triglyceride levels in a person.

The primary issue on appeal was whether Pronova's shipment of the samples and Skrinka's testing amounted to an invalidating public use.  Pronova argued that to be invalidating under § 102(b), an invention must be used by someone other than the inventor for its intended purpose—here, to reduce triglyceride levels.  The ANDA filers, on the other hand, contended that an invalidating public use need not be the intended use of the invention, as long as the invention is fully disclosed without restriction.

The Federal Circuit explained the test for "public use" in Invitrogen v. Biocrest:

The proper test for the public use prong of the § 102(b) statutory bar is whether the purported use: (1) was accessible to the public; or (2) was commercially exploited.  Commercial exploitation is a clear indication of public use, but it likely requires more than, for example, a secret offer for sale.  Thus, the test for the public use prong includes the consideration of evidence relevant to experimentation, as well as, inter alia, the nature of the activity that occurred in public; public access to the use; confidentiality obligations imposed on members of the public who observed the use; and commercial exploitation.

The Federal Circuit held that the "use" in Pronova met this test, stating:

Because we find that [Pronova] sent samples of the invention claimed in the '667 patent Skrinska . . . without restriction and Skrinska thereafter tested the samples, we hold that [Pronova] put its invention to an invalidating public use.

The court contrasted this case to Dey v. Sunovion, another recent case in which an ANDA filer asserted prior public use as an invalidity defense.  There, the purported public use was a clinical trial of the claimed pharmaceutical composition.  But there, as the court explained:

Because only the clinical trial administrator, not the subjects taking the medication, was made aware of the invention's claimed formulation and stability characteristics, and the administrator had signed a pledge of confidentiality, we held that "a finder of fact could conclude that the study was conducted with a reasonable expectation of confidentiality as to the nature of the formulations being tested, [such that] summary judgment on the public use issue was inappropriate."  A fact finder could so conclude even though the subjects did not likewise sign a confidentiality pledge because "they were given incomplete descriptions of the treatment formulation."

Finally, the court addressed Pronova's argument that only the "intended use" of a pharmaceutical can qualify as a "public use":

We are not persuaded by Pronova's argument that "use" of a pharmaceutical formulation cannot occur until it is used to treat the condition it is intended to counteract, or at least physically ingested.  Certainly, where . . . unsophisticated users are provided a compound with no detail regarding its formulation—as in Dey—there will be no public use.  Where, as here, however, a compound is provided without restriction to one highly skilled in the art, that compound's formulation is disclosed in detail, and the formulation is subject to confirmatory testing, no other activity is needed to render that use an invalidating one.  Once the formulation was disclosed in full to Skrinska, without any restriction on its use, it had been released into the "public domain" for purposes of 102(b).

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 Affirms Invalidity of Teva's Patent on Rosuvastatin Formulation

Teva Pharm. Indus. Ltd. v. AstraZeneca Pharms. LP, No. 2011-1091 (Fed. Cir.)

In a precedential opinion filed today, the Federal Circuit affirmed the invalidity of Teva's U.S. Patent No. RE39,502 under 35 U.S.C. § 102(g)(2).  Teva's '502 patent claims a rosuvastatin formulation comprising "a stabilizing effective amount" of crospovidone.  This post describes the district court decision and provides background on the case.

There was no dispute in this case that AstraZeneca manufactured rosuvastatin tablets falling within the scope of the '502 patent claims before Teva conceived and reduced to practice its claimed invention.  Instead, the principal dispute was whether, to prove prior invention under § 102(g)(2), AstraZeneca was required to prove that it "appreciated the stabilizing effect of crospovidone in its drug formulation."

In affirming the district court's answer to that question in the negative, the Federal Circuit traced a line of cases that it said demonstrate "consistent applications of the same rule."  According to the court, "[t]o establish prior invention, the party asserting it must prove that it appreciated what it had made."  In other words, an "unrecognized, accidental duplication" is not a prior invention.  But, the court continued, "[t]he prior inventor does not need know everything about how or why its invention worked.  Nor must it conceive of its invention using the same words as the patentee would later use to claim it."

Applying the rule to this case, the court explained:

AstraZeneca had to appreciate that the [formulation] it asserted as its invention was stable and what the components of this formulation were.  There is no question that AstraZeneca had this appreciation.  However, AstraZeneca did not need to appreciate which component was responsible for the stabilization.

Teva made other arguments as well, but the Federal Circuit summarily disposed of them.

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.

AstraZeneca Defeats Teva's Claim That Crestor Infringes Teva's Patent

Teva Pharm. Indus. v. AstraZeneca Pharms., No. 08cv4786 (E.D. Pa. 2010)

Here's something you don't see every day:  an ANDA filer suing a brand-name drug manufacturer for patent infringement, claiming that the brand-name drug infringes the ANDA filer's patent.

In late 2007/early 2008, AstraZeneca ("AZ") filed suit against nine different ANDA filers, including Teva, who sought approval to market generic versions of Crestor (rosuvastatin).  The cases were consolidated in multidistrict litigation (D. Del. No. 08-md-01949) and proceeding through discovery when, in October 2008, Teva sued AZ, alleging that Crestor infringes Teva's U.S. Patent No. RE39,502.  Claim 1 of the '502 patent reads:  "A stabilized pharmaceutical composition for the treatment of dyslipidemia, comprising [rosuvastatin] and a stabilizing effective amount of at least one amido-group containing polymeric compound . . . ."

AZ filed a motion for summary judgment of patent invalidity due to prior invention pursuant to 35 USC 102(g)(2), which states that a person shall be entitled to a patent unless "before such person's invention thereof, the invention was made in this country by another inventor who had not abandoned, suppressed, or concealed it."  AZ argued that it made a batch of Crestor tablets meeting each limitation of the asserted '502 patent claims prior to December 1, 1999, the earliest date by which Teva claimed to have conceived of and reduced to practice the claimed formulation.

Teva did not dispute that AZ made a batch of Crestor tablets before December 1, 1999.  Rather, Teva argued that even if AZ created the exact infringing commercial formulation in mid-1999, AZ still could not prove conception or reduction to practice of the invention claimed by Teva's '502 patent by that date because there was no evidence that AZ appreciated that crospovidone, the amido-group containing polymeric compound included in Crestor, contributes to the stability of the formulation.  According to Teva, because AZ never appreciated that crospovidone contributes to the stability of its Crestor product formulations, it cannot have "created an embodiment that literally met all of the limitations of Teva's claims."

Last month, the district court granted AZ's motion for summary judgment.  The district court explained in its opinion that to establish priority of invention, there must be evidence not only that the inventor "actually first made the invention" but also that he "understood his creation to have the features that comprise the inventive subject matter."  According to the court, however,

the inventor need not establish that he recognized the invention in the same terms as those recited in the claims as the invention is not the language of the claims but the subject matter thereby defined.  Rather, the inventor must establish that he recognized and appreciated a compound corresponding to the compound defined by the claims.

The court continued:

Applying this principle--that the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer--the Federal Circuit has held invalid for anticipation numerous patents claiming what amount to newly discovered properties of prior art compositions, where the missing characteristic was necessarily present, or inherent, in the prior art, even though there was no recognition of the missing characteristic in the prior art.

The court concluded that, in this case, "Teva's discovery that crospovidone contributes to the stability of the formulations resembles the sort of scientific explanation for a prior art composition's functuning that the Federal Circuit has found to be an inherent property of the prior art in other cases."