Patent Baristas

In an appeal from a summary judgment of noninfringement of U.S. Patent 6,054,482, the Fed Circuit concluded that the district court erred in determining that there were no genuine issues of material fact concerning whether Warner Lambert failed to meet its burden of proof that the accused products infringe the asserted claims of the ’482 patent.

See: In Re Gabapentin Patent Litigation (involving Warner-Lambert, Pfizer and Godecke Aktiengesellschaft v. Purepac Pharma, Faulding, Watson Pharma, Danbury Pharma, Teva, Zenith Labs, Ivax, Apotex, Torpharm and Eon Labs) United States Court of Appeals for the Federal Circuit (06-1572).

Warner Lambert sells Neurontin®, a drug used to treat certain cerebral disorders, including epilepsy. The active ingredient in Neurontin® is a compound called gabapentin, which is covered by Warner Lambert’s ’482 patent, directed towards a process for the preparation of, and compositions containing, gabapentin substantially free from a lactam contaminant.

Under certain conditions gabapentin has a tendency to form a lactam, which makes the drug unstable and unsafe. The lactam was shown to be twenty-five times more toxic than gabapentin, and is linked to causing seizures, rather than preventing them. In an effort to minimize the formation of lactam, Warner Lambert developed a process involving two limitations to achieve stable formations of gabapentin.

First, gabapentin must be highly purified before being formulated into the pharmaceutical preparation. The ’482 patent discloses that:

The active materials of formula (I) must be prepared as highly purified, nonderivatized free amino acids, for example, from the corresponding hydrochloride by ion exchange. The proportion of remaining hydrochloride admixtures should thereby not exceed 20 ppm. The same also applies to other mineral acids.

Second, certain adjuvants that reduce the stability of gabapentin must be avoided. The ’482 patent further discloses that:

The following adjuvant materials, for example, reduced the stability of the compounds (I) and should be avoided in the preparation of pharmaceutical compositions: modified maize starch, sodium croscarmelose, glycerol behenic acid ester, methacrylic acid co-polymers (types A and C), anion exchangers titanium dioxide, and silica gels such as Aerosil 200.

The district court granted summary judgment of noninfringement becuase Warner Lambert failed to adduce sufficient evidence to establish that the accused products meet the limitation that the anions of a mineral acid do not exceed 20 ppm (“the 20 ppm limitation”). Based on the undisputed fact that the test had a ± 5 ppm margin of error, the court determined that that evidence was insufficiently precise to prove infringement.

The parties gave conflicting expert opinions, based on different evidence and different methods of testing, regarding whether Teva’s samples infringed the ’482 patent. As such, Warner Lambert argues that genuine issues of material fact exist in the record, and thus summary judgment was not appropriate.

First, appellees challenged the accuracy and reliability of the pH testing method. Appellees assert that the pH testing method yielded inaccurate results because, inter alia, Warner Lambert’s expert failed to calibrate the standards used for the test. Second, appellees argued that pH testing is not competent proof of infringement in light of the test’s lack of precision.

The Federal Circuit agreed with Warner Lambert that genuine issues of material fact existed.

In moving for summary judgment of noninfringement based on Warner Lambert’s inability to meet its burden of proof, appellees informed the district court that:

It is important to note for the record that Defendants strongly dispute the capability of pH testing to make any scientifically meaningful distinctions between gabapentin samples at the trace levels of acidity relevant to the ’482 patent. However, for purposes of this motion, Defendants have placed that dispute to one side (as they must), and focused on the undisputed limitations on the precision of such comparative pH measurements.

At the summary judgment hearing, appellees expressly stated that:

Teva’s experts vehemently dispute the validity of the data [Dr. Bartlett] relied on, but I want to ignore that dispute. Those factual issues are in dispute, but should not be part of this motion, and we, you can ignore them.

Thus, appellees limited their summary judgment motion to the issue of the undisputed limits of the test’s precision, viz., the ± 5 ppm margin of error, which we have considered. As such, appellees waived any argument challenging the validity, including challenges to the accuracy or reliability, of the pH testing method for purposes of summary judgment.

Appellees also argued that the court erred in its construction of the “anion of a mineral acid” and adjuvant claim limitations, and that they should still be awarded judgment. They asserted that “anion of a mineral acid” refers to anions from any source capable of forming a mineral acid. That is, that the term refers to total chloride content and is not limited to acid-derived chloride ions.

The court stated:

We agree with the district court that the proper construction is “anion derived from a mineral acid.” “It is a ‘bedrock principle’ of patent law that ‘the claims of a patent define the invention to which the patentee is entitled the right to exclude.’” Phillips v. AWH Corp., 415 F.3d 1303, 1327 (Fed. Cir. 2005) (quoting Innova/Pure Water, Inc. v. Safari Water Filtration Sys., Inc., 381 F.3d 1111, 1115 (Fed. Cir. 2004)). Here, the plain language of the claim supports the construction that the anion specifically is derived from a mineral acid. Appellees’ assertion that the claimed anion refers to total chloride ions or anions from any source that is “capable of” forming a mineral acid is unsupported by the claim language. Had the patentees intended the anion to refer to any anion, regardless of its source, the patentees could have simply claimed “anions” and omitted the phrase “of a mineral acid.”

We have also held that claims “must be read in view of the specification, of which they are a part.” Phillips, 415 F.3d at 1315. While appellees argue that the specification provides no support for their construction, we find that the specification provides further support for the construction adopted by the district court. The specification teaches a multi-step process for making gabapentin that is substantially free from lactam.

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Jim Greenwood, CEO of the Biotechnology Industry Organization (BIO) gave a briefing to biotech & pharma bloggers on key issues related to follow-on biologics, patent reform and PDUFA pending legislation.

In the conference call, Greenwood provided an overview of the biggest issues for BIO and then fielded questions from the participants. Greenwood acknowledged that the Biotech industry is facing a perfect storm of troubles as it comes up against a myriad of legislation proposals aimed at the drug industry and patents.

On PDUFA:

While disappointed that about $250 million in fees, Greenwood felt that BIO has done well in getting sensible changes to the Prescription Drug User Fee Act (PDUFA) reauthorization bill. Particularly in that it has moved away from a one size fits all plan for risk management to a more rational approach on a case-by-case basis.

Mr. Greenwood said that the greatest concern right now is the timing of the renewal of the previous bill, which expires Sept. 30. He expressed concerns that moral at the FDA is not good because of layoff notices and indicated that there could be a temporary extension, which could futher lower moral.

PDUFA increases funding for the Food and Drug Administration through fees paid by the drug companies, which increase the speed of drug approval at the FDA. The user fees have gone from being 7 percent of the FDA’s budget to 59 percent.

On Follow-On Biologics:

In July, the Senate Health, Education, Labor and Pensions HELP Committee gave the thumbs up to the Biologics Price Competition and Innovation Act of 2007 (S. 1695), which lays out a pathway for approving the development of follow-on biologics. Greenwood said that they want to see a follow-on biologics law passed but that “a good law that parallels the framework laid out in the Hatch Waxman Act.

The Hatch-Waxman Act allows generic manufacturers to file an ANDA demonstrating bioequivalence to an innovator drug, rather than an NDA, which is far costlier as it requires data establishing safety and efficacy.

The legislation includes standards for the FDA to approve follow-on biologics as well as a period of exclusivity for the brand name drug company. The Act amends section 351 of the Public Health Service Act to provide for an approval pathway for safe biosimilar and interchangeable biological products (relying in part on the previous approval of a brand product):

• A biosimilar applicant is required to demonstrate that there are no clinically meaningful differences in safety, purity and potency between its product and the brand product. A demonstration of biosimilarity includes analytical data, animal testing and one or more clinical studies, unless such a requirement is determined by the FDA to be unnecessary.
• The Act provides incentives for the development of both new life-saving biological products and interchangeable biosimilar products: 12 years of data exclusivity for the brand company during which a biosimilar product may not be approved, and 1 year of exclusivity for the first interchangeable biological product.
• The biosimilar applicant must provide its application and information about its manufacturing process to the brand company. A series of informational exchanges then occur in which the biosimilar applicant and the brand company identify patents in question and explain their views as to their validity or infringement.

Unlike small molecule drugs, which are approved under the FDCA, most biologics are approved under the Public Health Service Act (PHSA). The FDCA provides a framework for approving generic copies of small molecule drugs, but no commensurate legal framework is currently in place for approving follow-on biologics either under the FDCA or under the PHSA. The complexity of biologics makes it impossible to analyze them in a laboratory to the degree possible with chemical drugs, and to show without clinical trials that one biologic has the same safety and effectiveness profile as another.

To be approved as a generic, a drug must have the same active ingredient, strength, dosage form, and route of administration as the reference drug, and it must also be bioequivalent. The bioequivalence of the generic drug is demonstrated through relatively simple analyses such as blood level testing, without the need for human clinical trials.

Currently, the full Senate has not considered the bill passed by the Senate committee, and the House has taken no action thus far on two different bills addressing regulation of biosimilars. Aaron Barkoff of the Orange Book Blog said that he wondered if generic companies would try to get the legislation delayed until the next administration. Greenwood acknowledged that it is a possibility and gave a nod to the many interests involved.

Mr. Greenwood stated that any legislation should include 14 years of data exclusivity in order to protect the investment needed in the drugs from the biotechnology industry. The current protection for small molecule drugs is, on average, 13.5 years prior to generic entry. Therefore, the length of time for data exclusivity would put the biotech industry on par with the pharmaceutical companies.

Earlier, BIO released a set of principles to guide the development of a pathway for the approval of follow-on biologics. BIO also developed a detailed rationale supporting the need for substantial data exclusivity. Meanwhile, generic manufacturers expressed concern that a 12 year exclusivity for the brand company is too long.

On Patent Reform:

Greenwood noted that patent reform is being inspired by the high-tech industry, which feels threatened by so-called patent trolls. While acknowledging that the high-tech industry needs to defend itself, he expressed concern that the proposed changes are not good for the biotech business model.

Donald Zuhn of Patent Docs asked what is the most significant issue in the current patent reform bills. Greenwood indicated that the proposed rules for apportionment of damages would be most harmful to the biotech industry. Unlike a computer, which may be made up of many (often insignificant) parts, a drug company may rely on just one or two patents and need to spend a dozen years developing a drug. Apportioning damages would never take into account the true value of the invention.

The Patent Reform Acts of 2007 (both House and Senate) propose changes to damage calculations that would require specific economic analysis to ensure that any reasonable royalty damage award captures “only [the] economic value properly attributable to the patent’s specific contribution over the prior art.” These calculations would apparently apply to calculations of both past and future damages.

Such a provision on apportioning damages could require courts to adjudicate the economic value of the entire prior art, the asserted patent claims, and also all other features of the accused product or process whether or not patented. A massive undertaking. Greenwood said that he did not see any convincing evidence of the need for such a provision over the current system.

Read the draft legislation here: Biologics Price Competition and Innovation Act of 2007 (S. 1695).

About Follow-on Biologics here.

About Patent Reform Act of 2007 here.

It appears, for now at least, that the legislation creating an approval pathway for follow-on biologics will not be included in the FDA Revitalization Act (FDARA). FDARA would reauthorize the Prescription Drug User Fee Act or PDUFA (pronounced puh-doo-fuh), which expires Sept. 30.

PDUFA increases funding for the Food and Drug Administration through fees paid by the drug companies, which increase the speed of drug approval at the FDA. The FDA attempts to review and act on at least 90% of the New Drug Applications and Biologic License Applications within 10 months of the date of filing and within six months for drugs given priority review. User fees have gone from being 7 percent of the FDA’s budget to 59 percent.

Many of the new additions to the PDUFA involve the FDA’s ability to increase drug safety in the wake of Merck’s (NYSE: MRK) Vioxx withdrawal. The House bill gives the FDA power to order companies to run additional clinical trials after the drugs have been approved for marketing and requires drug companies to make much of their clinical trial data available to the public. It also gives the FDA the ability to levy up to $250,000 fines for false or misleading advertisements.

A bigger issue is whether the FDA should approve generic biotech drugs or so-called follow-on biologics, sometimes called biosimilars or biogenerics. Unlike with small-molecule drugs, there’s no mechanism for generic-drug makers to gain approval for follow-on biologics.

The two versions of the bills, S. 1082 and H.R. 2900, are currently pending before a conference committee. The Senate version of the bill contains a placeholder for follow-on biologics legislation, but the House has not yet discussed the issue.

The Public Health Service Act, under which biologics are licensed, does not contain an abbreviated approval pathway analogous to the process used under the Food, Drug, and Cosmetic Act for generic drug approvals, according to the FDA. However, the agency has approved some follow-on biologics under the FD&C Act, such as GlucaGen, Hydase, Fortical and Omnitrope.

The Senate Health, Education, Labor and Pensions Committee passed the Biologics Price Competition and Innovation Act, S. 1695, by unanimous voice vote earlier this summer, establishing a way for the FDA to approve products as biosimilar to existing biologics. S. 1695 would grant 12 years of data exclusivity to innovator biologic drugs.

Under the bill, a follow-on biologic applicant would be required to demonstrate that there are no clinically meaningful differences in safety, purity and potency between its product and the brand product. The bill also allows the FDA to approve a follow-on biologic as interchangeable. However, the applicant must provide evidence that its product will produce the same clinical result as the brand product in any given patient and that it presents no additional safety risks or diminished efficacy if a patient alternates or is switched between products.

S. 1082 also includes language that prohibits the FDA from delaying approval of a generic drug on the basis of a citizen’s petition unless such a delay is necessary to protect the public health, according to a summary of the bill. In addition, it requires the FDA to take final action on a petition no later than 180 days after its submission unless such a delay is necessary.  The use of citizen petitions has been an effective tactic in delaying generic entrants to the market, such as with Wyeth’s injectable antibiotic Zosyn (piperacillin/tazobactam).

Recent news from Congress is it’s abandoning follow-on legislation and will address biogenerics in a separate bill. This will allow PDUFA IV to finally pass but, given the fact that sales of biotech drugs were $40.3 billion last year, this issue is far from dead.

The going has always been tough for getting pharmaceutical patents. The going is getting tougher. See Aventis Pharma Deutschland Gmbh and King Pharmaceuticals, Inc., v. Lupin, Ltd. (06-1530).

In a patent infringement action concerning the pharmaceutical compound ramipril, marketed by King as a blood pressure medication under the name Altace®, the U.S. Court of Appeals for the Federal Circuit followed the recent Supreme Court guidelines on obviousness and struck down a stereoisomer as obvious.

Lupin appealed from a judgment of infringement in which the district court concluded at summary judgment that Lupin’s filing of an Abbreviated New Drug Application (ANDA) for a generic version of ramipril infringed Aventis’s U.S. Patent. No. 5,061,722 under the doctrine of equivalents and concluding after a bench trial that the asserted claims of the ‘722 patent were not invalid.

On appeal, the Federal Circuit concluded that the subject matter of the asserted claims of the ‘722 patent would have been obvious.

The patent is directed to ramipril in a formulation “substantially free of other isomers.” Ramipril is one of a family of stereoisomers — an isomer in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. The following structural formula represents ramipril:

Because there are five carbon atoms that may take either of two orientations-or five “stereocenters,” as such atoms are known-ramipril is one of 25, or 32, stereoisomers. There are a number of different ways of naming these stereoisomers; one comparatively simple system, used by both parties and by the district court, involves labeling each stereocenter with an “R” or an “S” depending on its configuration. Using this system, all five stereocenters in ramipril are in the “S” configuration, so it is known as an “SSSSS” or “5(S)” stereoisomer. Other stereoisomers would include RRRRR, SSSSR, RRSSS, etc.

Some of the prior art references also use the terms “enantiomer” and “diastereomer.” Enantiomers are stereoisomers that are mirror images of each other, like left and right hands. Diastereomers are stereoisomers that are not enantiomers.

The asserted claims of the ‘722 patent read as follows:

1. A compound of the formula:

or a physiologically acceptable salt thereof, wherein R2 is hydrogen, methyl, ethyl, or benzyl, and wherein hydrogen atoms on the ring carbon atoms in the 1- and 5-positions are in the cis-configuration relative to one another, the carboxyl group on the ring carbon atom in the 3-position is in the endo position relative to the bicyclic ring system, and the chirality centers in the chain and on the ring carbon atom in the 3-position all have the S-configuration, said compound or salt being substantially free of other isomers.

Ramipril is one of a family of drugs known as “Angiotensin-Converting Enzyme inhibitors,” or “ACE inhibitors.” ACE inhibitors inhibit a biochemical pathway that constricts blood vessels and therefore are useful for treating high blood pressure.

Ramipril’s immediate predecessor is an ACE inhibitor known as enalapril. In a published article, Merck scientists explained that the all-S (SSS) stereoisomer of enalapril was found to have 700 times the potency of the SSR stereoisomer.

Soon after enalapril’s introduction, Dr. Elizabeth Smith, a chemist at Schering, conceived of the structure of ramipril and recorded it in her laboratory notebooks. Ramipril has the same overall structure as enalapril, with one distinction: where ramipril has two linked five-sided carbon rings (a “5,5 fused ring system”), depicted, in the chemical diagrams above, on the left side of the molecule, enalapril has only a single ring. The addition of the second ring gives rise to two more stereocenters than are present in enalapril; thus, ramipril has the same three stereocenters as enalapril, plus two new ones that span the fused ring system and are therefore known as “bridgehead” carbons, for a total of five as discussed above.

Schering obtained patents No. 4,587,258 and No. 5,348,944, which disclose the structure of ramipril but do not describe how its stereocenters should be configured. Example 20 of the ‘886 application discloses a method for making ramipril and yields a mixture of several, but not all, stereoisomers of ramipril, one of which is the 5(S) form.

In February 1981, Dr. Smith synthesized a mixture of 5(S)-configuration ramipril and its SSSSR stereoisomer. The district court concluded that Dr. Smith did not separate the 5(S) and SSSSR isomers, and there is no evidence that she conceived of a purified formulation containing only 5(S) ramipril.

The key question is whether the 5(S) stereoisomer of ramipril, in a form substantially free of other isomers, would have been obvious over the prior art still remaining “substantially free of other isomers.”

The district court held that Lupin failed to meet its burden of proof by clear and convincing evidence that a person of ordinary skill in the art would have been motivated to purify 5(S) ramipril into a composition substantially free of other isomers. The district court saw this as a close case based principally on the absence of a clear and convincing showing of motivation.

Since the date of that decision, however, the Supreme Court decided KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007), which counsels against applying the “teaching, suggestion, or motivation” (“TSM”) test as a “rigid and mandatory formula[].”

The Federal Circuit noted that:

Requiring an explicit teaching to purify the 5(S) stereoisomer from a mixture in which it is the active ingredient is precisely the sort of rigid application of the TSM test that was criticized in KSR.

The “reason or motivation” need not be an explicit teaching that the claimed compound will have a particular utility; it is sufficient to show that the claimed and prior art compounds possess a “sufficiently close relationship . . . to create an expectation,” in light of the totality of the prior art, that the new compound will have “similar properties” to the old.

The analysis is similar where, as here, a claimed composition is a purified form of a mixture that existed in the prior art. Such a purified compound is not always prima facie obvious over the mixture; for example, it may not be known that the purified compound is present in or an active ingredient of the mixture, or the state of the art may be such that discovering how to perform the purification is an invention of patentable weight in itself. However, if it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, or if the prior art would provide a person of ordinary skill in the art with reason to believe that this is so, the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified.

Ordinarily, one expects a concentrated or purified ingredient to retain the same properties it exhibited in a mixture, and for those properties to be amplified when the ingredient is concentrated or purified; isolation of interesting compounds is a mainstay of the chemist’s art. If it is known how to perform such an isolation, doing so “is likely the product not of innovation but of ordinary skill and common sense.”

The prior art supporting prima facie obviousness included the SCH 31925 mixture, and so Aventis must show that 5(S) ramipril had unexpected results not over all of its stereoisomers, but over that mixture, which did not contain the RRSSS form. And the potency of pure 5(S) ramipril is precisely what one would expect, as compared to a mixture containing other, inert or near-inert stereoisomers.

Well, by a 220-175 vote the U.S. House of Representatives passed its version (H.R. 1908, the Patent Reform Act of 2007) of an overhaul of patent laws designed to trim excessive litigation and improve patent quality, giving high-tech firms what they’ve been clamoring for: a weaker patent system.

If made into law, the legislation will make patents harder to obtain and easier to challenge. It would also try to cut down on the amount of litigation by limiting where patent owners can file suit and how much they can collect in damages if they win.

The changes are in response to a growing “gut feeling” that has been propagated that our patent system is somehow broken and in need of fixing, despite decades of established jurisprudence.

Approval came after last-minute changes to appease critics, including the Bush administration, labor groups, universities, and the pharmaceutical company Pfizer, which said the original proposal had gone too far in weakening patent rights.

The White House said it would oppose the bill unless it was revised to change limits on the discretion of a court to determine damages adequate for an infringement. The administration said it supported other aspects of the bill, including steps to bring the U.S. system in line with patent systems in Europe and Japan.

The U.S. is the only major industrialized country with a first-to-invent system that awards patents to the first inventor. The proposed bill would change the rules at the U.S. Patent and Trademark Office so patents would go to the first person to file an application. It would allow third parties to introduce evidence against applications, and create a system for post-grant opposition for challenging issued patents.

It would also limit where patent suits could be filed to keep lawyers from shopping for court districts deemed friendly to patent owners. The legislation also would create a new way to calculate damages and allow immediate appeals of court rulings on the interpretation of patent terms while the case is proceeding.

Republican leader, John Boehner of Ohio, and the party whip, Roy Blunt of Missouri pointed out that “While our patent system is in need of reform, we are very concerned that the bill in its present form picks winners and losers among industries with different business models in a way that has never before been attempted in patent law or practice.” In the current bill, Congress seems to side with high tech companies over pharma and biotech.

One contentious item is that the Act changes the apportionment of damages clause by reducing damage awards substantially. The effect can be disparate since the high tech industry is often based on products built on many patents covering incremental changes and improvements while the pharmaceutical industry typically would have one or two patents covering the compound at issue. High tech companies are out to quash so-called nuisance suits while pharmaceutical companies can live and die on a single patent.

There is a lot at stake and, as a result, a lot of organized lobbying from interested parties. U.S. intellectual property, dominated by patents, is valued at as much as $5.5 trillion, according to a 2005 study by USA for Innovation. That’s more than 40 percent of U.S. gross domestic product. While many experts credit a strong patent system with the rapid rise in develo[pment in the U.S., the proposed changes would now make patents weaker by making it easier to challenge patents.

Amendments For H.R.1908

1. H.AMDT.789. An amendment to incorporate a number of revisions including revisions to the sections on damages, willful infringement, prior user rights, post-grant review, venue, inequitable conduct, applicant disclosure information and inventor’s oath requirements, among others.

2. H.AMDT.790. An amendment to eliminate provisions in the law permitting certain applicants to delay or prevent publication of their applications. The amendment would strike that provision and permit applicants to delay publication until the later of (1) three months after a second PTO decision or (2) 18 months after the filing date.

3. H.AMDT.791. An amendment to change the section relating to United States Patent and Trademark Office regulatory authority by adding the requirement that Congress be provided 60 days to review regulations before they take effect. Congress may bar implementation of the regulation by enactment of a joint resolution of disapproval.

4. H.AMDT.792. An amendment to require the Director of the United States Patent and Trademark Office to conduct a study of patent damage awards in cases from at least 1990 to the present where such awards have been based on a reasonable royalty under Section 284 of Title 35 of the United States Code. The Director of the PTO would be required to submit the findings to Congress no later than one year after the Act’s enactment.

5. H.AMDT.793. An amendment to prohibit a post-grant review from being instituted based upon the best mode requirement of patent law.

See the Administration’s Concerns here: sap hr1908.pdf

The Federal Circuit upheld a judgment upholding the validity of U.S. Reissue Pat. No. 34,712 in favor of Forest Laboratories and H. Lundbeck A/S and enjoining Ivax Pharmaceuticals and Cipla Ltd. from infringing the ’712 patent — but only as it applies to escitalopram oxalate. See Forest Laboratories v. Ivax Pharmaceuticals and Cipla, Ltd. (07-1059).

Ivax filed an Abbreviated New Drug Application 76-765 (ANDA) for approval to market generic tablets containing 5, 10, or 20 milligrams of escitalopram oxalate (EO). The ANDA certified that the claims of the ’712 patent are invalid and/or not infringed by the products.

Forest filed suit that the ANDA infringed the ’712 patent, which relates to a substantially pure (+)-enantiomer of citalopram (escitalopram) and nontoxic acid additional salts thereof. Stereoisomers are compounds that contain the same constituent atoms and the same bonding between those atoms but have different spatial arrangements.

Enantiomers are stereoisomers that are nonsuperimposable mirror images of one another. Enantiomers exhibit different optical activity; the enantiomer that rotates a plane of polarized light in the clockwise direction is the (+)-enantiomer; the enantiomer that rotates a plane of polarized light in the counterclockwise direction is the (-)-enantiomer.

Enantiomers may also be designated as the S-enantiomer and the R-enantiomer according to a different criterion relating to the location of the chiral centers. In the case of citalopram, the (+)-enantiomer is also the S-enantiomer. A mixture of equal amounts of two enantiomers is called a racemic mixture or a racemate, and separating the two enantiomers from a racemate is referred to as resolving the compound.

Forest also owned the now expired U.S. Pat. No. 4,136,193 on the racemic form of citalopram and U.S. Patent 4,650,884 that claims a method for making racemic citalopram using an intermediate racemic 1,4-diol.

EO, which is the oxalate salt form of escitalopram, is one of the compounds encompassed by the claims of the ’712 patent. It is an antidepressant by virtue of being a selective serotonin reuptake inhibitor. Independent claim 1 of the ’712 patent reads as follows:

A compound selected from substantially pure (+)-1-(3-Dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof.

The Federal Circuit agreed that Ivax and Cipla had failed to prove that the ’712 patent is anticipated because the prior art did not disclose substantially pure escitalopram as claimed in claim 1 and it did not enable a person having ordinary skill in the art to obtain that compound.

The Federal Circuit upheld the district court’s finding that chiral HPLC was a relatively new and unpredictable technique at the time of the invention and referenced unsuccessful attempts to resolve racemic citalopram, even hrough the method of diasteriomeric salt formation. Thus, the court found that attempting to separate the enantiomers of citalopram based on the knowledge of one of ordinary skill in the art would have required undue experimentation. The district court concluded that Ivax and Cipla had failed to prove by clear and convincing evidence that any of the asserted claims of the ’712 patent were obvious.

In looking at the scope of the injunction, the Fed Circuit held:

On Reducing the Scope of the Products:

We do not agree with the scope of the district court’s injunction that includes products other than escitalopram oxalate. “Although the standard of review for the issuance and scope of an injunction is abuse of discretion, whether the terms of the injunction fulfill the mandates of Federal Rule of Civil Procedure 65(d) is a question of law that this court reviews de novo.” Signtech USA, Ltd. v. Vutek, Inc., 174 F.3d 1352, 1356 (Fed. Cir. 1999). In International Rectifier, we held that “the only acts [an] injunction may prohibit are infringement of the patent by the adjudicated [products] and infringement by [products] not more than colorably different from the adjudicated [products]. 383 F.3d at 1316. In order to comply with Rule 65(d), the injunction should explicitly proscribe only those specific acts.”

Thus, while the injunction may properly extend to the “approved drug,” it should not extend to the remainder of the products covered by the patent. The injunction is therefore modified to delete the language “any products that infringe the ’712 patent, including.”

On Adding Cipla to the Injunction:

However, we find that it was not inappropriate for the district court to include Cipla within the scope of the injunction. Section 271(e)(2) may support an action for induced infringement. … Under the standards for inducement which we apply to 35 U.S.C. § 271(b), Cipla has therefore actively induced the acts of Ivax that will constitute direct infringement upon approval of the ANDA, and it was thus not inappropriate for the district court to include Cipla within the scope of the injunction.

[J]ust as Ivax will be liable for, and hence is being enjoined from, the commercial exploitation of escitalopram when it is approved by the FDA and during the life of the patent, so should Cipla be enjoined. They are partners. Cipla would be contributing to the infringement by Ivax, so the injunction should cover both partners. It is true that, as the dissent states, § 271(e)(2) defines Ivax’s filing of its ANDA as an infringement, and Cipla did not file the ANDA; however, when the question of an injunction against commercial activity arises, Cipla is as culpable, and hence entitled to be enjoined, as Ivax.

Is there an inconsistency here?

This video made me wonder more about whether YouTube had jumped the shark than about Patent Reform.