America-Israel Patent Law

The USTR's Rite of Spring

Igor Stravinsky’s The Rite of Spring describes, in musically graphic terms, the sacrificing of a young maiden as part of a pagan ritual.  In recent years, the United States Trade Representative has taken to engaging in its own rite of spring, namely publishing its “Special 301 Report”.  This report purportedly addresses “the adequacy and effectiveness of U.S. trading partners’ protection of intellectual property rights (IPR)”.  In fact, that description of the report, taken from the USTR website, is something of a misnomer, as the bulk of the report focuses on what the USTR considers to be the inadequacy and ineffectiveness of its trading partners’ protection of IP rights: of the 77 countries reviewed, over half – 42 – wound up on one of the three lists of countries that don’t measure up to the USTR’s standards.  

As has become an annual part of the USTR’s ritual, Israel once again has found itself on the “Priority Watch List”, i.e. among the worst of the worst, like China.  Which for several reasons makes people who follow the Israel IP scene pause to wonder what political agenda was behind this year’s Special 301 Report, and why yet again Israel merited being the USTR’s sacrificial maiden.  

First, categorizing Israel with China is absurd.  Ignore for the moment that population-wise China is about 200 times larger than Israel, and that its GDP likewise dwarfs Israel’s.  Among the major issues with China are the widespread production of counterfeit goods and theft of trade secrets.  But there’s nothing to compare when it comes to Israel.  Regarding counterfeits, even proportionally to Israel’s size, the problem of counterfeit of goods in Israel nowhere near approaches that in China.  That’s in large part because Israel has statutory measures granting IP rights, and the executive and judicial bodies in Israel work with the rights holders to enforce those rights.  Contrast that with China, where, if statutory protections even exist, the authorities often turn a blind eye to the goings-on.  China manufactures and exports goods bearing counterfeit marks, but if those goods show up Israel, the mark owner can have them seized; Customs will sua sponte hold such goods at the port; and once seized, the fakes will eventually be destroyed, with someone from the infringing side being made to bear the costs.  Similarly, Israel has trade secret legislation, which likewise can be and is enforced.  

In fact, the USTR deems Israel’s level of protection in these areas to be sufficient.  So if Israel provides what the USTR considers to be adequate protection and enforcement on the counterfeit and trade secret theft front, what’s the USTR’s beef with Israel?  Purportedly inadequate legislation in three areas, two of them tied explicitly to pharmaceuticals: data exclusivity, patent term extension calculation, and early (18-month) publication of patent applications.  

 This brings to the fore the second puzzling aspect of the USTR’s categorization of Israel: Israel already has data exclusivity and patent term extension provisions.  It’s just that the USTR decided the protections already in place aren’t quite good enough.  That issue was actually addressed last year, when the U.S. Secretary of Commerce and the Israel Minister of Industry and Trade reached an agreement, and the USTR seemed prepared to divest Israel of its “habitual offender” status.  As reported in earlier posts (here and here), in accordance with that agreement, changes would be made to Israel’s existing data exclusivity legislation (the period of exclusivity would be lengthened from five to six-and-half years, although the legislation would still not be an impediment to Israeli drug exporters), and to its existing patent term extension (PTE) legislation (the process for obtaining PTEs and calculating PTE would be simplified, and a mechanism for filing PTE requests before receipt of MOH approval or grant of the patent would be enabled).  Furthermore, Israel patent applications, which hitherto were opened to the public only upon completion of substantive examination by the ILPTO, would be opened 18 months after the priority date.  (In fact, as reported here, a draft bill to this effect had already been circulated for comment before the agreement was signed.)  It was agreed that the legislative changes would be made quickly, and once they were made, Israel would be dropped not only from the “priority watch list” but also from the “watch list” (which lists not the worst of the worst but the merely bad). 

What the USTR may or may not have taken into account when making that last stipulation was the snail’s pace of the Israel legislative process.  Even if that was an oversight, it doesn’t make the USTR’s position any less disingenuous.  It’s not like Israel hasn’t moved at all on these things, or that the Minister out-and-out lied.  To the contrary: as the USTR well knows, there is movement, and a good faith effort is being made to push all the pieces of legislation forward.  In some cases, the delay has been due to as mundane an issue as the government ministries responsible for drafting the legislation being short-staffed.  That makes Israel an “IP offender” on the order of China? 

Moreover, the USTR didn’t tell the Israelis was that the USTR itself would further slow the amendment process, by insisting on reviewing and approving drafts of legislation.  (Why the Israeli bodies charged with drafting that legislation acceded to the USTR’s request is both puzzling and disconcerting.)  So while legislation on all three fronts is slowly making its way through the system, that’s not good enough for the USTR, which cited the failure to enact the promised reforms – the “failure” to which the USTR is partly to blame – as the primary reason for putting Israel back on the priority watch list.  As Arlo Guthrie might say, you got a lot of damn gall. 

It’s also more than a little hypocritical for the USTR to be impatient with Israel.  The Israeli legislation isn’t moving along any more slowly than “patent reform” in the USA, which has been percolating in Congress in one form or another since 2005, and only now appears to be on the cusp of being adopted.  And unlike the changes Congress seems set to adopt, Israel’s changes probably won’t gut its patent system, as Senator Leahy seems hell-bent on doing in the USA. 

The Special 301 also "encourages" Israel to adopt statutory damages for copyright infringement.  Hello, McFly?  Someone at the USTR ought to learn Hebrew: Israel copyright law has had statutory damages for an awfully long time, including in the 2007 revision of the Copyright Act.  Actually, they don't even need to learn Hebrew: learning how to use the internet would be sufficient, since WIPO Lex actually contains an English text of that statute, and section 56 says in plain English that a copyright holder is entitled to up to 100,000 shekels for damages, without the need for proof.  So before the USTR criticizes Israel for not having what it deems to be 21st century IP laws, the USTR itself might try joining the 21st century.

By publishing this report, and continuing to equate Israel with China because Israel’s data protection and patent term extension schemes aren’t quite what the USTR wants, the USTR only undermines its position in the eyes of Israeli policy makers and those who follow IP law.

Physician's Lament: Let's Give Away New Drugs For Free

In October I wrote about the paragraph IV challenge to Eli Lilly’s anti-lung cancer drug Alimta^®, royalties from which had paid in full for a new $280 million chemistry building at Princeton University, the patentee.  In November, Princeton and Lilly prevailed at the district court, and in December the Princeton Alumni magazine carried a story about the university’s victory.  This prompted a letter from an alumnus – a physician by trade – bemoaning the P-IV lawsuit instituted by Princeton and Lilly, and the resulting “additional five years” of exclusivity, beyond the original patent term expiry in 2011, from which Princeton and Lilly would now benefit.  “It is likely that the standard seven-year period of patent protection has been enough to cover the development cost of the drug”, he wrote, asserting that while the university had benefited immensely from the drug, the deferment of the entry date for generic competition until 2016 would harm low-income patients who could not afford the $2800 per dose price tag.  “It is disheartening to see the University harming low-income patients and contributing to the high cost of American health care in this way”, he concluded.

 

Now, this may sound surprising coming from a patent attorney who spends a fair amount of his time protecting new molecules, but I’m a big fan of generic drugs.  You won’t catch me buying a name-brand version of ibuprofen, my pain-killer of choice.  However, I’m also a big believer in new drug development, and that costs big bucks.  And frankly, if it’s a choice between erring on the side of giving an innovator a longer period of exclusivity than necessary for its new life-saving drug – with a concomitantly high price for the drug – versus never having that drug reach the market because sufficient exclusivity wasn’t available, I’d rather have the innovator benefit from a few extra years of exclusivity.  So between that and some factual errors in his letter, I couldn’t let Dr. Herr’s remarks go without comment.  I reprint below (with some hyperlinks inserted) the long version of a letter I sent to the Princeton alumni magazine; my understanding is that a much-edited 275-word version will appear in the print edition of the magazine a few weeks hence.

As a patent attorney who has worked on both sides of the innovator/generic drug company divide, I was disappointed to see the position espoused by a health care professional with regard to the economics of innovative drugs like Alimta^® (David Herr ‘65, letters, January 19, 2011).

The FDA, acting as the public’s guardian, requires that new drugs meet stringent safety and efficacy standards.  The overwhelming cost of new drug development lies in the hundreds of millions of dollars spent in clinical trials to demonstrate compliance with those standards.  Furthermore, for every new drug candidate that receives FDA approval, dozens more fail somewhere during clinical trials, and hundreds more never even make it out of the laboratory.  Those many failures are funded by the few successes.  Put bluntly, if you want new drugs tomorrow, you’re going to have to foot part of bill today, because without a reasonable expectation of profit, no company is going to invest the kind of money required to develop new drug candidates.  So while Alimta^®, now approaching seven years on the market, may or may not have already paid for its own development, giving it away to generic competition at this time, as Dr. Herr seems to suggest be done, would doubtless harm the development of the next cancer-curing drug. 

Indeed, that Alimta is an anti-cancer drug already makes it exceptional.  According the only peer-reviewed study published on the subject (Grabowski, Nature Reviews Drug Discovery, Vol. 7 (June 2008) pp. 479-488), a new drug needs about 13-16 years of market exclusivity following its launch in order to justify its development.  Such market exclusivity is presently pegged to patents, which since 1995 have been limited temporally to 20 years from filing, with a possible extension of up to five years for delays in launch due to the FDA approval process.  But meeting FDA requirements for drugs for the treatment of cancer and chronic diseases like Alzheimer’s takes longer than it does for other types of drugs. 

Alimta^® itself is a case in point: the first patent application on the active ingredient was filed in 1989 and eventually granted as US 5,344,932 in August 1994 (not 2004, as stated by Dr. Herr), giving rise to an August 2011 expiration date.  However, FDA approval for the drug only came nine-and-a-half years later, in February 2004 – fourteen-and-a-half years after the filing of the initial patent application.  Without the possibility of a patent term extension to compensate for slow FDA approval (which extension was ultimately granted, until 2016), it is doubtful that Alimta^® would have reached the market; without the profits generated by Alimta^® over the next five years (for example, if another generic drug company were to successfully challenge the patent during that time), other promising new drugs may die in the pipeline.

Incidentally, neither the grant of a patent nor a patent term extension is a guarantee that the innovator will have market exclusivity for that optimal 13-16 year period.  Under the current system, which ties new drug exclusivity to patents, litigation over the validity of those patents is de rigueur; generic drug companies will usually be considered remiss if they don’t challenge an innovator’s patents.  And for reasons I won’t go into here, the deck is currently stacked against the innovators when it comes to patent validity challenges.  What bears mention is that making the timing of entry of generic competition dependent on the outcome litigation creates unpredictably for both innovators and generics manufacturers.  The potential for the untimely loss of market exclusivity due to the loss of a patent thus becomes part of the pricing calculus for innovators.  For this and other reasons, it would probably better to move to a set-term-from-FDA-approval regimen for determining market exclusivity; I discussed this a few months ago in a blog post written in response to an earlier PAW article about the Alimta^® litigation.

Returning to Dr. Herr’s letter, it is heart-wrenching to see someone suffer from a terminal disease solely because they can’t afford the treatment.  But would Dr. Herr prefer that in 30 years’ time his progeny have no more choices for life-saving therapies than are currently available, because in his own lifetime he gave away today’s profit-generating drugs and thus undermined future drug development?

There is, of course, a place for generic drugs in this system: after the 13-16 year window of exclusivity that makes new drug development financially worthwhile.  Not only does the arrival of generic competition cause the price of drugs in the U.S. to plummet precipitously, making those medications affordable for nearly everyone, but without the threat of generic competition, innovator companies would have less incentive to develop new drugs.  

Finally, in the global scheme, the construction of a new chemistry building at Princeton using royalties from Alimta^® is also a good thing.  The old Frick building was well past its prime was I was there in the late 1980’s; at least a few of the many students who will be trained in the new building will over the course of their careers contribute to humanity by participating in new drug development, or by developing generic versions of older drugs.

Daniel Feigelson '90

Rehovot, Israel

Another Fine Mess: What do IBM, Boehringer Ingelheim and Amgen Have In Common?

A few weeks ago I posted about the Commissioner of Patents getting very publicly raked over the coals by a legislator for having unilaterally decided a few years earlier to cease paper publication of the Patents Journal by the Government Press Office (GPO), as required by statute, and to instead only publish the Journal on the ILPTO’s website, all the while continuing to collect the publication fees set by law.  The incident occurred in the context of a committee hearing in the Knesset in which the topic of discussion was a statutory amendment that would enshrine the practice prospectively and ex post facto give legal force to the online publication that had already taken place.  Although the committee decided to put off further discussion until later, I noted at that time that (a) the failure to engage in paper publication cast a cloud over the validity of several thousand patents, but (b) for that very reason the Knesset would enact the proposed legislation to retroactively fix the situation. 

Perhaps unsurprisingly, it only took a few days for some cash-hungry lawyers and some potential plaintiffs to find each other and to file suit against the Commissioner, seeking to have the suit declared a class action.  After all, a single thousand-shekel publication fee paid by an individual applicant is hardly worth fighting over, but if several million shekels in official fees paid by thousands of applicants are at stake, a win would be a windfall for the lawyers, and the plaintiffs might even see a few shekels themselves.  The reasoning evinced in the complaint is seriously flawed, but that’s the topic for a later post. 

In the interim, the ILPTO got the message: on October 31, 2010, it published Patent Journals Nos. 2/2010, 3/2010 and 4/2010, but this time it made sure to have the GPO simultaneously print a copy of each Journal, so that there was simultaneously publication online AND in “Reshumot”, the official state publication organ.  No doubt about it, these three Patents Journals are definitely kosher.  

Today’s post focuses on some of the many patents the status of which is presently in question, and which are in need of a legislative fix.

Exhibit A is a group of patents belonging to IBM.  The four patents in question, IL 151545, IL 153888, IL 157506, and IL 159655 all lapsed in 2007-2008 for failure to pay maintenance fees.  When IBM discovered the oversight, it filed requests to reinstate the patents, in August and October 2009.  Notice of the requests to reinstate were published in the Patents Journal online on the ILPTO website, but paper copies weren’t published.  In the absence of opposition, all four patents were reinstated.  Or were they?  The statute requires that notices of requests to reinstate be published in “Reshumot” by the GPO.  Since formally such publication never took place, it can be argued that technically these four patents still haven’t been reinstated and are therefore presently unenforceable.

Actually, in this particular case, it gets even better: it’s not clear that any of the four patents were actually granted.  The original publication per §26 of the statute of notices that the applications had been allowed by the ILPTO also took place on the ILPTO’s website, without a corresponding paper publication in “Reshumot”.  Since publication in Reshumot is a sine qua non of the patent grant process, it can be argued that technically these patents are still merely applications awaiting publication in Reshumot.  If that’s the case, then IBM should probably ask for a refund of the fees it paid to reinstate the “patents”…

Of course, at worst for IBM, the ILPTO could now publish a paper version of the Patents Journal that would list these four patents.  While that would represent several years lost from the life of the patents, the patents would still be in force.  As will presently be explained, that option isn’t available for our next exhibit.

Exhibit B is IL 95691.  This patent covers tiotropium bromide monohydrate.  That’s the active ingredient in Boehringer Ingelheim’s product Spiriva®, a drug for treating chronic obstructive pulmonary disease.  Spiriva had worldwide sales of over 2 billion Euros in 2009.  The patent was filed on September 14, 1990, but the drug wasn’t approved by the local health authorities until 2004, making the patent eligible for a patent term extension (PTE).  Boehringer timely applied for a PTE, and in March 2010 the ILPTO published notice of intent to grant the extension; the PTE was ostensibly granted several months later in the absence of any opposition thereto. 

But here too, the publication of the notice of intent to grant the PTE occurred only on the ILPTO website, not in the GPO-published, cellulose-based “Reshumot”.  Technically, then, the Commissioner wasn’t authorized to grant the PTE, the “granted” PTE is a nullity, notice of the intent to grant still awaits paper publication in “Reshumot”, and only thereafter can the Commissioner grant the PTE.  

Now we come to the real problem: without a valid PTE, this patent expired in September 2010.  And under the current statute, the Commissioner is neither empowered to grant interim PTEs prior to expiration of the patent (in contrast to the situation in the USA), nor is he authorized to grant a PTE after the expiration of the patent.  In other words, without amendment of the statute to retroactively give legal force to the online publication, this patent is dead.  I don’t know what the local market for Spiriva is, but if it’s doing 2B Euros annually it has to be worth at least a few million here in Israel.

Exhibit C is IL 95572.  This patent covers etanercept, a version of the alpha- and beta-receptors of tumor necrosis that is the active ingredient in Immunex’s (Amgen’s) Enbrel®.  Enbrel, which is indicated for various types of arthritis, had sales of nearly 3.5 billion dollars in 2009.  Enbrel was approved by the Israel Ministry of Health in 2000.  Unfortunately for Immunex/Amgen, although the patent application was filed in 1990, the ILPTO didn’t allow the application until 2008, at which point it was published in the Patents Journal.  Online.  Without a paper publication in “Reshumot”.  So again, technically, the grant of this patent is a nullity, and Immunex needs to await paper publication before it can get its patent.  The only problem with that is that the 20-year term for this “patent” ended in April 2010.  Moreover, this “patent” was eligible for a PTE, and ostensibly received such a PTE, but again, the notice of intent to grant the PTE was only published online, not in “Reshumot”.  So, as in the case of Spiriva, the patent for the API for Enbrel is no longer in force, the Commissioner can’t grant a PTE, and the only hope for getting patent protection at this point is for a retroactively effective amendment to the statute.  The good news for Immunex/Amgen is that since this is a biologic drug rather than a traditional small molecule, it may be a while before generic competition is in a position to receive Israel Health Ministry approval. 

It’s unclear to me why the Knesset committee chose to stall action on this amendment last month.  If, as it seems it may be, the committee chairman, David Rotem, is either trying to capriciously flex his legislative muscle or simply nursing a bruised ego, the present situation is reminiscent of a Laurel & Hardy film.  I stand by my prediction that the Knesset will enact the necessary amendment to fix this problem.  The Commissioner’s motives in this case were the right ones: online publication is a faster and far more efficient way to disseminate the notices that hitherto have been published in “Reshumot”.  True, he should have lobbied the Knesset to make the change first, or at least seen to it that at least one paper copy of the Journal would be published by the time the Journal went online.  Nevertheless, the fact that he didn’t get the statute changed first is no excuse for committee chairman to keep the necessary amendment holed up in committee.  Such failure to act would be folly.  Ultimately, no one has been harmed by the online-only publication.  To the contrary: the filing of oppositions to patent applications has continued apace, indicating that the notice function of publication is being met.  Israel patents continue to be indexed in international patent databases, such as the EPO’s Inpadoc and Derwent’s WPI.  It’s inconceivable that the thousands of patent applicants stand to lose their patents because of Knesset inaction.

Getting the Best Medicines to Market, Not Just the Medicines with the Best Patents

Yesterday the latest copy of my college alumni magazine arrived.  The magazine included an article on the campus’ new chemistry building, built at a cost of about 280 million dollars, and funded entirely by royalties from U.S. patent no. 5,344,932.   That patent covers pemetrexed, the active ingredient in Eli Lilly’s Alimta^® anti-lung cancer drug, which first received FDA approval in 2004.  

Aside from making me wistful for my college years – it turns out that youth really is wasted on the young – and envious of the students who will have the opportunity to do labwork in this stunning new edifice (instead of toiling in the bowels of a 1930’s-era labyrinth, as did yours truly), what struck me was the accompanying article on the litigation around the ‘932 patent.  Or rather, my nonchalance with respect thereto.  

Specifically, my wife thought it interesting that my alma mater is suing Israel-based Teva, its subsidiary Barr and APP Pharmaceuticals for infringing the ‘932 patent.  I was unperturbed.  “Hon, this kind of litigation is routine with drug patents.  I’d be shocked if the generic drug manufacturers didn’t challenge the validity of the patent and there wasn’t a lawsuit.”  Only after making the remark did it strike me how utterly bizarre it is not only that Orange Book listings, paragraph IV certifications and the resulting lawsuits, and reverse payment settlements are the norm, but just how inured those of us who practice in this area of the legal world have become to this situation. 

The incident drove home, not for the first time, the picture painted by Robert Armitage in a presentation he gave last May at the American Intellectual Property Law Association’s spring meeting in New York.  Mr. Armitage is Senior Vice President and Chief General Counsel of Eli Lilly, and his talk focused on the fact that under the Waxman-Hatch system, the new drugs that get developed are those with the best patent protection; these are not necessarily the drugs for which there is the greatest need.  The following summary is my own restatement of Mr. Armitage’s talk, but I strongly urge readers to read his entire paper, which may be downloaded here, with the gracious permission of Mr. Armitage.

The talk began by looking at the motivations and goals surrounding the enactment of the Hatch-Waxman amendment in 1984.  New drug development, including the requisite clinical testing and the physician education and marketing necessary to get new drugs prescribed, is inherently a high-risk investment.  Consequently, new drugs are priced to provide a return commensurate with that high risk.  Waxman-Hatch was designed to create a generic drug industry that would sell copied versions of new medicines for roughly the cost required to manufacture those medicines.  It was anticipated that because generics would in effect be government-certified substitutes for the new medicines, which could be prescribed and dispensed to patients in lieu of the new medicines, generics would be able to take over the market for the new medicine, without the need to brand the copied versions, to otherwise promote them, or to educate physicians regarding their use.  Unburdened of these needs and the costs of new drug development, the entry of generic competitors to a particular drug would cause the price of that drug to drop.  In this regard, the legislation was right on the mark: in the United States, the entry of generic competition causes drug prices to plummet.

Nevertheless, Hatch-Waxman appreciated that the originators of new drugs would need to be able to recoup their investments and produce profits, or else those investments wouldn’t be made in the first place and the new drugs would never see the light of day.  The legislation chose to protect the innovators’ interests in a patent-centric manner: 

●             On the one hand, under Waxman-Hatch innovators were required to list relevant patents with the FDA, and the entry of generic drugs into the market was to await the expiration of those FDA-listed patents that would be infringed if the generic version were to be marketed.  Generic drug manufacturers, on the other hand, were provided with a vehicle to seek approval for their copies of the innovator drug prior to patent expiration, and were provided a mechanism to challenge the validity, and to defend against a prospective charge of infringement, of any of the originator’s FDA-listed patents, in order to determine the actual timing for generic drug entry. 

●                Furthermore, to encourage prompt challenges of questionable patents, generic companies were given an incentive to challenge the validity or the infringement of the FDA-listed patents: successful challengers were given the right to be the exclusive generic drug entrant into the market for a 180-day period.  This generic exclusivity period was justified on the basis that, absent the successful challenge, there would have been no generic drug entry until a later patent expiration date.

●                Additionally, recognizing that the time taken to prove the safety and efficacy of a new drug might eat into the patent lifetime, Hatch-Waxman provided a means for innovators to obtain up to five years of extension for a patent covering a new drug whose entry into the market had been delayed by the FDA approval process. 

This patent-centric regime does a poor job of ensuring that important new drugs reach the public.  The principal problem with Hatch-Waxman in creating this patent-centric regime was that, even when originally enacted, the legislation didn’t take into account the fact that patent life doesn’t correspond to the realities of pre-market drug development, let alone post-market drug development.  There is a time lag between patent filing and FDA approval; since the enactment of Hatch-Waxman, that time delay has only gotten worse. 

Thus under the no-publication-until-grant, 17-years from patent grant system in place at the time Hatch-Waxman was enacted, the scheme envisioned by the legislation wasn’t perfect, although it wasn’t necessarily unreasonable either.  Innovators with still-pending patent applications on new active ingredients that were likely to mature into drugs could delay the grant of the patents until around the time of FDA approval by making appropriate use of continuation applications.  And innovators with granted patents could still obtain an extension of patent term to compensate for time lost from the effective patent life due to regulatory review.  Nevertheless, it was possible for innovators to lose effective patent life due to the lag between patent grant and FDA approval of the new drug.

Subsequent to Hatch-Waxman, as part of its obligations under GATT-TRIPS, the United States moved to a 20-years-from-earliest filing regime.  This change in the law, without a commensurate change in the Hatch-Waxman provisions, meant that the effective lifetime of patents on new active ingredients was significantly foreshortened.  Under the post-TRIPs regime, patent applications still need to be filed early in the development process, but if FDA approval takes more than five years – which is routinely the case – the innovator isn’t compensated for the lost effective patent lifetime. 

Moreover, as part of the Medicare amendments of 2003, the 180-exclusivity for first generic filers was spread around to all generic drug companies that were the first to file abbreviated new drug applications (ANDA) on the same day, rather than the one company that was first to file in absolute terms, even if that was by a matter of minutes.  This has resulted in more generic challenges to listed patents.

As a result of this situation, companies that develop new drugs are reluctant to do so for any particular drug candidate if the drug approval process will be too long, because their period of market exclusivity – the period in which they will realize a return on their investment and generate profits for shareholders and, more importantly, for re-investment in the development of newer drugs – will simply be too short to justify the investment.  That’s the case even for drug candidates for which patent protection is available.  If there is no patent protection, forget about it: there will be no new drug, because no one will invest the hundreds of millions of dollars necessary to bring the drug to market.  (Although in the USA an innovator receives 5 years of FDA data package exclusivity protection independent of the existence of any patent protection, that five-year period is insufficient to warrant the necessary development in new drugs.)

Perversely, it is precisely the potential drugs that require the most testing, such as drugs for cancer or chronic diseases, that are the victims of this situation.  A case in point from Israel: there’s a research group here that in the early 1990’s synthesized and identified some potential anti-Alzheimer’s drugs, and file a patent application at that time.  Sometime after June 1995, the group filed a new application on some new compounds synthesized as part of their ongoing research.   Unfortunately for the group – and, possibly, for people with Alzheimer’s and their families – the group’s patent attorney made the mistake of filing the new application in the USA as a continuation-in-part of the first application, even though the new compounds could have been filed in a stand-alone application.  As a result, the new compounds lost several years of patent protection, and no one wanted to make the investment necessary to develop a commercially available drug from the group’s research.  The compounds are still sitting on the shelf today.  Maybe one of those compounds will make a good medicine for Alzheimer’s, but unde the current Hatch-Waxman scheme, we’ll never know, since at present, good patent protection is a necessary component of new drug development.

Mr. Armitage’s proposed solution for this problem is to de-couple protection for innovators from patent portfolios, by granting innovators 14 years of data exclusivity for their newly-approved drugs.  (The 14-year figure is taken from the article by Henry Grabowski published in 2008 in Nature Reviews Drug Discovery, Vol. 7, pp. 479-488.) 

This would elegantly address several issues: 

●             First, it would establish for all parties when generic competition may enter the market, rather than leaving that determination in limbo as courts deal with multiple Hatch-Waxman challenges to an innovator’s FDA-listed patents.  This in turn would enable innovators to properly assess the economics of proceeding with drug development.  It would also liberate resources within both innovator and generic companies that currently are directed to patent litigation.

●             Second, it would enable innovators to conduct after-launch testing and monitoring of the drug, including the development of new indications for the drug.  Such after-launch monitoring has become a matter of increasing concern in recent years, as the public has come to understand that the FDA does little in the way of after-launch monitoring. 

●             Third, it would not preclude others from conducting their own clinical trials and bringing their own copies of the approved drugs to market before the end of the 14-year period.   

●             Fourth, and most importantly, it would facilitate the development of drugs for cancer and chronic diseases, as the innovator would not have to concern itself with a ticking patent clock while it conducts the clinical trials necessary for drug approval.  In other words, it would enable development of the best medicines, not just the medicines with the best patents.

Mr. Armitage’s proposal makes awfully good sense.  Which is why I don’t hold out hope of it being adopted by legislators any time soon…although occasionally politicians do get things right…

Angiomax (Bivalirudin) – Another Day, Another Interim Extension and Another Patent

As discussed in earlier posts, back in early 2001 The Medicines Company (TMC) missed by one day the deadline to request a patent term extension (PTE) for US 5,196,404, which covers bivalrudin, the active ingredient in its flagship Angiomax^® drug product.  In March of this year, just days before the ‘404 patent was to expire, TMC convinced a federal judge in the Northern District of Virginia to order the USPTO to grant an interim PTE.  Per that order, the USPTO granted an interim extension until May 23, 2010. 

 

It’s now May 25, and inquiring minds are doubtlessly wondering, is the ‘404 patent in force or not?  Well, according to the Transaction History on PAIR, on Friday, May 21, 2010, the USPTO granted another interim PTE, although as of this writing that document does not appear in the Image File Wrapper; presumably it will be posted in the coming days.  Interestingly, neither the IFW nor the TH list a request for a second interim extension as having been filed, so it’s unclear from PAIR if such a request was filed by TMC or if the PTO itself docketed to issue an interim extension sua sponte in the absence of resolution of the district court proceedings in NDVa.  However, as reported by Kurt Karst at the FDA law blog, the second interim extension was granted by court order, upon an emergency motion filed by TMC.

 

Interestingly, apparently the PTO, in opposing an TMC’s emergency motion, said that it lacked the statutory authority to issue a second interim extension, and that the judge could not order the PTO to exceed its authority and in so doing violate an act of Congress, although it said it would comply with such an order if one issued.  It would have been fascinating to see what would have happened had the USPTO not obeyed the order and not issued the interim extension, thereby letting the patent expired.  The statute and rules provide for reinstatement of a patent that lapsed due to failure to pay a maintenance fee (see 35 U.S.C. §41(c) and 37 C.F.R. 1.378), with rights accruing to third parties who rely on the lapse during the intervening period.  And the statute provides for the PTO to issue interim extensions if the patent-protected product is still undergoing FDA review at the time the patent reaches the end of its natural life, at the request of the patentee (see 35 U.S.C. §156(d)(5)(B) and (C)).  But there’s nothing in the statute about reinstating a patent the term of which has expired.  Clearly, the drafters of §156 didn’t contemplate it taking over nine years from grant of FDA approval to determine whether or not a patentee was entitled to a patent term extension.  (I wonder why not?)

 

So had the USPTO had not issued a new interim PTE last Friday, and yesterday a competitor imported bivalirudin to the USA, would TMC have had any recourse?  Clearly the USPTO would disagree with the power of an Article III judge to order reinstatement of a patent in such a situation.  But even if the USPTO reinstated the patent under such circumstances, would the competitor now have acquired the right to sell the product imported while the patent was dead?

 

 

In a most definitely real and not hypothetical vein, TMC also recently acquired another patent to protect bivalirudin.  US 7,713,928, titled “Ready-to-use bivalirudin compositions”, issued on May 11, 2010 from USSN 12/563,821, filed in September 2009 as a continuation of 12/545,036, filed a month earlier.  (Curiously, PAIR does not link the issued patent to the earlier application.)  Like US 7,582,727 and US 7,598,343, both of which were filed in July 2008 and issued in the second half of 2009, the ‘928 patent was filed with both a non-publication request and a request for accelerated examination.  (Another case, USSN 12/180,550, also filed in July 2008, remains pending and unpublished, and from an IDS filed in during prosecution of the ‘928 patent, it appears there are two other related, still-pending applications, USSN 12/652,872 and 12/683,045, that have not yet come up for publication.)  However, the non-publication request was rescinded in January 2010, apparently to facilitate the filing of corresponding cases abroad. 

 

The independent claims of the ‘928 patent read as follows:

 

1.     A ready-to-use composition comprising (i) bivalirudin (SEQ ID NO: 1), or salts thereof; (ii) one or more pharmaceutically acceptable stabilizing agents, selected from the group consisting of buffering agents having a pK_a of about 2.5 to about 6.5, pH-adjusting agents, polymers, preservatives, antioxidants, sugars or polyols, and combinations thereof; and (iii) a pH of about 4 to less than 5, wherein total impurities are less than about 15% area-under-the-curve ("AUC") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 215 nm after storage at 25ºC for 1 month.

 

19.    A ready-to-use composition comprising bivalirudin in an amount of about 5 mg/mL; (ii) a buffering agent having a pKa of about 2.5 to about 6.5, wherein the buffering agent is acetate; (iii) [9-10]-cycloimido bivalirudin; (iv) [11-12]-cycloimido bivalirudin; and (v) a pH of about 4.25, wherein after storage at 25ºC for one month, total impurities are less than about 15% area-under-the-curve ("AUC") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 215.

 

20.    A ready-to-use composition comprising (i) bivalirudin in an amount of about 5 mg/mL; (ii) a buffering agent having a pKa of about 2.5 to about 6.5, wherein the buffering agent is acetate; (iii) sodium chloride; (iv) [9-10]-cycloimido bivalirudin; (v) [11-12]-cycloimido bivalirudin; and (vi) a pH of about 4.2, wherein after storage at 25ºC for one month, total impurities are less than about 15% area-under-the-curve ("AUC") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 215 nm.

 

These claims will not present an impediment to companies wishing to copy Angiomax^®: that product is sold in lyophilized form and is reconstituted within 24 hours of use, whereas the specification of the ‘928 patent defines “ready-to-use composition” as excluding compositions which have been reconstituted within 24 hours of use.  This is in keeping with the goal, stated in the patent, of providing a bivalirudin composition that does not require reconstitution and which is stable for a long period of time in liquid form. 

 

Claims 19 and 20 are interesting in that they recite the presence of two impurities, viz. [9-10]-cycloimido bivalirudin and [11-12]-cycloimido bivalirudin.  The specification surmises that these impurities are intermediate structures involved in the formation of other, previously-identified impurities; the ‘727 and ‘343 patents are actually directed to compositions having low levels of these previously-identified impurities.  As there doesn’t appear to be any utility for the compositions containing the recited cycloimido bivalirudins, one wonders what would happen if the defense of claims 19 or 20 against the prior art came down to the presence of these two impurities.  An echo of the SKB-Apotex fight over crystalline paroxetine hydrochloride?