America-Israel Patent Law

Hey Rocky, Watch Me Pull A Rabbit Out of My Hat (or Maybe a Last-Minute Patent Term Extension) – The Bivalirudin (Angiomax) Saga Continues

 

As noted here and elsewhere, The Medicines Company (TMC) failed to secure a patent term extension (PTE) for US 5,196,404, its patent on bivalirudin, a peptide drug that is used as an anti-coagulant during surgery and marketed by TMC as Angiomax.  The deadline for filing a request for PTE is 60 days after FDA approval, but the FDA and USPTO determined that TMC filed its PTE request for the bivalirudin patent one day late.  Oops.  The patent is set to expire next month, on March 23.

 

But when you have a drug worth several hundred million dollars per year, like Angiomax, you don’t take no for an answer.  So TMC first tried to get the USPTO and the FDA to change their minds, filing a request for reconsideration in 2002.  No dice.  Then the Congressman from TMC’s district introduced legislation that would have provided a fix, but the bill is still languishing on Capitol Hill.  So TMC secured two further patents, US 7,582,727 and US 7,598,343, on what Madison Avenue might call “new and improved” versions of bivalirudin (with a third application still in the pipeline at the USPTO), promptly listed those in the Orange Book, and when Teva filed paragraph IV certifications against those patents, sued Teva for infringement in October and December 2009.  Unfortunately for TMC, since Teva’s ANDA for bivalirudin was filed before the new patents were listed in the Orange Book, there’s no automatic 30-month stay, and the best TMC can hope for right now in that litigation is a preliminary injunction, which may or may not issue before March 23, if it issues at all.

 

The latest round in the saga is that last week TMC filed suit against the USPTO, the FDA, the Department of Health and Human Services, and their various heads.  Two days later TMC filed a motion for summary judgment (Download TMC SJ motion).  TMC’s argument boils down to the following:

 

1.     The FDA faxed its approval letter for Angiomax to TMC after business hours on Friday, December 15, 2000. 

 

2.     The FDA regards after-hours submissions made to the FDA under 35 U.S.C. §156 as having been filed on the next business day.

 

3.     In contrast, the PTO and the FDA regard the after-hours fax to TMC, a communication from the FDA under 35 U.S.C. §156, as having been sent on December 15, i.e. on the day it was sent, rather than December 18, 2000, the next business day.

 

4.     The PTO and FDA should interpret like terms in 35 U.S.C. §156 consistently, and thus, consistent with FDA policy regarding incoming submissions, should regard the FDA’s approval letter as having been sent on December 18, 2000, i.e. the next business day.  If the date of the approval letter was December 18, 2000, then the PTE request, submitted on February 14, 2001, was timely filed.

 

TMC asserts some other points, e.g. in the context of a refusal of request for reconsideration in 2007, the USPTO announced for the first time a new policy of calculating the 60 day deadline as beginning on the date the FDA approval letter was mailed, and not beginning on the next day, as had been done until that point (with the effect being that the PTE request was filed two days late rather than a day late).  But the crux of its argument is that the inconsistency in interpretations of deadlines under the same statutory section is not required by the statute itself, and therefore constitutes arbitrary and capricious agency action.

 

Reading the SJ motion, it’s hard not to feel some sympathy for TMC: it picked up a drug product that other companies didn’t want and brought it to market, at a cost of several hundred million dollars, and then it (or its lawyers) goofed when calculating the deadline for filing the PTE request. 

 

And it does sound ridiculous that the FDA can use a double-standard when it comes to dating incoming submissions from pharma companies (must be received by the end of the business hours to be accorded a filing date of that day) versus outgoing correspondence (given the date on which it is sent, even if sent after-hours). 

 

It also sounds ridiculous that the USPTO has apparently changed its view mid-stream, and now for purposes of calculating the deadline for requesting a PTE says the 60 day window starts on the day the FDA mailed its approval, whereas filing deadlines for claiming priority from patent applications or for filing responses to Office Actions begin the day after filing (e.g. if you file a provisional on January 1, you have until the following January 1, not December 31, to file a non-provisional claiming priority therefrom; a response to an action mailed on February 1 with a three month deadline must be filed by May 1 to avoid incurring extension fees). 

 

None of that, however, changes the fact that TMC (or its lawyers) goofed.  Reading between the lines (I have not checked PACER to see if any of the documents referred to in the SJ motion are available, let alone read them), it seems that TMC only decided to rely on the distinction in the FDA’s practice regarding the dating of incoming versus outgoing correspondence after the mix-up occurred.  True, if TMC had reasoned a priori that the effective date for the FDA’s approval letter was December 18, and that its filing deadline should be calculated as 60 days beginning December 18 inclusive, then it would have determined that the deadline was February 16, a Sunday, and might have pushed its filing up to Friday, February 14.  But TMC doesn’t actually allege that it calculated the date in accordance with the December 18 date; TMC only asserts that now, December 18 is the date that should be used to calculate the PTE filing deadline.  More importantly, when you’re dealing with what is likely to be a big seller for you, you err on the side of caution in calculating the date; and normally, you assume the date something was mailed or faxed is the date stamped on it.  In which case TMC should have calculated the deadline correctly.  So it seems unlikely that TMC itself bought into this “next business day” calculation at the time it filed the PTE request.

 

My own suspicion is that TMC either calculated the deadline as two months, rather than 60 days, beginning on December 15, thus making the deadline February 14; or it calculated the deadline as two months beginning from December 16, making the deadline February 15, 2001, a Saturday, and pushed the filing up to the last business day before the deadline.  It’s not necessarily unreasonable to confuse a 2-month deadline with a 60-day deadline, but the statute does say 60 days, not two months.  And whereas the statute provides the Director with discretion to extend certain deadlines, the deadline for filing a PTE isn’t one of them.

 

TMC’s implied assertion, viz. that it’s unfair to penalize TMC for missing the filing by a single day, also rings hollow.  The law is full of examples where a single day makes all the difference.  If you were born 18 years before election day, you get to vote; but if your 18th birthday falls the day after election day, you don’t get to vote.

 

Nor does TMC make a compelling argument for why the inconsistency in FDA policy regarding dating, if it needs to be resolved, should be resolved as TMC proposes it, viz. that after-hours communications from the FDA should be accorded a date of the next business day.  Why shouldn’t the matter be resolved in the other direction, so that the filing date of a paper would be the day on which it is submitted?  On its face, that seems a more logical approach. 

 

Anyway, whatever sympathy one might have toward TMC’s predicament tends to dissipate in view of the fact that the suit was filed so close to the date of patent expiration, when, evidently, the suit could have been filed almost three years earlier.  According to the SJ motion, TMC filed a request for reconsideration that was rejected by the USPTO in April 2007; in December 2009 it filed a second request for consideration, which was rejected in January 2010, and only then did TMC file suit under the Administrative Procedures Act.  But already in 2007, TMC argued that the FDA’s and PTO’s calculation of the deadline was improper, and should have started from December 18, 2000.  So if TMC had these arguments in hand in 2007, why did it wait over two-and-half years to again request reconsideration and then to sue the PTO, the FDA and HHS? 

 

I don’t know enough about APA proceedings to know if TMC could have sued right away in 2007, or if laches (an equitable argument) could apply in the present case (a case brought at law) due to the delay, but I hope that that’s part of the Federal Government’s response.  

 

The delay in the filing of the suit isn’t just whistling Dixie: there was reliance by third parties on the non-issuance of the PTE.  Teva/Barr/Pliva filed an ANDA with a paragraph III certification regarding the patent in question (i.e. that it won’t sell its product until after the expiration of the patent), not a paragraph IV certification.  Grant of a PTE here will force Teva to revise its ANDA to include a P-IV certification against this patent; or to wait close to another five years to introduce its product, until the extension expires; or to launch its product at risk.  But since the ‘404 patent was listed in the Orange Book at the time the ANDA was originally filed, if the PTE is granted and Teva files a P-IV certification, TMC would be entitled to a 30-month stay when it sues Teva for infringement of the ‘404 patent (unlike the already pending suits on the newly listed patents).  Which presumably is why TMC waited to file suit against the government.

 

Finally, an interesting question to ponder is, what happens if the court doesn’t rule before the patent expires?  Or if it rules against TMC but TMC appeals?  35 U.S.C. §156(e)(2) says,

(2) If the term of a patent for which an application has been submitted under subsection (d)(1) would expire before a certificate of extension is issued or denied under paragraph (1) respecting the application, the Director shall extend, until such determination is made, the term of the patent for periods of up to one year if he determines that the patent is eligible for extension.

 

§156(e)(2) empowers the Director to issue a temporary extension under because the PTO hasn’t yet completed its determination of the eligibility of the patent for the extension.  But that’s not the case here.  Here, the PTO’s position is that, for purposes of §156(d)(1) and (e)(2), TMC didn’t submit an application, because the so-called application was submitted after the deadline and therefore, for purposes of the statute, was not submitted.  There is no provision for the Director to issue an interim extension because there is a dispute over whether or not the PTE application was timely filed.  (§156(d)(5)(B) provides for interim extensions when FDA review is still ongoing.)  But if no interim extension is granted, and on appeal TMC wins, what then?  And if the court preliminarily orders the Director to grant an interim extension, only to eventually rule against TMC, will TMC have to compensate Teva, and the consumers who paid higher prices than they should have while the temporary extension was in place?

 

Against the foregoing discussion, the last line of its SJ motion is almost comical.  It reads, “The Court should also order the PTO to take such actions as necessary to ensure that the ‘404 patent does not expire pending further resolution of these proceedings”.  Well, sure.  Wait until the last minute to file suit and then ask that the court ensure your rights aren’t harmed as a result of that late filing – in so doing possible unnecessarily prejudicing third parties and the public.  It’s not quite the classic case of the man who kills his parents, then pleads for mercy before the court because he’s an orphan, but it’s not so far off either.

So by waiting to file its suit, TMC has created a cloud over the status of the ‘404 patent.  TMC is the only beneficiary of the existence of that cloud.  While it’s not as good a position to be in as having the PTE in hand, it’s not a bad position for a company that missed its filing deadline.

Prosecution Laches and Inequitable Conduct: Cancer Research Technology et al. v Barr Laboratories et al.

Cancer Research Technology et al. v Barr Laboratories et al., D-Del, Civ. No. 07-457-SLR, January 26, 2010, Judge Sue L. Robinson.  Download CRT v Barr

 

A fellow patent attorney (who wishes to remain anonymous) called my attention to a recent decision issued by Judge Sue L. Robinson of the Delaware District Court.  I’m not a district court decision junkie: since most patent cases revolve, at least in part, around claim construction, and since under Cybor the Federal Circuit reviews claim construction de novo, I tend to ignore many district court decisions – why bother getting into a claim construction-based case before the Federal Circuit has had its say on claim construction?  This case, however, Cancer Research Technology, et al. v Barr Laboraties et al. (really Schering v Barr) dealt with the question of prosecution history laches and inequitable conduct.  The i.c. part is primarily of interest to people practicing in the pharma and biotech fields, where patent applications are usually filed before extensive laboratory and clinical testing of compounds has been carried out.  The laches part is of greater general interest, although less so under the 20-years-from-filing regime.

 

At issue was US 5,260,291, directed to tetrazine derivatives and their use in treating various cancers.  The patent covers the compound temozolomide, which Schering markets under the name Temodar^® for the treatment of two types of brain cancers, glioblastoma multiforme and refractory anaplastic astrocytoma.  As explained in the ruling, the story started in the early 1980’s, when some researchers at Alston University in England developed some tetrazine derivatives and, in conjunction with UK pharmaceutical company May & Baker, began testing these for use against various cancers.  A priority application was filed in England in 1981; a US application, 06/410656, claiming priority to the UK application was filed in 1982. 

 

A first OA was mailed November 18, 1983, in which the Examiner rejected the application for lack of utility, asserting (on the basis of an MPEP section that has long since been supplanted) that it was necessary for the application to include data showing efficacy of the compounds in humans, but that the application lacked such data.  Rather than file a substantive response, the applicants filed a continuation on March 6, 1984 and let the parent case go abandoned.  In October 1984 the same examiner made the same rejection against the continuation application, and again, the applicants didn’t respond, but instead filed another continuation and let the parent case go abandoned. 

 

Although at various points in time the representatives before the USPTO changed, this pattern of rejection-for-lack-of-utility followed by non-response-file-a-continuation repeated itself.  Again. 

 

And again. 

 

And again. 

 

And again. 

 

All in all, over the course of ten years, the applicant filed ten continuations before it filed a substantive response to the lack-of-utility rejection, in February 1993.  And what was the substance of that substantive response?  That according to a 1986 BPAI decision, Ex Parte Krepelka, the applicants didn’t need to provide data showing efficacy in humans, and the animal test data already present in the application was sufficient.  In response, the examiner mailed a Notice of Allowability, and pointed to a 1987 journal article by one of the inventors that showed that some of the compounds were active against tumors in mice as further evidence of utility. 

 

The ‘291 patent issued in November 1993, 11 years after the first application in the chain had originally been filed, entitled to 17 years of term from grant.  It then lay dormant until 2007, when Barr filed an ANDA and CRT/Schering sued. 

 

At trial Barr stipulated to infringement of the asserted claims, but argued that the patent should be unenforceable due to prosecution history laches, i.e. unreasonable delay in prosecution by the applicants.  Judge Robinson accepted this argument, in the process rejecting CRT’s assertion that it hadn’t substantively responded because the examiners required human trial data, which was unavailable.  Judge Robinson ruled that not only was there no explanation given for the delay, but that the response actually filed in 1993 was based on a 1986 BPAI decision which itself invoked a 1969 CCPA decision.  Thus much earlier in prosecution, the applicants could have presented plausible arguments asserting that human test data was unnecessary, and at least made a reasonable attempt to advance prosecution of the case.  From the evidence adduced at trial, the only reason apparent to Judge Robinson for the prolonged delay was to enable CRT to find a strategic partner with which to commercialize the invention.  That was not a good enough reason.  Thus, said the Judge, the patent is unenforceable for prosecution laches.

 

The groundbreaking part of the decision dealt with the question of intervening rights.  In previous cases of prosecution laches, the defendants had relied on the long delay in prosecution – at a time when US patent applications were kept secret until they actually issued – to develop a business; in the words of the case law, the defendants had “intervening rights”.  CRT/Schering argued that Barr (nor anyone else) had developed such intervening rights here, and therefore Barr was not entitled to the relief sought.  Judge Robinson disagreed: the seminal CAFC cases dealing with prosecution laches, the 2002 and 2005 Symbol Technologies v Lemelson cases, did not impose a requirement for intervening rights to exist in order for a patentee to be guilty of prosecution laches.  Put differently, laches is wholly dependent on the applicant, and has nothing to do with whether or not third parties are in fact adversely affected by the applicant’s delaying tactics.

 

If upheld on appeal, this aspect of the decision could have adverse effects for parties with patents that issued on pre-June 1995 applications and that are thus still in force.  In principle it could also affect patents filed after June 1995, although presumably the fact that it was known to the applicants that those patents would be subject to a 20-years-from-earliest-filing term induced them to avoid delaying the grant of their patents.

 

With regard to inequitable conduct, the decision doesn’t break new ground, but it does serve as a reminder to practitioners in the life sciences to be in touch with the inventors through prosecution and continually remind them of their duty to disclose relevant information – and not necessarily just prior art.  The issue here was that the application specifically identified and claimed about a dozen compounds as being “particularly active” against lymphomas and leukemia, and described those compounds as being “important individual compounds” of the disclosed genus, and even describing three of them as being “of particular importance”. 

 

The rub was that research by at least one of the inventors in the late 1980’s, while the application was still being kept alive at the USPTO, showed that, in fact, some of those compounds weren’t active.  Such inactivity per se wouldn’t have been fatal, had the applicants then scaled back the scope of the claims to cover only the active compounds.  But they didn’t: they pressed on with the broad claims and claims on the now-known-to-be-inactive compounds.  Which meant that the data showing inactivity was highly material to patentability: when an examiner says your claims lack utility, and you have data that shows he’s right, that data is going to be of interest to him. 

 

Turning to the second prong of the i.c. inquiry, intent to deceive the USPTO, Judge Robinson inferred this on the part of the inventor on the basis of the fact that during prosecution of the patent he had published more than 40 papers on tetrazine derivatives, including papers showing the inactivity of some of the compounds, yet didn’t see fit to provide this information directly the USPTO.  She also noted that one of the attorneys involved in prosecuting the case testified that he would have explained to the inventors their duty to disclose, and that in any event the inventor had signed a declaration stating that he was aware of the disclosure requirement. 

 

Having found both high materiality and intent, the finding of i.e. was inevitable.  Whether or not this part of the decision will hold up on appeal will hinge in no small part on the CAFC judges assigned to the case.  Reading the district court decision, it’s not clear that the inventor intended to deceive the USPTO.  There were several changes of attorneys during the long prosecution of the ‘291 patent, both in the U.S. and in England, and it seems likely that the inventor may not have know that patent prosecution was ongoing and even if he did, that he didn’t realize he had a duty to disclose the negative test results to the USPTO. 

 

Irrespective of how the CAFC holds on the inequitable conduct question, it’s clear that practitioners need to stay in contact with the inventors during prosecution, advising them that if newly-gathered data impacts the patentability of the pending claims (e.g. shows that the claimed invention lacks utility, at least across its full breadth), that information may need to be reported to the USPTO.  Then again, more often than not, negative data developed along the way leads to an abandonment of the application or diminution of the scope of the claims, so not it’s not clear that facts analogous to those of the present case will repeat themselves anytime soon.

Angiomax (Bivalirudin): The Medicines Company sues Teva et al.; Teva as plaintiff against Lupin

Last month I discussed the issuance of The Medicines Company’s US 7,582,727, which caught my attention because (a) uncommonly for a pharmaceutical patent, it had been filed not only with request a for accelerated examination, but also with a non-publication request, and (b) it issued less than seven months before TMC’s earlier US 5,196,404, the patent that covers its product bivalirudin (sold in the USA under the name Angiomax^®), was due to expire on March 23, 2010.  Within days of the issuance of the patent, Teva and one of its daughter companies had filed a paragraph IV certification. 

 

Now, in the words of the late, great Paul Harvey, we get the rest of the story: Sherri Oslick at PatentDocs reports today that (not unexpectedly) last week TMC filed suit against Teva, Barr (a Teva subsidiary), and Pliva (which is owned by Barr).  Hello 30-month stay to Teva/Barr/Pliva’s ANDA for Angiomax.  Ok, not quite: Teva et al.’s ANDAs were filed before the ‘727 patent was listed in the Orange Book, so no 30-month stay is available.  But TMC will no doubt seek a preliminary injunction, which can still be quite valuable, even if it doesn’t extend for a full 30 months.

 

Given the relative ease with which infringement of the claims of the ‘727 patent can be avoided, and Teva’s position as the first paragraph IV challenger of this patent, it will be interesting to see if this case settles with some sort of reverse payment scheme. 

 

No less interesting is the filing last week by Teva of its own suit as a patentee against another ANDA filer, Lupin Pharmaceuitcals of India.  Lupin filed a paragraph IV certification for US Reissue Patent No. 39,861, which claims a method for the co-administration of estrogen and progestin for female contraception.  Teva is no stranger to litigation, but Teva is usually positioned as a defendant in patent infringement actions, or as a plaintiff in actions for declaratory judgment of non-infringement and/or patent invalidity.  While the suit against Lupin is not the first time Teva has sued someone for infringement of one of its patents – Teva sued Amgen last spring for infringement of its US 7,449,603 – infringement suits in which Teva is the plaintiff remain the exception.

Angiomax (Bivalirudin): Last-Minute Extension of Pharmaceutical Product Life, or Just Throwing Up a Smokescreen?

(revised September 6, 2009)

 

The Medicines Company (TMC) has a problem.  US 5,196,404, the patent that covers its product bivalirudin (sold in the USA under the name Angiomax^®), will expire on March 23, 2010. 

 

Bivalirudin is a 20-amino acid peptide, provided in Angiomax as the trifluoroacetic acid salt, that corresponds to a portion of the naturally occurring protein hirudin.  Hirudin is found in the saliva of leeches; it irreversibly binds to thrombin and thus inhibits blood clotting.  Bivalirduin, on the other hands, binds thrombin reversibly, and thus resultinig in fewer instances of severe bleeding when administered to people and making it suitable for temporary prevention of blood clotting during catheterization procedures, such as angioplasty.

 

Sales of Angiomax are on the order of $500 million annually.  In principle, TMC could have gotten a patent term extension (PTE) under 35 U.S.C. §156, but Angiomax was approved by the FDA on December 15, 2000, and TMC filed its PTE submission on February 14, 2001, missing the 60-day filing deadline by one day.  TMC petitioned the USPTO to accept its PTE submission anyway, but the USPTO said no dice: a deadline is a deadline. 

 

As some readers may recall, TMC then did what any red-blooded, deep-pocketed, well-connected American facing the potential loss of a significant revenue stream would do: it spoke to its Congressman (Rep. William Delahunt of Massachusetts) and asked him to change the law so that the PTO Director could accept TMC’s PTE application as having been timely filed.  Although a version of such a bill passed in the House (see, e.g. Kevin Noonan’s post on this bill here), no corresponding bill made it through the Senate, so the expiration date for the ‘404 patent remains March 2010.

 

Apparently realizing that the game might be up if its lobbying efforts failed, TMC at the same time decided to resort to the tried-and-true method for extending product protection: it filed a new patent application – actually, at least three – on an improvement in the drug product.  One of those patent applications issued on September 1, 2009 as US 7,582,727, and by September 3 was listed in the FDA’s Orange Book.  According to the patent, the asparagine at position 9 of bivalirudin can undergo de-amination to aspartic acid both during peptide synthesis as well as during compounding of the drug product, resulting in unacceptably high levels of Asp⁹-bivalirudin, and causing the reconstitution time of the drug (which is sold in dry form after lyophilization and reconstituted before use) to be about 72 seconds.  During compounding, this aspartic acid formation results from efforts to raise the pH of the TFA salt to a higher, more physiologically acceptable pH.  So TMC developed a new process for reproducibly compounding bivalirudin in a way that limits the amount of Asp⁹-bivalirudin produced, and facilitates reconstitution of the subsequently lyophilized product in 42 seconds or less.  

 

On July 27, 2008, TMC filed USSN 12/180,553, which matured into the ‘727 patent.  The ‘727 patents claims “Pharmaceutical batches of a drug product comprising bivalirudin” and having either certain purity characteristics or certain reconstitution characteristics.  Evidently, the concomitantly-filed and still-pending USSN 12/180,550 and 12/180,551 applications (which have not yet been published but which are referred to in the file history of the ‘727 patent) have similar disclosures but claim the process per se and the product when produced by the process.

 

There are several interesting aspects to this patent and its brethren.  First, the patent was filed with a request for accelerated examination.  Much of the patent practitioner community has shied away from such requests, in large part due to the greater likelihood of an eventual finding of inequitable conduct versus applications that do not undergo accelerated examination.  This increased likelihood is the result of the various disclosure and analysis requirements imposed on the applicant under the accelerated examination process, and the correspondingly increased number of chances for the practitioner to muck something up.  Nevertheless, accelerated examination requests have begun to find favor with certain applicants and in certain technologies, specifically technologies where a product can quickly be brought to market, tends to be most valuable shortly after being introduced to the market, and loses commercial value over time.  This is generally not the case with pharma patents, where there usually isn’t even a product on the market at the time the first patents covering the putative product are issued.  Actually, given the way patent term adjustments under 35 U.S.C. §154 are calculated (which operate without respect to §156), it may even be to a pharma patentee’s advantage to have the USPTO drag its feet during prosecution, so as to get adjusted patent term at the back end of the patent life, when every additional day of exclusivity can be worth tens of millions of dollars. 

 

In the present case, with Anigomax already being sold, and the expiration of TMC’s lone patent looming less than two years after the filing of the ‘553 application, it made sense to request accelerated examination.  Until now, a generic drug company could have contented itself with filing an abbreviated new drug application (ANDA) that stated it would not sell its generic product until after the expiration of the ‘727 patent in March 2010, a so-called paragraph III certification.  By having the ‘727 patent issue before the expiration of the ‘404 patent, and by immediately listing the ‘727 patent in the Orange Book, TMC has forced generic manufacturers to assess their products in view of the claims of the ‘727 patent.  This in and of itself could take time on the part of the generic manufacturers – although as will be discussed below, at least two such manufacturers apparently had no difficulty in quickly making such assessments. 

 

More to the point, ANDA filers will not opt to wait until 2028 when the ‘727 patent expires to introduce their products.  Instead, during the life of the ‘727 patent, they will have to file a “paragraph IV” certification with the FDA, stating that their products do not infringe the ‘727 patent, or that this patent is invalid.    This will give the Medicines Company the opportunity to file suit against each ANDA filer under 35 U.S.C. 271(e)(2).  If the ANDA was only filed after the ‘727 patent was listed in the Orange Book, the filing of such a suit will trigger a 30-month stay in the FDA’s ability to approve the ANDA. 

 

The situation isn’t quite as rosy for TMC if the ANDA was already filed before the ‘727 patent was listed.  In that case, TMC can’t get a stay against the ANDA filer who as a result of the OB amends his ANDA to include a paragraph IV certification regarding the ‘727 patent, and who promptly notifies TMC of the paragraph IV certification.  TMC will only be able to file suit and attempt to get a preliminary injunction preventing approval of the ANDA while the litigation is pending (or at least for part of the litigation.)  While that isn’t quite as nice as a 30-month stay, even if TMC gets a PI that runs for part of the litigation, each additional day of exclusivity will be worth over $10 million.

 

This, of course, assumes that TMC files suit against the ANDA filer.  TMC may choose not to do so, for example if it believes that the ANDA filer doesn’t infringe the patent.  (Under 21 U.S.C. 355 (j)(5)(C)(i)(III), and ANDA filer may make an offer of confidential access the ANDA, to allow the patentee to determine if it believes the ANDA filer infringes or not.)  We’ll know soon enough if a suit is filed.  Nevertheless, even if TMC doesn’t file suit, it will benefit by the filing of a paragraph IV certification, because from the time the first ANDA filer to make a paragraph IV certification begins to market its bivalirudin product, it will be entitled to 180 days of exclusivity versus any other generic manufacturers.  Assuming that the first paragraph IV ANDA filer will only begin to market its product after expiration of the ‘404 patent, Angiomax will only have one direct competitor; and TMC may be able to further temporarily mitigate the damage through the sale of an “authorized generic”, viz. Angiomax sold under another label, which is not subject to the 180-exclusivity period.

 

It may be that the latter outcome was the one desired by TMC, because it appears that in terms of actually protecting TMC from competing bivalirudin products, generic manufacturers can readily avoid infringement of the claims of the ‘727 patent, which may make a colorable claim of infringement difficult for TMC and could thus make the filing of an infringement suit ill-advised.  The three independent claims of the patent read,

 

1.     Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO: 1) and a pharmaceutically acceptable carrier for use as an anticoagulant in a subject in need thereof, wherein the batches have a pH adjusted by a base, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum impurity level of Asp⁹-bivalirudin that does not exceed about 0.6% as measured by HPLC.

 

11.     Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO: 1) and a pharmaceutically acceptable carrier for use as an anticoagulant in a subject in need thereof, wherein the batches have a pH adjusted by a base, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum reconstitution time that does not exceed about 42 seconds and a maximum total impurity level that does not exceed about 2% as measured by HPLC.

 

19.     Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO: 1) and mannitol for use as an anticoagulant in a subject in need thereof, wherein the batches have a pH adjusted by sodium hydroxide, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum reconstitution time that does not exceed about 42 seconds and a maximum total impurity level that does not exceed about 2% as measured by HPLC.  [emphasis added - DJF]

 

Thus, anyone producing a drug product having an Asp⁹-bivalirudin content greater than 0.6% and a reconstitution time of greater than 42 seconds would not infringe the claims of the ‘727 patent.  According to statements repeatedly made by the patentee during prosecution, its own originally-FDA approved product does not meet these limitations (and hence is not invalidating prior art).  Thus generic companies can produce products are bioequivalent the original Angiomax and approvable by the FDA, but do not infringe the claims. 

 

In addition, the claims are directed to “batches”.  Only 16 patents in the USPTO’s database contain the phrase “pharmaceutical batches”, and the ‘727 patent is the only one that contains this phrase in the claims.  The specification defines “batches” as follows:

 

“As used here, "batch" or "pharmaceutical batch" refers to material produced by a single execution of a compounding process of various embodiments of the present invention. "Batches" or "pharmaceutical batches" as defined herein may include a single batch, wherein the single batch is representative of all commercial batches (see generally, Manual of Policies and Procedures, Center for Drug Evaluation and Research, MAPP 5225.1, Guidance on the Packaging of Test Batches at 1), and wherein the levels of, for example, Asp⁹-bivalirudin, total impurities, and largest unknown impurity, and the reconstitution time represent levels for all potential batches made by said process. "Batches" may also include all batches prepared by a same compounding process.”  [emphasis added – DJF]

 

According to statements made by the patentee during prosecution, one of the difficulties with its own prior art compounding process was that the levels of Asp⁹-bivalirudin differed from batch to batch.  Thus, given the patentee’s own definition of “batches” and the fact that batches of varying consistency were known, it would seem that a competitor could even avoid infringement by insuring that only some of its commercially acceptable batches fall outside the scope of the claims, even if some of those batches fall within the scope of the claims.  (Of course, if the patent is upheld as valid, TMC will be able to tout its product as being purer and/or more quickly reconstitutable than its competitors’, since at least some of the competitors’ products will have a higher impurity level and/or longer reconstitution time.)

 

I initially posted this post on September 4.  Later that day, TMC announced the receipt of of two paragraph IV certification notice letters regarding the ‘727 patent, one from Teva Parenteral Medicines, the other from Pliva Hrvatska, d.o.o.  (In fact, Pliva is a subsidiary of Barr, which is a subsidiary of Teva; it’s not clear why the same parent company filed two paragraph IV certifications.)  I don’t know if that constitutes a record for the time between the listing of a patent in the Orange Book and the filing of a paragraph IV challenge, but it certainly was quick.  I also don’t know if the fast turnaround signifies extreme vigilance and prescience on the part of Teva, or if it signifies something else.

 

Another interesting aspect to the ‘727 patent is that it was filed with a non-publication request.  This isn’t usually done in applications being examined under the accelerated examination, unless they claim priority to an earlier application (which is not the case here), as such applications usually issue as patents within 18 months, rendering the non-publication request superfluous.  The only reason for filing a non-publication request would have been to ensure that in the two-and-half months between January 8, 2010 (the earliest date on which the ‘553 application could have published) and March 23, 2010, the application would not publish, thus allowing the patent to function as a submarine patent in the event that prosecution dragged on.  But in today’s patent enforcement landscape, submarine patents don’t have quite the bite that they did in the heyday of Jerome Lemelson.  Short of preventing competitors from making bivalirudin products that consistently meet the limitations of the claims, it’s not clear what benefit would have obtained for TMC had the patent issued after March 23, 2010, with the non-publication request in place: generic competitors who had already placed product in the marketplace would not be forced to recall that product; since the generic products would already have been approved by the FDA, TMC would be unable to obtain a 30-month stay in the approval process, should it have chosen to sue; and in the wake of the Supreme Court’s eBay decision and the anti-big pharma climate now prevalent in the USA, there is no guarantee that had TMC sued first the court would have issued an injunction preventing the sale of additional generic products.

 

On the other hand, the risk involved in filing a non-publication request is palpable: if TMC filed corresponding applications abroad and did not withdraw the non-publication request – and if it filed such applications, it would have had to do so by July 8, 2009, in which case it would have already had to notify the USPTO of such filing and withdrawn its non-publication request, an event which according to the file history did not transpire – the ‘727 patent could go down in flames under 35 U.S.C. 122(b)(2)(B)(iii). 

 

So on its face, there would seem to be little benefit, and great risk, in filing the non-publication request in parallel with the accelerated examination request.  (There would have been a small upside to having the ‘727 issue as a submarine patent: it would have provided TMC with time before grant of the patent to investigate competing products, and to be ready to file suit against competitors the day the patent was granted, albeit with a decreased ability to obtain an injunction post-eBay.) 

 

Then again, given the ease of working around the ‘727 patent, there would be little incentive to file in jurisdictions that do not have provisions similar to those of Waxman-Hatch (i.e. all jurisdictions outside the USA), so maybe TMC really didn’t file elsewhere and its risk in making the non-publication request was minimal.  TMC thus gained the benefit of possible grant of the patent before expiration of the ‘404 patent, thus setting itself up to enjoy a 30-month stay in the approval of competing products, or at least a 180-day period in which it would have only one competing product; or conversely, in the worst case, grant of the patent after competitors had already launched, giving TMC the element of surprise and the possibility of immediately suing them for infringement.

 

All in all, for TMC this appears to be a reasonable recovery after having fumbled the patent term extension for the ‘404 patent.  We’ll be watching to see if TMC sues Teva/Pliva in the next 45 days.