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 pKa 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?
