GLG News by Patrick Joseph Igoe

Implications: * As noted in the Wall Street Journal article, Aricept® is a blockbuster drug for the treatment of Alzheimer's disease.  And, as noted in Judge Ackerman's ruling, Aricept sales are a huge source of Eisai's revenue - "sales of Aricept® in the United States constitute 70% of Eisai’s U.S. subsidiary’s profits, and 25% of Eisai’s revenues worldwide". * In patent infringement litigation at a Federal trial court, a preliminary injunction in favor of Eisai and against Teva has just been granted which orders Teva not to sell generic Aricept® as claimed in US Patent 4895841. * The Fri 28 Mar 2008 26-page Opinion & Order (Doc #191) by Judge Harold A. Ackerman of the United States District Court for the District of New Jersey grants Eisai's Motion for Preliminary Injunction (Doc #141).

Analysis:
As always in Life Science Patent Battles, the details of this particular dispute, at this particular point in the litigation timeline, are critical.  With that in mind, a closer examination of the present context is warranted.

Prior filings established that Teva's generic drug [i.e., its generic variant of Aricept® under Teva's ANDA/Abbreviated New Drug Application which the FDA had tentatively approved in January, 2008] would infringe Claims 8, 10, and 13 of US Patent 4895841.  Other filings established that the only remaining attack upon the '841 Patent was that, due to alleged inequitable conduct, it should be determined to be unenforceable.  At least up through this point, Teva has failed in this remaining attack.

Upon the April, 2008 expiration of the 30-month Hatch-Waxman stay, the prior FDA tentative approval of Teva's ANDA could then be made a final approval, and, at that point, Teva would be free to engage in an "at-risk" launch of its generic product.  Clearly, from Eisai's perspective, preventing Teva's at-risk launch is of the utmost importance.

The Preliminary Injunction effectively achieves Eisai's #1 goal in stopping Teva's launch.

Implications: (1) The US Court of Appeals for the Federal Circuit - in a complicated 22-page split Opinion earlier today Wed 19 Mar 2008 - provided Amgen another victory in its long patent battle(s) with Hoffmann-LaRoche. (2) Amgen's Aranesp® and EPOGEN® (each a prescription only product that relates to EPO/erythropoietin) are protected by multiple US patents. (3) As indicated in the Wall Street Journal article, Aranesp® and EPOGEN® are each critical revenue-producers for Amgen with combined sales in excess of $6 billion. (4) Further ITC proceedings may ultimately transform the current intermediate patent victory into a more effective and more valuable ruling in favor of Amgen.

Analysis: (1) As always in Life Science Patent Battles, the details are critical.  The reported Opinion is Amgen/Appellant versus ITC/Appellee and Hoffmann-LaRoche/Intervenor ( Case No. 2007-1014).

(2) The WSJ correctly notes that "... the decision to send the case back to the ITC is the latest step in a long feud between the pharmaceutical companies, as Amgen tries to prevent Roche from bringing its anemia drug onto U.S. turf. Amgen has argued that Roche's Mircera infringes on its patents, and that Roche's application for U.S. Food and Drug Administration approval to sell the drug in the U.S. established an intent to sell."

(3) Using a more detailed viewpoint, the Federal Circuit (a) affirmed-in-part the prior ruling by the US International Trade Commission; (b) reversed-in-part that same ruling; and (c) remanded the case back down to the ITC for further proceedings.  At one-level, the "safe harbor" protection of Title 35 United States Code, Section 271(e)(1) rescues certain aspects of Hoffmann-LaRoche's conduct which relate to regulatory submissions to the FDA/Food and Drug Administration.  But at the next level of more and more details, the Federal Circuit clearly held that this same "safe harbor" protection is not unlimited; beyond the protected activities, other conduct might ultimately be held to be patent infringement.  In essence, the court held that the ITC improperly (due to inadequate evaluation) found virtually all of Hoffmann-LaRoche's conduct to fall within the zone of safety.  Upon the subsequent remand back down to the ITC, Amgen will have the possibility of proving patent infringement by Hoffmann-LaRoche.

BOTTOMLINE CONCLUSIONS At the ITC, Amgen will have an opportunity to secure another patent victory in defense of its EPO products.  The "safe harbor" aspects of the Court Opinion should not be overhyped; although they are important, new on-the-merits proceedings at the ITC might ultimately prove favorable to Amgen.

Implications: The at-risk product launch by [NasdaqGS:TEVA] Teva of generic equivalents to [NYSE:PFE] Pfizer's Neurontin® (gabapentin) might - and the emphasis is clearly on might - yet prove to be an expensive mistake by Teva. The recent Opinion by the United States Court of Appeals for the Federal Circuit [also known as Federal Circuit, Fed Cir, or CAFC] essentially provides Pfizer a new opportunity to proceed with an actual on-the-merits trial. Upon remand, Plaintiff Pfizer will seek to establish patent infringement by multiple Defendants, including Teva. Pfizer previously enjoyed blockbuster Neurontin® sales of at least $2 Billion/year. As reviewed in-depth later, the CAFC Opinion - (a) reverses-in-part; (b) affirms-in-part; and (c) remands for further proceedings - the prior trial court judgment which had granted summary judgment of no patent infringement in favor of multiple Defendants.

Analysis: As always in Life Sciences Patent Battles, the details are critical. In this particular case, Pfizer appealed from the judgment of the United States District Court for the District of New Jersey [USDC/DNJ]. That prior trial court decision had granted summary judgment of no patent infringement of claims 7-11 of US Patent 6054482 in favor of Defendants [Teva, IVAX, and Eon Labs].

Of the asserted Claims 7-11, only Claim 7 is independent while the remaining Claims 8-11 are dependent. In fact, each of Claims 8-11 directly depends upon Claim 7. In its entirety, Claim 7 reads. "7. A stable and pure pharmaceutical composition in unit dry medicinal dosage form consisting essentially of: (i) an active ingredient which is gabapentin in the free amino acid, crystalline anhydrous form containing less than 0.5% by weight of its corresponding lactam and less than 20 ppm of an anion of a mineral acid and (ii) one or more pharmaceutically acceptable adjuvants that do not promote conversion of more than 0.2% by weight of the gabapentin to its corresponding lactam form when stored at 25.degree. C. and an atmospheric humidity of 50% for one year." The 2 key claim phrases are " less than 20 ppm of an anion of a mineral acid" (see clause (i)) and "adjuvants" (see clause (ii)).

With respect to the trial court's legal conclusions of the meaning of each of these 2 key claim phrases, the Federal Circuits affirms the interpretation set forth by the trial court. However, with respect to the trial court's factual findings relating to the 20 ppm limitation, the Federal Circuit disagrees with the prior analysis. More specifically, the CAFC concludes that there exist genuine issues of material fact regarding whether or not Teva's samples contained less than 20 ppm of acidic chloride ions. In other words, a full on-the-merits trial will be necessary and is now required in order to answer this factual question over the 20 ppm limitation. Thus, the Federal Circuit reverses the USDC/DNJ's grant of summary judgment of no patent infringement in favor of the Defendants and remands back down to the lower court for further proceedings (i.e., a full on-the-merits trial).

At least for now, Pfizer might still achieve victory in this long-running patent battle to enforce its umbrella of patent protection which covers the Neurontin® (gabapentin) products. Any such victory will, of course, be inherently limited and not total. There are numerous generic variants of Neurontin® (gabapentin) which are currently on the market. Tremendous amounts of lost sales continue to occur on a daily basis. If Pfizer ultimately prevails over the generic infringers, the potential money damages that Pfizer might be awarded from the Defendants are simply staggering. With that ultimate goal now clearly being - at a minimum - at least a possibility, Pfizer will surely spare no effort in its renewed patent infringement litigation proceedings at the District of New Jersey.

Implications: In my prior Tue 31 Jul 2007 Analysis available here http://news.glgroup.com/CM/Analysis/PostDetail.aspx?pid=14722 I stated: The upcoming Altace ® Opinion will most likely fall in line with this noted trend. In other words, King Pharmaceutical [NYSE:KG]'s patent protection for Altace ® (ramipril) appears to be a prime candidate for invalidation due to § 103 obviousness.  In today's 19-page Opinion by the United States Court of Appeals for the Federal Circuit [2006-1530, 2006-1555], this exact scenario has now occurred.  Sweeping generalizations about the fate of 2nd-generation, single-isomer active product ingredient patents are not helpful.  Only an individualized assessment of the particular marketed drug product in question is likely to be meaningful.

Analysis: Note first that in the recent Lexapro ® Opinion by the Federal Circuit, the Innovator Company - Forest Labs [NYSE:FRX] - successfully sued Ivax and Cipla for patent infringement based upon a 2nd-generation single-enantiomer variant of the active product ingredient (escitalopram oxalate).  In my corresponding Analysis of last week, I cautioned against concluding that 2nd-generation, optically-pure API patents will routinely withstand the invalidation arguments asserted by the Defendant Generic Companies. In other words, the specific facts of each particular Paragraph (IV) patent infringement litigation are of the utmost importance and they must not be lightly assumed to apply to a different but similar situation.

Turning to the details of this major defeat for King Pharmaceuticals, the Appellate Court: (a) reversed the trial court [the US District Court for the Eastern District of Virgina or USDC/EDVA] in holding that, as a matter of law, all of the asserted claims of 5061722 - i.e., Claims 1,2,4,5 - are invalid as being obvious under § 103 of the Patent Laws; (b) declared all remaining issues as having been rendered moot; and (c) stated that accordingly the Defendant Lupin Pharmaceuticals is entitled to entry of judgment in its favor. The different outcomes of Lexapro ® (victory for Plaintiff) in comparison to Altace ® (defeat for Plaintiff) arise from the different facts in existence for these 2 different prescription drug products. The Court noted, among other items, that the Lexapro ® molecule was one in which the "evidence indicated that the isomers would have been difficult for a person of ordinary skill in the art to separate").  Unfortunately for Plaintiff King Pharmaceuticals, evidence pointing to factual considerations in favor of establishing nonobviousness were, simply stated, thin and weak.  Thus, the ultimate result is not surprising.

Implications: With respect to the blockbuster antidepressant drug Lexapro®, the US Court of Appeals for the Federal Circuit, CAFC or Fed Cir, affirmed the prior November, 2006 Opinion of the Delaware District Court with respect to Plaintiff Forest Labs (NYSE:FRX) Paragraph (IV) patent infringement litigation against Ivax and Cipla. More specifically, the CAFC (a) affirmed that Reissue Patent 34712 [an Orange Book patent which protects Lexapro®] is valid; (b) affirmed the trial court's injunction order against both Ivax and Cipla; and (c) modified the scope of the injunction to apply only to escitalopram oxalate (the active product ingredient in Lexapro® - the single-isomer). This Fed Cir ruling is a definitive, solid win for Forest Labs; however, it does not mean that other currently marketed optically-pure drugs are all safe from generic manufacturers' assertions of patent invalidity.

Analysis: Paragraph (IV) Abbreviated New Drug Application (ANDA) patent infringement litigation is of high-stakes critical importance to both innovator and generic pharmaceutical manufacturers. On the positive side (from Big Pharma's perspective) this Federal Circuit victory for Forest Labs shows that 2nd generation, single-enantiomer drug products can be successfully asserted against possible generic product launches. On the other hand, for the generic manufacturers seeking early market entry, the assault against the Orange Book innovator patents will continue. The specific facts of this Lexapro® litigation do not imply that other optically-pure branded drug patents will survive the Paragraph (IV) Patent Challenges. The Federal Circuit's Opinion notes the following in reaching its conclusions: (a) a key prior art reference, Smith, is not enabling with respect to anticipation or obvious patent invalidity; (b) a team of chemists at Lundbeck had unsuccessfully tried for 2 years to separate the enantiomers of citalopram (the active product ingredient as a racemic mixture) into the 2 individual stereoisomer; and (c) the intentional use of an optically-pure diol intermediate enantiomer in the chemical synthesis of Lexapro® is yet another factor used in reaching the decision to reject the assertions of patent invalidity by the Defendants Ivax & Cipla.

Implications: KSR involved mechanical technologies, but its rulings apply to all different arts, including biotechnology, medical devices, and pharmaceuticals.  The applications of KSR analysis by the Federal Circuit are multiplying and the results are not in favor of patent owners, including those patent owners within Life Sciences.  The upcoming Altace ® Opinion will most likely fall in line with this noted trend.  In other words, King Pharmaceutical [NYSE:KG]'s patent protection for Altace ® (ramipril) appears to be a prime candidate for invalidation due to § 103 obviousness.

Analysis: The hyperlinked Mon 23 Jul 2007 Federal Circuit Opinion affirms the trial court's invalidation of USPN 5081154 for Toprol-XL ® (metoprolol succinate) for double patenting.  Footnote 2 reads as follows - "Moreover, the omission of the known elements from the composition in this case is "the product not of innovation but of ordinary skill and common sense." KSR Int’l Co. v. Teleflex Inc., 550 U.S. ----, 127 S. Ct. 1727, 1742 (2007). "  Logic similar to this was expressed during oral arguments held Thu 12 Jul 2007 in the Altace ® litigation - albeit in the slighly different context of the selection/purification of a particular enantiomer of ramipril.

Implications:

If the March 20, 2007 rulings of US District Judge Stanley R. Chester withstand further challenges, then JNJ's TOPAMAX(R) sales will not suffer - at least with respect to Mylan Labs.

 

Analysis:

Judge Chester's rulings are sweeping in scope and represent a definitive victory for JNJ, and, from the other perspective, a complete loss for Mylan. A brief summary of these rulings follow.

With respect to the asserted patent, 4513006: (a) Mylan infringed 9 claims; and (b) the patent is both valid and enforceable.

With respect to regulatory actions: (a) Mylan cannot (until the September 26, 2008 expiration date of 4513006) market generic substitutes for TOPAMAX(R); and (b) the FDA cannot establish an effective approval date for the corresponding ANDA filings of Mylan earlier than the noted September 26, 2008 date.

If this permanent injunction withstands further challenges, then at least with respect to Mylan, JNJ's best-selling TOPAMAX (R) migraine drug will enjoy the full benefits of patent protection of 4513006 until the very last day of that patent's term. This result would be against the noticeable trend - at least in comparison to several recent court opinions of the Federal Circuit - which in effect seems to be tipping the innovator/generic patent battles against the NDA holders and towards the generic ANDA filers.

 

Implications: The March 22, 2007 CAFC Opinion invalidates claims 1-3 of US Patent 4879303, which is listed in the FDA Orange Book for Pfizer's blockbuster blood pressure drug NORVASC® (amylodipine besylate).  For companies other than Pfizer, this is great news - but it is not the end of the story.  Numerous recent filings at the FDA and other courts plainly show that the NORVASC® disputes continue and that multiple parties with differing views are willing to fight to the end.

Analysis: In the linked Pfizer v Apotex case at the Court of Appeals for the Federal Circuit (CAFC), Pfizer (NYSE:PFE) sued Apotex for infringement of 3 claims (1-3) of the '303 patent.  Note that this patent contains 11 claims (1-11).  Many unresolved questions remain relating to the determination of the effect of such invalidation, see below.

Pfizer's position, as evidenced by recent filings, is that the March 22 decision did not by itself invalidate claims 1-3; it did not invalidate the entire patent; and it did not have any immediate effect on any unapproved ANDAs for amylodipine besylate.  Although the '303 patent expired this March 25 (the natural expiration date), Pfizer argues 6-month pediatric exclusivity attached by operation of law to this expiration date; thus, any unapproved ANDAs cannot now be approved before September 25, 2007; and the '303 patent should remain Orange Book listed.

Watson Pharmaceuticals (NYSE:WPI) position is that the case has the following effects (all of of 03.25.07):  the '303 patent is invalid; 6-months pediatric exclusivity vanishes; 180-days ANDA exclusivity vanishes; and Paragraph (iv) ANDA filings become immediately approvable.

Other generic companies are asserting a wide spectrum of other conflicting views; many litigations are now ongoing.

Implications: From among 5 patents listed in the FDA Orange Book, Novartis sued Teva for patent infringement of only 1 patent.  Teva filed a corresponding declaratory judgement action against Novartis seeking adjudication of the remaining 4 patents.  In its recent ruling, the Federal Circuit agrees with Teva and sends this ongoing litigation back down to the District Court for litigation concerning all 5 Orange Book patents.

Analysis: To protect its genital herpes Rx drug product Famvir, the innovator company Novartis listed 5 patents in the FDA Orange Book.  Upon the ANDA filing by the generic company Teva, Novartis sued Teva for patent infringement of only 1 of its 5 Orange Book patents.

Unfortunately for Novartis, there is now a noticeable trend in recent court decisions - including, most importantly, the recent US Supreme Court Medimmune/Genentech case, against court rulings which effectively prevent patent litigation cases from starting until the plaintiff patentee sues the alleged infringer for patent infringement.  This trend is now extended by the Federal Circuit in Teva v Novartis.  Here the plaintiff patentee Novartis is prevented from selectively asserting some but not all of its patents against Teva.  This case hands Teva a victory that ensures that Teva will have the opportunity to attack all 5 Orange Book patents controlled by Novartis.  In its analysis, the Federal Circuit relies heavily upon the Medimmune/Genentech decision.

This case may significantly limit patent infringement tactics of innovator Rx drug companies against generic Rx drug companies.  Piecemeal assertion of selective patents only (not the complete set of interrelated patents) will likely become more and more difficult or risky for the branded manufacturer.  At the same time, it strengthens generic manufacturers' litigation alternatives.