Tenofovir disoproxil & Emtricitabine - France

On May 25, 2018, the Paris Court of First Instance revoked the SPC on the combination of "tenofovir disoproxil & emtricitabine", marketed under trade name Truvada® by Gilead.

As per the decision summary reported on ‘SPC blog’, the Paris Court of First Instance held that "the patent on the basis of which the SPC 0032 was granted does not mention emtricitabine in the wording of its claims, neither makes it necessarily and specifically identifiable, nor does it mention a functional formula implicitly but necessarily and specifically.

Gilead holds European patent No EP 0 915 894 (‘the basic patent’). This patent was expired on 24 July 2017. It covers, in general terms, a series of molecules, which are helpful in the therapeutic treatment of a number of viral infections in humans and animals, in particular HIV. Claim 27, which is important here, reads as:

‘A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients’.

Previously on Sep. 05, 2017 the High Court of Paris issued its decision on the validity of the Gilead SPC on Truvada® & denied injunction because of chances that SPC may be found invalid.

On similar line various courts have decided this issue:

On May 15, 2018, Federal Patent Court (FPC) of Germany revoked SPC to Gilead’s product, Truvada® in a validity proceeding challenged by generic filers.

On Apr. 25, 2018, in a request for a preliminary ruling, Advocate General Wathelet (UK) revoked the SPC.

On Oct. 26, 2017, the Danish Maritime and Commercial High Court issued a decision rejecting Gilead's motion for preliminary injunction against Accord Healthcare & found Gilead's Danish SPC for the combination invalid.

On Oct. 3, 2017, the Federal Patent Court of Switzerland rejected the application for annulment of SPC & held that it is only required by the law that the product is protected by a patent under fosinopril decision.

Tenofovir disoproxil & Emtricitabine - Germany

On May 15, 2018, Federal Patent Court (FPC) of Germany revoked SPC to Gilead’s product, Truvada® in a validity proceeding challenged by generic filers.

As per the decision summary reported on ‘SPC blog’, the 4th Nullity Senate of the German Federal Patent Court nullified Gilead’s German SPC. Gilead’s holds German SPC DE 2005 000 0041.8, which had been granted for tenofovir disoproxil in combination with emtricitabine. Gilead holds European patent No EP 0 915 894 (‘the basic patent’). This patent was expired on 24 July 2017. It covers, in general terms, a series of molecules, which are helpful in the therapeutic treatment of a number of viral infections in humans and animals, in particular HIV. Claim 27, which is important here, reads as:

‘A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients’.

Generic filers specifically argued that emtricitabine is not implicitly, but necessarily and specifically mentioned in claim 27. The term ‘other therapeutic ingredients’ is very general & covers wide compound classes with different medicinal characteristics. The FPC decided that this term was insufficient to specify the active ingredient emtricitabine according to the criteria set by the Eli Lilly decision. Consequently, the requirements of Article 3(a) SPC-Regulation were not fulfilled for the product in dispute.

On similar line, on Apr. 25, 2018, Advocate General Wathelet (UK) also found that the combination (Tenofovir & Emtricitabine) SPC was not protected by same basic patent.

Lacosamide - USA

On May 23, 2018, Federal Circuit affirmed a Delaware court's finding that a UCB Inc's patent on the epilepsy drug Vimpat® is not invalid for double patenting or obviousness or anticipation.

This case arises under the Hatch-Waxman Act. UCB holds NDA that cover its lacosamide anti-epileptic drug approved by USFDA and marketed under the tradename Vimpat®. Appellants are generic drug manufacturers who filed Abbreviated New Drug Applications (“ANDAs”), seeking approval for generic versions of Vimpat® before expiration of U.S. Patent No. RE38,551. The ’551 patent covers lacosamide compound. As disclosed in the ’551 patent, lacosamide is the R-enantiomer of N-benzyl-2-acetamido-3-methoxypropionamide. The specification teaches that “the R stereoisomer is unexpectedly more potent than the corresponding S stereoisomer and the racemic mixture.” The claims of the ’551 patent at issue in this case are dependent claims 9, 10, and 13.Claim 9 covers (R) N-Benzyl 2-Acetamido-3-methoxypropionamide containing at least 90% (w/w) R stereoisomer. Claim 10 covers therapeutic composition & claim 13 covers method of treating human.

Before the district court, Appellants asserted that claims 9, 10, and 13 of the ’551 patent are invalid for obviousness-type double patenting, alleging that they are not patentably distinct from claims 44–47 of the U.S. Patent No. 5,654,301 (continuation-in-part of the 5,378,729). Appellants also argued that the compound described in the asserted claims of the ’551 patent is merely an obvious species of the genus claimed in the ’301 patent. Following a bench trial, the district court found that it would not have been obvious to a person of ordinary skill in the art to make lacosamide by placing an unsubstituted benzyl at R or an unsubstituted methyl at R1 in combination with methoxymethyl at R3. Appellants also asserted that LeGall’s disclosure of the racemic mixture compound 107e alone, or in combination with the ’729 patent’s disclosure of the genus and Kohn 1991’s disclosure of compound 3l rendered the asserted claims of the ’551 patent obvious. The district court applied a lead compound analysis and concluded that, as of March 1996, a skilled artisan would not have selected any Functionalized Amino Acid (FAA) genus, let alone compound 107e (LeGall) or compound 3l (Kohn 1991), as a lead compound. Finally, Appellants asserted that the ’551 patent was anticipated by LeGall’s disclosure of the racemic mixture of compound 107e, which necessarily discloses the enantiomers of that mixture, including the R enantiomer. The district court held that LeGall does not anticipate the asserted claims because, while it discloses the racemic mixture compound 107e, it does not explicitly disclose the R-enantiomer or its characteristics. Thus, district court made exhaustive fact findings based on the trial evidence and concluded that the asserted claims (9, 10, and 13) of the ’551 patent are not invalid. Appellants appealed.

Obviousness-type double patenting:

Appellants asserted that claims 9, 10, and 13 of the ’551 patent are not patentably distinct from claims 44–47 of the ’301 patent and are thus invalid for obviousness-type double patenting. Because these claims only have a common methoxymethyl group at the R3 position, the question before court was whether a person of ordinary skill in the art, starting with claim 45 of the ’301 patent, would have been motivated to place an unsubstituted benzyl at R and an unsubstituted methyl at R1 in combination with the methoxymethyl group at R3 with a reasonable expectation of success.

Claim 9 of the ’551 patent requires the R-enantiomer with 90% or greater purity; while claim 45 of the ’301 patent allows for any substituted or unsubstituted group. Focusing on these differences, the district court found that as of the priority date, a person of ordinary skill in the art would not have had a reasonable expectation that placing an unsubstituted benzyl at R or an unsubstituted methyl at R1 with a methoxymethyl group at R3 would have yielded an efficacious anticonvulsant FAA. Also by the priority date not a single reference disclosed any anticonvulsant data for any compound comprising a methoxymethyl group at R3 let alone lacosamide. Because these findings are supported by expert testimony and the record, Federal circuit concluded that they are not clearly erroneous & affirmed that the asserted claims of the ’551 patent are not invalid for obviousness-type double patenting.

Obviousness:

Appellants next asserted that claim 9 of the ’551 patent would have been obvious based on LeGall’s disclosure of compound 107e as a racemic mixture. Appellants further asserted that LeGall alone, or in combination with the ’729 patent and Kohn 1991, render claim 9 obvious. Applying a lead compound analysis, the district court concluded that a person of ordinary skill in the art would not have selected any FAA, let alone the compounds disclosed in LeGall and Kohn 1991, as lead compounds in the lead compound analysis. Appellants argued that because Aventis did not apply a lead compound analysis, no such analysis is required in this case. Federal circuit said that we are not aware of any authority holding that a lead compound analysis is or is not required in cases involving purifying mixtures. LeGall contains no data that would have led a person of ordinary skill in the art to select compound 107e among the many compounds disclosed in LeGall as a lead compound. Dr. Roush also testified that based on LeGall’s disclosure, a person of ordinary skill in the art would not have been motivated to develop compound 107e. Federal circuit saw no clear error in the district court’s factual findings based on such evidence.  Based on this evidence, Federal circuit sustained district court's conclusion that the asserted claims of the ’551 patent would not have been obvious.

Anticipation:

Only Appellants Accord Healthcare, Inc. and Intas Pharmaceuticals Ltd. raised anticipation on appeal. They argued that because LeGall discloses the chemical structure of the racemic compound 107e, it necessarily discloses the R-enantiomer (lacosamide) recited in claim 9 of the ’551 patent. Relying principally decision in Sanofi, 550 F.3d at 1084, the district court found claim 9 of the ’551 patent not anticipated, concluding that LeGall discloses neither the R-enantiomer of compound 107e nor any of its characteristics. Federal circuit held that the district court did not clearly err in finding that LeGall does not anticipate claim 9 of the ’551 patent. “[T]he knowledge that enantiomers may be separated is not ‘anticipation’ of a specific enantiomer that has not been separated, identified, and characterized.” Federal circuit stated that “the novelty of an optical isomer is not negated by the prior art disclosure of its racemate.” In re May, 574 F.2d 1082, 1090 (CCPA 1978). Thus, Federal circuit found no clear error in the district court’s finding of no anticipation.

PROST, Chief Judge, dissenting:

Chief Judge, Prost dissented mainly on double patenting issue addressed by district court. Specifically, she said that the district court clearly erred when it found there would not have been a reasonable expectation of success in selecting unsubstituted benzyl for R and unsubstituted methyl for R1. She said that although we cannot reject the district court’s finding that drug development is unpredictable, “obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.” Pfizer, 480 F.3d at 1364. In reality, “there were many tests conducted on FAAs with benzyl at R and methyl at R1.” And indeed, as the district court found 75% of Dr. Kohn’s experimental compounds contained benzyl at R and methyl at R1, and most of these were unsubstituted. The district court’s findings of fact as to the prior art provided ample evidence showing that a person of skill in the art would have had a reasonable expectation of success in creating an FAA with anticonvulsant activity by selecting an unsubstituted benzyl for R and an unsubstituted methyl for R1.

She further said that the district court also erred when it found that the limited data that did exist at the time would not have led a person of ordinary skill to place an unsubstituted benzyl at R or an unsubstituted methyl at R1. Indeed, the data that were available showed that unsubstituted benzyl at R and an unsubstituted methyl at R1 were comparable to, if not better than, any other substituents tested.

Finally, and perhaps most importantly, the district court erred when it did not consider the LeGall Thesis in its primary double-patenting analysis. For purposes of this litigation, the parties agreed that the LeGall Thesis constitutes a “printed publication” within the meaning of 35 U.S.C. § 102(b). Importantly, the LeGall Thesis disclosed compound 107e which, exactly like lacosamide, has a methoxymethyl group at R3, an unsubstituted benzyl at R, and an unsubstituted methyl at R1. Compound 107e is identical to lacosamide except that it contains both the R- and Senantiomers in a mixture, rather than just the Renantiomer. Thus, to the extent the district court found that there was no indication in the prior art that benzyl and methyl would have been successful with a methoxymethyl group, it clearly erred.

She further held that "taking the district court’s clear error together with the remainder of its fact findings, I would have concluded that claims 9, 10, and 13 of the asserted ’551 patent are not patentably distinct from the reference claims. Thus, I would reverse the district court’s conclusion and hold that the asserted claims of the ’551 patent are invalid for obviousness-type double patenting. I therefore respectfully dissent".

Accolade

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INOmax® - USA

On May 16, 2018, Federal Circuit upheld the Patent Trial and Appeal Board’s decision to invalidate Mallinckrodt patent on respiratory drug Inomax.

Mallinckrodt owns U.S. Patent 8,846,112, which is directed to methods of distributing nitric oxide gas cylinders for pharmaceutical applications. Inhaled nitric oxide is approved by the USFDA for treating neonates with hypoxic respiratory failure, a condition where oxygen levels in the blood are too low. Mallinckrodt exclusively supplies inhaled nitric oxide in the United States for pharmaceutical use under the brand name INOmax®. The claims of the ’112 patent generally require supplying a medical provider with a cylinder of nitric oxide gas and providing the medical provider with certain prescribing information relating to the harmful side effects of nitric oxide for certain patients. Certain dependent claims add additional steps directing what a recipient of the provided information should do with it. Praxair petitioned for inter partes review of claims 1– 19 of the ’112 patent, which the Board instituted. The Board held that claims 1–8 and 10–19 would have been obvious over the INOmax Label, Bernasconi, Loh, and Goyal. Mallinckrodt appealed.

During appeal, Mallinckrodt argued that the Board erred in applying the printed matter doctrine during claim construction rather than when it assessed patentability. Furthermore, Mallinckrodt contended that the Board erred in construing the term “pharmaceutically acceptable,” and that the broadest reasonable interpretation of the term supplies a functional relationship between any claimed printed matter and the other limitations of the claims of the ’112 patent. If a claim limitation is directed to printed matter, then the next step is to ascertain whether the printed matter is functionally related to its “substrate.” Printed matter that is functionally related to its substrate is given patentable weight. [DiStefano, 808 F.3d at 850]. Likewise, “[w]here the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability.” [In re Ngai, 367 F.3d 1336, 1339 (Fed. Cir. 2004)]. Merely adding an instruction sheet or other informational content to a drug product is not sufficient to create a functional relationship, even if required by the FDA for approval. [AstraZeneca, 633 F.3d at 1065; (holding that FDA-required instructions did not create functional relationship to drug)].

Federal circuit while applying precedent to this case, agreed with Praxair that the Board properly addressed the printed matter doctrine during claim construction. Because claim limitations directed to mental steps may attempt to capture informational content, they may be considered printed matter lacking patentable weight in an obviousness analysis. According to Mallinckrodt, this is because the term “pharmaceutically acceptable” incorporates the claimed information into the concrete step of supplying nitric oxide gas. Court agreed with the Board that the ordinary meaning of “pharmaceutically acceptable” here only refers to the physical condition of the gas, not prescribing information that may accompany it. And even if “pharmaceutically acceptable” did include the informational content, it would only make the claim redundant, not supply a functional relationship, as “providing” a drug product together with FDA-required prescribing information does not suffice to create a functional relationship between the information and methods of providing and potentially administering the drug. Thus, the Board did not err either in construing “pharmaceutically acceptable” or in concluding that the term did not create a functional relationship.

Mallinckrodt’s final argument regarding claims 1–8 and 10 was that the Board improperly discounted evidence of secondary considerations. Mallinckrodt contended that one must weigh secondary considerations of nonobviousness even if the secondary considerations only relate to printed matter lacking patentable weight. Specifically, Mallinckrodt argued that the INOT22 study unexpectedly uncovered the potentially harmful effect of inhaled nitric oxide on neonates with preexisting LVD. Court agreed with Mallinckrodt and held that relevant evidence of secondary considerations must be considered in an obviousness analysis, the evidence submitted here was not relevant to claims 1–8 and 10. The only secondary consideration Mallinckrodt alleges was based on the information claimed in the providing information limitation, which court have held lacks any functional relationship to the non-printed matter limitations in claims 1–8 and 10. That claimed information has no patentable weight in an obviousness analysis because printed matter without a functional relationship to a substrate is not eligible subject matter. Such printed matter cannot be brought within the ambit of patent eligibility by showing that it was surprising. No patentable weight means no patentable weight. Thus, court affirmed the Board’s decision holding claims 1–8 and 10 unpatentable as obvious.

Praxair argued in its principal appeal that the Board erred in holding claim 9 not unpatentable as obvious. Praxair contended that the Board improperly construed “in accordance with” in claim 9. Properly construed, Praxair argued that there is no functional relationship between the discontinuing step of claim 9 and the recommendation limitation. And even accepting the Board’s construction, Praxair argued that claim 9 would have been obvious. By interrelating the claimed information regarding correlations between nitric oxide, LVD, and pulmonary edema with the concrete step of discontinuing treatment because of the information, court agreed with Mallinckrodt that the Board did not err in concluding that the printed matter in claim 9 has a functional relationship to the rest of the claim and giving the printed matter patentable weight. Therefore, Board held that Bernasconi did not render claim 9 obvious. Court, however, rejected the Board’s conclusion and held that Board’s finding is premised on an incorrect reading of claim 9. In sum, both the Board’s findings regarding the differences between the prior art and claim 9 and its findings on secondary considerations depended on an incorrect interpretation of that claim, and court therefore held that they are not supported by substantial evidence.

Thus, Court affirmed the Board’s decision with respect to claims 1–8 and 10–11, and reversed the Board’s decision with respect to claim 9.

Oxymorphone - USA

On May 16, 2018, Federal Circuit affirmed district court & found two opioid patents owned by Endo Pharmaceuticals valid and infringed by ANDA filers in Opana® ER Hatch-Waxman litigation.

Endo holds the approved new drug application for OPANA®ER, a controlled release formulation of the painkiller opioid oxymorphone. Endo Pharmaceuticals Inc. and Grünenthal GmbH sued generic drug manufacturers under the Hatch-Waxman Act in the U.S. District Court for the Southern District of New York, alleging infringement of U.S. Patent Nos. 8,309,122 B2 and 8,329,216 B2. These patents relate to a controlled release formulation of the painkiller opioid oxymorphone. The asserted claims of the two patents generally recite the following categories of limitations: (1) A “dissolution” or “release rate” limitation, which describes the release of oxymorphone at a specified rate and is measured using the “USP Paddle Method at 50 rpm in 500 ml media.” (2) A pharmacokinetic limitation, which describes how OPANA®ER tablets affect the human body once ingested like analgesic effect, food effect etc. The generic drug manufacturers argued that the asserted patents’ claims were invalid or not infringed. The district court rejected those arguments and found all asserted claims of the ’122 and ’216 patents not invalid, and all but two asserted claims infringed. Specifically, the court found that the asserted claims of the two patents are not invalid for obviousness; that the asserted claims with the dissolution limitations are not invalid for lack of written description; and that the asserted claims reciting the multiple peaks limitations are not invalid for indefiniteness. The court also found that Endo carried its burden to show that defendants infringe or will infringe all but two of the asserted claims of the ’122 and ’216 patents. ANDA filers appealed.

Obviousness:

Appellants first argued that the district court erred in concluding that the asserted claims are not invalid as obvious. Court said that the prior art references in the record strongly discourage a controlled release formulation of opioids with low bioavailability, such as oxymorphone, and, more critically, do not suggest the dissolution and pharmacokinetic limitations recited in the asserted claims of the ’122 and ’216 patents. Expert testimony showed that a skilled artisan would not have been motivated to select oxymorphone for use in a controlled release setting because of its “exceptionally low bioavailability.” The court also observed that “[t]he notion that low-bioavailability drugs were considered unsuitable for extended-release formulation is reinforced by the fact that, until Endo’s development of OPANA®ER, there were remarkably few such examples.” Appellants argued further that the district court erred by giving patentable weight to the pharmacokinetic limitations inherent to the formulations disclosed by the prior art. The district court found that none of the prior art references in the record discloses the analgesic effectiveness of oxymorphone over a twelve-hour period; the claimed food effect limitations; the multiple peaks in blood concentration levels exhibited by controlled release oxymorphone over a twelve-hour period; or the detectable level limitations of the Endo patents. The district court also relied on secondary considerations, which “strongly indicate[d]” the non-obviousness of the invention. Endo’s expert on commercial success established that OPANA®ER achieved tremendous sales growth since its launch. The expert also demonstrated a clear nexus between the asserted claims of the two patents and the market success of OPANA®ER. Endo’s expert on long-felt need separately testified that the medical community had long sought to effectively combat chronic pain, but the numerous immediate release opioids on the market had a short duration of effectiveness and often involved inconvenient routes of administration. Federal circuit held that on balance, Appellants failed to carry their burden to show, by clear and convincing evidence, that claims reciting the dissolution and pharmacokinetic limitations are fairly suggested by any prior art of record or combination thereof. The district court therefore did not err by concluding that the asserted claims of the ’122 and ’216 patents are not invalid as obvious.

Written Description:

Appellants next argued that the district court erred by concluding that the asserted claims of the ’122 and ’216 patents that recite the dissolution limitations are not invalid for lack of written description in the specification. Specifically, Appellants argued that the asserted claims reciting the dissolution limitations claim a much broader range of release rates (15–50% of the drug after one hour, 45–80% after four hours, and more than 80% after ten hours), but the specification discloses much narrower ranges of release rates (27.8–32.3% at one hour, 58.1–66.9% at four hours, and 85.3–95.8% at ten hours) for formulations having 12 hours of analgesic efficacy. Court held that the specification clearly explains that an analgesically effective dosage could contain as low as about 5 mg to as high as about 80 mg of oxymorphone hydrochloride. Accordingly, Endo is entitled to claim not just the narrower range based on a 20 mg dosage, but a broader range based on 5 mg to 80 mg dosage—and that is exactly what it did in the claims reciting the dissolution limitations. The district court therefore did not err by concluding that the asserted claims of the ’122 and ’216 patents that recite the dissolution limitations are not invalid for inadequate written description.

Indefiniteness:

Appellants next argued that the district court erred in concluding that the asserted claims that recite the multiple peaks limitations are not invalid for indefiniteness. Specifically, Appellants argued that claims 1, 71, and 78 of the ’216 patent are invalid for indefiniteness because the claims recite the term “peaks,” contending that the patents contain no explanation of how peaks should be measured or what constitutes peaks. Court said that upon looking at the charts in the specification, a skilled artisan would recognize a peak as occurring where blood concentration of oxymorphone reaches a high-point before declining. In fact, the court’s definition of the term peaks is no different from that offered by Appellants’ own expert at trial. In sum, the district court did not err by concluding that the asserted claims that recite the multiple peaks limitations are not invalid for indefiniteness.

Infringement:

Appellants also argued that the district court erred in finding that Endo showed infringement of all but two asserted claims of the ’122 and ’216 patents. Appellants argued that the district court erred in finding infringement because the ANDA products do not infringe the “food effect” limitations. But the court found that “[d]efendants’ package inserts expressly state that their products satisfy the AUC and Cmax limitations of the ’122 and ’216 patents.” There is no basis to disregard the information contained on the package inserts, which are representations made to the FDA to establish that the proposed generics possess the same characteristics, including the food effect limitations, present in Endo’s approved products. Thus, the court did not clearly err by finding infringement of all but two of the asserted claims of the patents.

Tavaborole - USA

On May 14, 2018, Federal Circuit affirmed PTAB’s decision & held patent covering toenail fungus treatment Kerydin® invalid for obviousness.

The patent in suit, U.S. Patent No. 7,582,621 is entitled “Boron-containing Small Molecules.” The patent is directed to the use of 1,3-dihydro-5- fluoro-1-hydroxy-2, 1-benzoxaborole, also known as tavaborole, to treat fungal infections. In particular, the patent teaches the use of tavaborole as a topical treatment for fungal infections that develop under fingernails and toenails (Onychomycosis). In its final written decision, the Board observed that Austin teaches that tavaborole is a known fungicide with particular potency against C. albicans. The Board also found that another prior art, Brehove taught the treatment of onychomycosis with boron heterocycles and, in particular, that Brehove’s compounds were effective against C. albicans, which Brehove characterized as a common cause of onychomycosis. In light of Brehove’s test results, the Board concluded that a person of ordinary skill in the art would have used Austin’s tavaborole in Brehove’s topical treatment of onychomycosis with a reasonable expectation of success. Anacor appealed.

On appeal, Anacor first argued that the Board violated due process and the procedural requirements of the Administrative Procedure Act (“APA”) by failing to provide Anacor with adequate notice of, and an opportunity to respond to, the grounds of rejection ultimately adopted by the Board. Anacor argued that the Board’s decision violated the APA and due process in two related ways. First, Anacor contends that the petitioner abandoned one prior art reference in its reply (Brehove) and shifted to a new theory of invalidity (relying on Austin in light of Segal and Mertin), and that the Board adopted that new theory without giving Anacor proper notice or an opportunity to respond to it. Second, Anacor argued that, in bolstering this new theory of obviousness, the petitioner impermissibly relied on new evidence, not included in the petition, to satisfy its burden of showing a prima facie case of obviousness. Court, however, rejected Anacor’s argument that the Board violated the APA or due process by adopting a new theory of obviousness not presented in the petition. Court held that the Board did not materially deviate from the theory of obviousness set forth in the petition, and Anacor had ample notice of and an opportunity to respond to the Segal and Mertin references, which in any event were properly offered in reply to arguments made by Anacor and for the purpose of showing the state of the art at the time of the patent application.

Anacor next argued that the Board improperly shifted the burden of proof by requiring the patent owner to disprove obviousness. In substance, Anacor’s argument was not that the Board shifted the burden of proof to Anacor, but that the Board improperly relaxed the burden on the petitioner to prove its case. Austin disclosed the use of oxaboroles, a subset of boron heterocycles, as fungicides that were effective against five different species of fungi, including C. albicans. It stated that compounds containing an oxaborole ring, such as tavaborole, are particularly effective against fungi. The compounds of Brehove, also boron heterocycles, were shown through in vitro testing to be effective against C. albicans. The results of Brehove’s in vivo testing showed that Brehove’s compounds were effective against onychomycosis in each of the patients suffering from that condition. Also approximately 90 percent of all onychomycosis cases are attributable to dermatophytes. In light of the full record before the Board, court concluded that substantial evidence supports the Board’s findings that a person of ordinary skill in the art would have been motivated to combine the pertinent teachings of Austin and Brehove and would have had a reasonable expectation of success in doing so.

In its third argument, Anacor challenged what it refers to as the Board’s “conclusion that the compounds of Austin are ‘structurally similar’ to the compounds of Brehove.” Anacor contended that the compounds are structurally dissimilar, and that a person of ordinary skill in the art would have expected that even small structural differences between tavaborole and the Brehove compounds would result in significant differences in their chemical and biological properties. Court said that the Board correctly acknowledged that there “are obviously structural differences between the dioxaborinanes of Brehove and the benzoxaboroles of Austin,” but it concluded that “the combination of the structural similarities and the similar fungicidal activity against C. albicans would have led a person of ordinary skill in the art to combine Brehove’s method of treating onychomycosis using Austin’s tavaborole instead of [Brehove’s compounds]. The obviousness inquiry often depends on whether there is evidence demonstrating a nexus between structural similarities (or dissimilarities) and functional similarities (or dissimilarities). In this case, although there is only limited structural similarity between the compounds disclosed in Austin and Brehove, we conclude that, in light of the combination of the structural and functional similarities between the compounds, substantial evidence supports the Board’s findings.

Thus, court rejected Anacor’s challenges to the Board’s reasoning and upheld the Board’s conclusion that claim 6 of the ’621 patent is invalid for obviousness.

Pemetrexed - Europe

EP1313508 patent owned by Lilly covers combination containing pemetrexed disodium (ALIMTA) with vitamin B12 & folic acid for treatment of certain cancer (lung cancer). Generic filers developed different salt of pemetrexed. Below are some those recent infringement outcomes in major countries across Europe for EP’508 (expiring on Jun 15, 2021).

Netherlands: On May 08, 2018, Court of Appeal the Hague denied appeal filed by Fresenius / Teva & affirmed lower court’s decision of infringement.

Sweden: On 31 Jan 2018, the Swedish court granted Lilly the infringement order against Actavis.

Finland: On 29 Dec 2017, the Finnish judge granted an infringement ban against Actavis and Ratiopharm at the request of Lilly.

Austria: On 22 Dec 2017, the court imposed a ban on Fresenius Kabi in an inter partes procedure.

Denmark: On 8 Dec 2017, the Danish Maritime and Commercial Court granted Lilly a preliminary injunction against Fresenius Kabi.

Switzerland: On 20 Oct 2017, the Bundesgericht annulled the decision of lower court and held that the product Amtiris® marketed by Actavis infringes EP 508.

Italy: On 10 Sept 2017, Milan court held that Fresenius did not infringe EP’508 with its pemetrexed tromethamine product. The pending appeal is not yet decided.

United Kingdom: On 12 July 2017, the UK Supreme court ruled that the scope of protection of EP’508 also extends to salts other than pemetrexed disodium.

Germany: In Nov 2016, the Landgericht München imposed an ex parte ban based on direct infringement of the German part of EP 508 on the grounds of equivalence.

Pemetrexed - Netherlands

On May 08, 2018, Court of Appeal The Hague handed down its decision in ALIMTA case & denied appeal filed by Fresenius & Teva against lower court’s decision of infringement.

Lilly markets the Alimta® for the treatment of certain lung cancers (tumor growth). The active ingredient in Alimta® (after solution) consists of pemetrexed anions. In Alimta® the anions are bound to sodium ions and thus the pemetrexed disodium salt is formed. Lilly is holder of the European patent EP (NL) 1 313 508 for a 'Combination containing an antifolate and methylmalonic acid lowering agent'.

Fresenius and Teva both appealed an interlocutory judgment of 24 October 2017 (the first instance judgments). In the first instance, Lilly has demanded that the relief judge prohibit Fresenius & Teva from infringing the Dutch part of EP 508. Lilly has argued for that “pemetrexed tromethamine” product of both appellants’ falls within the scope of protection of EP 508. The preliminary relief judge awarded the infringement prohibition. Both Fresenius & Teva appealed.

The question that kept the parties divided is whether pemetrexed tromethamine falls within the scope of protection of EP 508. Court said that the person skilled in the art knows that only the anion is responsible for the efficacy (and toxicity) of pemetrexed. He furthermore finds confirmation for the insight that the invention relates more to the active form of pemetrexed after its administration and not to the specific disodium salt form disclosed therein in EP’508. In the opinion of the court, the average person skilled in the art would recognize that the disodium salt form was not mentioned in the description for the technical advantage associated with that salt form or a salt test (for which the description does not contain any indication), but rather because the disodium salt form was available. Precisely because, on the basis of his general professional knowledge, the average person skilled in the art knew that the acid form and other salt forms of pemetrexed were also possible. He understood that the explicit mention of disodium was motivated by the fact that this form already existed and had been used in research into the invention and therefore should rather be seen as illustration. It was clear to him that also for other forms of pemetrexed they were within the inventive concept of EP 508, while the description did not give rise to the assumption that there was a technical reason for the patent holder to limit himself to the disodium salt form.

In the Court's opinion, the description does not give the average person skilled in the art any reason to suppose that there is a technical reason why Lilly intended to limit the scope of protection of  EP 508 to the disodium salt form of pemetrexed. The experts of appellants have also failed to clarify this. The court agreed with Lilly that the pemetrexed diacid with tromethamine in the appellant’s product should be regarded as a technical equivalent to pemetrexed disodium. The cations differ, but do not play a role in the function, mechanism of action and outcome of both drugs. In both cases there is dissociation in aqueous solution, whereby the same active pemetrexed anion becomes available, which performs the same function, namely to work as an antifolate in the body, with the same result: the prevention of tumor growth and toxicity.

Thus, the appeal was dismissed & infringement affirmed.

Methylnaltrexone - USA

On May 01, 2018, New Jersey district court granted a motion for partial summary judgment of validity of a formulation patent for RELISTOR® (methylnaltrexone bromide) Injection.

This is a Hatch-Waxman case involving a patent dispute regarding Defendants Mylan Inc., Mylan Laboratories Ltd., Mylan Pharmaceuticals, Inc., and Actavis LLC (collectively, “Defendants”) seek to make and sell a generic version of Plaintiff’s Relistor® (methylnaltrexone bromide) pharmaceutical product prior to the expiration of the relevant patents. Plaintiffs’ motion concerns claim 8 of US Patent No. 8,552,025 (the “’025 patent”). Plaintiffs, Progenics Pharmaceuticals, Inc., Salix Pharmaceuticals, Inc., Valeant Pharmaceuticals International, Inc., and Wyeth LLC (collectively, “Plaintiffs.”) moved for partial summary judgment on Defendants’ affirmative defense to infringement of invalidity due to obviousness. Plaintiffs contended that, as to claim 8, Defendants cannot prove invalidity due to obviousness.

Claim 8 relates to stable pharmaceutical preparation comprising a solution of methylnaltrexone comprises a pH between about 3.0 and about 4.0 & wherein the preparation is stable to storage for 24 months at about room temperature.

In moving for summary judgment, Plaintiffs made three arguments: 1) Defendants have failed to identify any motivation to modify the prior art methylnaltrexone products; 2) Defendants cannot establish that the “stable to storage for 24 months” element was known in the prior art; and 3) Defendants cannot prove their “obvious to try” theory. Court said that based on the record, the prior art did not teach how to formulate an injectable pharmaceutical solution that is stable for 24 months. Defendants have offered no evidence to the contrary. Thus, while the idea of an injectable pharmaceutical solution stable for 24 months seems unlikely to have been unknown, there is no evidence before this Court that the art taught how to make one. The evidence of record showed that the prior art taught a variety of techniques for improving the stability of such solutions, but there is no evidence that anyone had ever achieved an injectable pharmaceutical solution stable for 24 months. Court further said that, for the principle of overlapping ranges to apply, the difference between the claimed invention and the prior art must be the range or value of a particular variable. The differences between claim 8 and each of the prior art references (Bahal ’154, Oshlack ’111, and Fawcett 1997) is greater than the value of the pH variable. Thus Court was not persuaded, as a matter of law, that any of the cited prior art references which teach the use of naloxone and naltrexone presents an overlapping pH range sufficient to make out a prima facie case of obviousness. Defendants have not persuaded the Court that any of the prior art references dealing with naloxone and naltrexone – that is, Bahal ’154, Oshlack ’111, and Fawcett 1997 – taught something that would have made claim 8 a predictable result.

The motion for partial summary judgment of validity of claim 8 thus granted.