Zolmitriptan – USA

On Jun 28, 2018, the Federal Circuit affirmed district court’s decision that formulation patents of drug, ZOMIG® are valid.

Lannett appealed from the decision of the District of Delaware concluding, after a bench trial, that claims 4, 11, 12, and 14 of U.S. Patent 6,760,237 (“the ’237 patent”) and claims 6 and 14– 16 of U.S. Patent 7,220,767 (“the ’767 patent”) were not shown to be invalid.

AstraZeneca owns NDA for Zomig® (zolmitriptan) Nasal Spray, 2.5 mg/spray and 5 mg/spray, approved by USFDA for treatment of migraine. AstraZeneca owns and Impax is the exclusive licensee of the ’237 and ’767 patents, which relate to formulations of zolmitriptan for intranasal administration. The claims at issue in this appeal are directed to pharmaceutical formulations with particular pH in the range 3.5 to 5.5, intranasal administration devices, or aqueous solutions, of zolmitriptan. Other formulation claims of the ’237 and ’767 patents at issue include similar limitations with regard to pH ranges and buffering, and some formulation claims include additional limitations relating to sterility. In June 2014, Lannett notified AstraZeneca that it had filed an ANDA with P-IV seeking approval for a generic version of Zomig® Nasal Spray, alleging non-infringement and/or invalidity of the ’237 and ’767 patents.

In July 2014, AstraZeneca (Appellees) filed suit against Lannett in the District of Delaware for infringement of the ’237 and ’767 patents. In December 2015, the district court issued its claim construction opinion and order. The court agreed with Appellees that the preamble of “[a] pharmaceutical formulation suitable for intranasal administration” is limiting. The court also adopted Appellees’ construction of “zolmitriptan” as meaning its chemical name and structure, declining to adopt Lannett’s proposed construction that would include “ionic and covalently bonded forms thereof that preserve the pharmaceutical activity of the structure.” The court, however, agreed with Lannett regarding the construction of the word “buffer,” adopting the “functional definition” proposed by Lannett. In September 2016, a four-day bench trial was held on the issues of infringement and validity. Following the bench trial, the parties stipulated that Lannett’s product described in its ANDA with a target pH of 5, if approved by the FDA, will infringe the ’237 and ’767 patents. In March 2017, the district court issued its decision on validity, holding that Lannett failed to prove by clear and convincing evidence that the asserted claims were invalid based on anticipation & obviousness challenges. Specifically, in reaching the non-obviousness conclusion, the court found that: (1) the prior art, including Chauveau, taught away from formulating zolmitriptan for intranasal administration because zolmitriptan was known to be active, not by itself, but through its more potent metabolite, 183C91; (2) the prior art at the time failed to teach that zolmitriptan by itself, as contrasted with its metabolite, would have been effective; and (3) a skilled artisan would not have been motivated to make with a reasonable expectation of success nasal formulations of zolmitriptan.

Lannett appealed. During appeal Lannett did not argue anticipation as a defense and did not challenge the district court’s claim constructions. The sole issue on appeal was whether it would have been obvious to make zolmitriptan into a nasal spray. On appeal, Lannett contended that the district court erred in concluding that the claims at issue would not have been obvious, based on an erroneous finding that the prior art taught away from nasal formulations of zolmitriptan. According to Lannett, the court improperly disregarded express teachings in the prior art. Lannett alleged that it made a strong showing of obviousness, and therefore, even accepting the district court’s findings of teaching away and objective indicia of nonobviousness, the court still erred in its ultimate conclusion of obviousness.

Federal circuit said that the prior art, Chauveau is generally directed to formulating an active ingredient using capryl caproyl macrogol glycerides for oromucosal administration of the active ingredient. Chauveau discusses that its teachings can be applied to formulations for buccal, nasal, or pharyngeal administration, among which the nasal route is preferred. The court found that Chauveau “offers a laundry list of potential active ingredients,” including “over twenty-five categories or examples of medications.” At the end of the list, Chauveau states that “[t]he active substance can also be, in particular, an antimigraine active substance, such as a triptan, such as sumatriptan or zolmitriptan.” Court held that, Chauveau, as a whole, is not about intranasal formulations of zolmitriptan, which is barely mentioned. It is about formulations of a wide variety of compounds with capryl caproyl macrogol glycerides. Zolmitriptan is mentioned once, with no further mention in an example or claim. Specifically, the court found that the prior art taught that zolmitriptan has a “unique attribute” in that its “[f]irst pass metabolism results in an active metabolite, 183C91, which is two to eight times more powerful than zolmitriptan itself.” The court credited Appellees’ expert, Dr. Rapoport, who provided his opinion on the state of the prior art in support of this finding. The court also noted that Lannett’s expert did not dispute the relevance of zolmitriptan’s active metabolite in considering whether to develop zolmitriptan formulations. Contrary to Lannett’s contentions, the district court found that zolmitriptan’s more potent, active metabolite was actually thought to be significant for its efficacy by a person of skill in the art at the time. Specifically, the court credited Appellees’ evidence of expert testimony and studies and found that a skilled artisan would have expected delayed or lower therapeutic effectiveness from zolmitriptan if administered nasally because it would have been “absolutely counterintuitive to make a nasal spray when you have an active metabolite which is more potent . . . than the drug itself.” As such, the court found that “because of zolmitriptan’s reliance on its active metabolite, the prior art failed to teach that zolmitriptan by itself would be effective.” Thus district court did not err in its findings.

The district court also considered evidence of secondary considerations, including the 2012 license agreement between Impax and AstraZeneca covering the Zomig® products for which Impax paid $130 million. The court found that this 2012 agreement favored Appellees as it found a nexus between the agreement and the ’237 and ’767 patents. However, it found that Appellees’ other evidence of secondary considerations was inconclusive. Federal circuit held that in view of other underlying factual findings, it is sufficient for us to find that the district court did not clearly err in finding that the 2012 agreement is at least in part attributable to the patents at issue.

Federal circuit then considered whether the district court reached a legally erroneous conclusion of non-obviousness. The court called this case indeed a “close one.” Federal circuit deferred to the district court in its fact findings, including what Chauveau discloses and the state of the prior art as a whole. And especially court persuaded by the testimony of Appellees’ expert, Dr. Rapoport, on which the district court relied, who opined that it would have been “absolutely counterintuitive” to make an intranasal formulation of zolmitriptan, given that its activity primarily came from its metabolite, and the agreement between AstraZeneca and Impax covering the intranasal product and its patents for which the latter paid $130 million. Federal circuit therefore concluded that the district court did not commit reversible error in its non-obviousness conclusion. Thus, Lannett failed to prove by clear and convincing evidence that the claims of the ’237 and ’767 patents are invalid.

Tenofovir + Emtricitabine - Switzerland

On June 11, 2018, the Federal Supreme Court dismissed Mepha’s appeal & affirmed Validity of Gilead’s Swiss TRUVADA® SPC.

By submission of 3 Jan 2017 to the Federal Patent Court, Mepha (Plaintiff) requested Swiss SPC to be declared invalid. The Plaintiff claimed that the Swiss practice should be disregarded and adapted to the case law of the Court of Justice of the EU (CJEU). Following the so-called Medeva practice, the Gilead’s SPC was to be declared valid, according to the Plaintiff. With its decision of 3 Oct. 2017, the Federal Patent Court dismissed the revocation action. The court came to the conclusion that the Gilead’s SPC was valid under the so-called “infringement test”, applied in Switzerland since long. There was no reason for a change in case law according to this decision, since the CJEU's practice was not clear with respect to interpretation of Article 3(a).

Mepha filed appeal. Supreme Court said that the endeavor to align Swiss regulations to the law of neighboring EU states to the extent possible is considered in the interpretation of the corresponding legal provisions according to consistent practice of the Federal Supreme Court, particularly in the context of teleological and historical interpretation. As a result of a consultation process, a letter from the IPI of 13 January 2017 which contained principles for the planned amendment of the relevant Granting Directive (13.2.1); the interested parties have essentially agreed to this proposal, believing that the proposed new Directive will enable the criteria of the CJEU's "Medeva" decision to be implemented in a manner that provides sufficient legal certainty and consistency. Since the CJEU practice now appears to be established, there are genuine reasons for changing Swiss case-law in order to adapt it to the concept pursued by the CJEU, specifically for combination products.

On the validity of SPC, Supreme Court held that the supplementary protection certificate for the contested product (Tenofovir + Emtricitabine) was granted to the Gilead with a formal and legally binding decision. It was not granted contrary to Art. 140b PatA and therefore there is no ground for invalidity according to Art. 140k PatA.  Accordingly, the legally binding nature and consequences of acts which took place before the commencement hereof, remain subject to the law which was applicable at the time. If a change of law had occurred after the grant of the supplementary protection certificate, in principle the certificate could not be taken away from the entitled party. In principle, legally binding administrative orders cannot be reconsidered or revised due to a change in case law.

On 29 August 2008 the Gilead was formally and lawfully granted the supplementary protection certificate. Such certificate could not be revoked even in case the requirement provided for in respect of the granting at hand, namely "protected by a patent" within the meaning of Art. 140b PatA according to the now changed practice was no longer met. As a result, the appeal was dismissed.

Thus, in conclusion the Federal Supreme Court decided that while the infringement test shall still apply to existing SPCs, new SPCs for combination products shall be examined in light of the Medeva ruling and other decisions of the CJEU.

Pemetrexed - USA

On Jun 22, 2018, U.S. District Court for the Southern District of Indiana ruled in favor of Lilly finding that Dr. Reddy’s alternate salt would infringe dosing regimen patent of ALIMTA® (pemetrexed disodium).

This is a Hatch-Waxman patent infringement action brought by Eli Lilly against Dr. Reddy’s for filing of NDA No. 208297 with USFDA seeking approval to market the product, pemetrexed ditromethamine.   US 7,772,209 patent owned by Lilly covers the method of administration of ALIMTA®, requiring that physicians co-administer the drug with folic acid and vitamin B12.  The primary focus of this infringement trial is on whether Dr. Reddy’s label, specifically the use of pemetrexed ditromethamine product described therein, infringes the ‘209 Patent, which uses pemetrexed disodium, under the doctrine of equivalents.

A. Prosecution History Estoppel:

The Court found Lilly was not barred, as a matter of law under prosecution history estoppel, from asserting the doctrine of equivalents. Specifically, claim was narrowed to overcome a rejection in view of Arsenyan, a prior art article about a different antifolate, methotrexate. Accordingly, the Court concluded that Lilly’s rationale for limiting its claim to pemetrexed disodium (to avoid a rejection based on the prior art Arsenyan) is tangential to the accused equivalent—pemetrexed ditromethamine.

B. Disclosure-Dedication Rule:

It was undisputed that the ‘209 Patent’s specification did not expressly disclose pemetrexed ditromethamine. Rather, Dr. Reddy’s based its disclosure-dedication argument on the fact that the ‘209 Patent referenced U.S. Patent No. 4,997,838 to Akimoto and that from Akimoto the hypothetical person of skill in the art (“POSA”) could find pemetrexed ditromethamine disclosed among the alternatives disclosed in Akimoto. Court held that because Akimoto was not expressly incorporated, as required, in the ‘209 Patent, and in any event Akimoto does not specifically disclose pemetrexed ditromethamine as an alternative to pemetrexed disodium, the disclosure-dedication rule does not bar Lilly’s doctrine of equivalents claim.

C. Doctrine of Equivalents:

Lilly asserted that healthcare providers using the proposed Dr. Reddy’s product will directly infringe under the doctrine of equivalents, and that Dr. Reddy’s is liable as an indirect infringer under 35 U.S.C. §§ 271(b) and (c). Court said that under the relevant context that the claim relates to medical treatment, pemetrexed ditromethamine treats the patient’s cancer in exactly the same way as pemetrexed disodium. It is undisputed that when both pemetrexed disodium and pemetrexed ditromethamine are placed in solution, that both compounds dissociate completely in solution resulting in free pemetrexed and therapeutically irrelevant counter-ions. In fact, in aqueous solution, the two products will be identical.

The differences in the chemical properties between pemetrexed disodium and pemetrexed ditromethamine with regards to solubility, stability, pH, and buffering capacity are irrelevant in the context of the claimed method which is a liquid administration of pemetrexed sodium. What is in fact ultimately administered to the patient is injectable pemetrexed ions that enter the patient’s cells.

D. Inducement and contributory infringement:

Court said that as Dr. Reddy’s product infringes the ‘209 Patent under the doctrine of equivalents, it cannot avoid intent or infringement on the bases that it possessed a “good faith belief that its proposed product[s] would not infringe.” Moreover, the Court found, based on a preponderance of the evidence, Dr. Reddy’s label instructs users to perform the patented method by both inducing and contributing to infringement and that Dr. Reddy’s had the requisite specific intent and knowledge that its label would cause such infringement. Dr. Reddy’s product does not have a substantial non-infringing use to avoid contributory infringement. A physician administering Dr. Reddy’s product would constitute direct infringement under § 271(a); thus, the use the Dr. Reddy’s NDA products would constitute inducement and contributory infringement of the ‘209 Patent by Dr. Reddy’s under 35 U.S.C. § 271(b),(c).

Zoledronic acid – USA

PGR decision (Jun. 22, 2018):

AIA Review	Institution Date	Petitioner	Patent No.	Final Written Decision
PGR2017-00008	07/07/2017	Grunenthal GmbH	9,283,239	Claims 1–17 are unpatentable

This is a Final Written Decision in a post-grant review challenging the patentability of claims 1–17 of U.S. Patent No. 9,283,239 B2.

Petitioner contended that claims 1–17 are unpatentable for insufficient written description of the dosing regimen limitation “about 80 to about 500 mg of zoledronic acid within a period of six months” as recited in independent claim 1. Petitioner separately challenged claim 17 for lacking written description of an oral dosage form containing “at least 10% zoledronic acid.” PTAB held that the specification discloses the range of “about 50 mg to about 500 mg,” thereby giving literal support to this range and to the endpoint of “about 500 mg.” However, the ’239 patent specification does not clearly allow persons of ordinary skill in the art to recognize the “about 80 mg” endpoint as part of invention described in the ’239 patent. There is no disclosure of “about 80 mg” as a preferred endpoint, no disclosure of a specific embodiment including a dose of 80 mg, nor any other description suggesting the importance or criticality of the “about 80 mg” endpoint. Moreover, PTAB noted that the claims do not merely require administration of a dose of about 80 mg to about 500 mg of zoledronic acid, they also require that dose to be administered “within a six month period.”

Thus, PTAB concluded that Petitioner has shown by a preponderance of the evidence that claims 1–17 are unpatentable for a lack of written description.

Glycerol Phenylbutyrate – USA

On Jun 18, 2018, the Federal Circuit in one-liner order affirmed PTAB’s decision that method of treatment patent of drug, RAVICTI® is valid.

US 8,642,012 (Hyperion; Exp: Sep. 22, 2030) claims a method of treating a patient having a urea cycle disorder comprising (a) determining a target urinary phenylacetyl glutamine (PAGN) output (b) calculating an effective initial dosage of a phenylacetic acid (PAA) prodrug selected from glyceryl tri-[4-phenylbutyrate] (HPN-100) and phenylbutyric acid (PBA) or a pharmaceutically acceptable salt of PBA, wherein the effective dosage of PAA prodrug is calculated based on a mean conversion of PAA prodrug to urinary PAGN of about 60%; and (c) administering the effective initial dosage of PAA prodrug to the patient.

Previously, on April 29, 2015, Par Pharmaceutical, Inc. filed a Petition (IPR2015-01117) requesting an inter partes review of claims 1–12 of US 8,642,012. On Nov. 4, 2015, PTAB instituted trial & Lupin joined (IPR2016-00283) that petition. On Nov. 3, 2016, PTAB found that Par has failed to carry its burden of proving by a preponderance of the evidence that claims 1–12 would have been unpatentable over the prior art.

Rituximab - Australia

On Jun 12, 2018, Federal Court of Australia granted Roche a preliminary injunction against Sandoz’s biosimilar on the basis prima facie case for infringement & validity of patents.

In the present interlocutory application the originator (Hoffman / Roche) seeks urgent orders to restrain a respondent (Sandoz) from launching a Rituximab biosimilar on the basis that the biosimilar will infringe some of the claims of four asserted patents. The respondent contends that the asserted claims are invalid for want of inventive step and that the balance of convenience and justice lies against the grant of the injunction sought.

Mabthera (Rituximab) is a biologic therapy prescribed in Australia to treat a number of immunology conditions including Non-Hodgkins Lymphoma (NHL), chronic lymphocytic leukaemia (CLL) and rheumatoid arthritis (RA) which is owned by Hoffman / Roche. Sandoz has applied to have RIXIMYO listed on the Pharmaceutical Benefits Scheme (PBS). On March 2018, a number of positive recommendations were made for the RIXIMYO products. The evidence suggests that it is likely that, absent an injunction, Sandoz’s products will be listed on 1 August 2018. Roche is concerned that the effect of the PBS listing will be to cause a sequence of irreversible and harmful consequences to it. It now seeks interlocutory orders to restrain Sandoz from infringing the patents; AU2008207357 (NHL patent), AU761844 (CLL patent), AU2005211669 (DLCBL patent) & AU2007242919 (RA patent).  Each of the claims is for a method of treating particular medical conditions using rituximab.

Sandoz argued invalidity arguments (lack of inventive step) based on various prior arts, with the common general knowledge. However, court was not persuaded by its Expert & held that Professor did not give evidence about the effects of the combination of these prior art documents, so there remains a question about whether this would occur. However, the evidence of the experts on both sides appears to be rational and persuasive and, having regard to the differences between them, court can see no rational basis for concluding other than that the lack of inventive step is arguable.

Alternatively, Roche has established a prima facie case for infringement of the asserted claims. Sandoz has by its evidence demonstrated that it has an arguable case for challenging the validity of those claims; however, the evidence does not permit a provisional view that rises above that level. The balance favors the preservation of the status quo and the rights protected by the asserted claims in respect of which a serious question to be tried as to the entitlement to final injunctive relief has been established. Overall, the balance of the case and justice lies in favor of the granting of interlocutory injunctive relief.

Valsartan & Amlodipine - France

On Jun 07, 2018, the tribunal de grande instance of Paris issued a preliminary injunction against Teva’s generic of anti-hypertensive drug EXFORGE®.

As reported on “EP law blog”, the judge rejected all the invalidity arguments raised by Teva (double patenting, insufficiency, extension, obviousness). Teva’s generic had been put on the market in October 2017; therefore the court ordered Teva to pay Novartis more than €13,000,000 as an advance on damages.

Patent-in-suit was EP 2322174 entitled, “combined use of valsartan and calcium channel blockers for therapeutic purposes”. The EXFORGE®, which includes valsartan and amlodipine, is covered by EP 174.

Rosuvastatin - Netherlands

On Jun 08, 2018, the Supreme Court of Netherlands upheld the decision of Court of Appeal & held that the AstraZeneca’s Crestor® patent is valid & would be infringed even though alternate salt is used.

Present case is dealing with the extent of the protection that is conferred by EP 0521471 patent. Specifically, the question is whether definition in the description of the claim feature “pharmaceutically acceptable salt” is limiting one. District Court, following an extensive substantiation held that the definition is limiting; but Court of Appeal reversed the decision & held that it is not. Resolution appealed to Supreme Court. Supreme Court followed Advocate General’s opinion of Nov 24, 2017 & dismissed the appeals in cassation.

Background:

Shionogi is a Japanese pharmaceutical company that is the holder of the supplementary protection certificate 300125 (SPC) for the Netherlands that has been granted for the product ‘Rosuvastatinum, if required in the form of a non-toxic pharmaceutically acceptable salt, in particular calcium salt’. The SPC, which is based on European patent EP 0521471 has been exclusively licensed to Astrazeneca B.V. In the Netherlands, Astrazeneca B.V. markets rosuvastatin calcium under the brand name Crestor®. The SPC expired on 29 June 2017. Claim 1 pertains to the compound rosuvastatin acid or a non-toxic pharmaceutical salt thereof. Specification in paragraph 7 defines the term “a non-toxic pharmaceutically acceptable salt” refers to a salt in which the cation is an alkali metal ion, an alkaline earth metal ion, or an ammonium ion”.

On 17 April 2014, Resolution initiated proceedings against AstraZeneca in accordance with the rules regarding accelerated proceedings on the merits in patent cases, in which Resolution inter alia moved that the District Court nullifies claims 1 and 2 of the Dutch part of EP 471 and the dependent claims, and further nullifies SPC 300125 to the extent that the subject matter of this SPC pertains to a compound other than rosuvastatin calcium and/or rosuvastatin sodium. Resolution developed Rosuvastatin product with zinc salt. By virtue of a judgment dated 15 July 2015, the District Court of The Hague nullified the SPC to the extent that the protection it confers extends to products other than the nontoxic pharmaceutically acceptable salts of rosuvastatin in which the cation comprises an alkali metal ion, an alkaline earth metal ion or an ammonium anion. The District Court held that the average skilled person would read the feature “a non-toxic pharmaceutically acceptable salt thereof” mentioned in EP 471 in conjunction with the definition that the invention previously discloses in paragraph [0007] of the description. AstraZeneca initiated an appeal against the District Court’s judgment. By virtue of a ruling dated 16 February 2016, the Court of Appeal of The Hague set aside the District Court’s judgment and dismissed Resolution’s claims.

Present appeal:

Resolution has brought an appeal in cassation against this ruling in time. On 16 December 2016, oral pleadings were held before the Supreme Court. The issue in this case is whether part of the protection has been “waived” in paragraph 7 of the description and in this scope, whether the waiver doctrine as formulated in the Van Benum/Kool ruling is still applicable law. Particularly, the question to be answered is how the claim feature ‘or a non-toxic pharmaceutically acceptable salt thereof’ in claim 1 of EP 471 must be interpreted.  Attorney General held that the waiver doctrine does not seem to be very compatible with the interpretation system of Article 69 EPC. This is in line with the system of Article 69 EPC and which could replace the waiver doctrine, is – within the scope of the point of view of the inventive idea – to allocate weight to whether and, if so how, according to the average skilled person there was an intention to limit the extent of the protection. In other words: according to the skilled person, was a specific limited extent of the protection deliberately chosen.  In view of the description considered as a whole, taking into account his general professional knowledge on the priority date, the average skilled person will understand that the invention pertains to a new group of statins – in particular the specifically claimed rosuvastatin – whose biological activity is superior to a known first generation of statins.

The Court of Appeal also used this method in present case. Specifically, average skilled person, based on his general professional knowledge, knows that the active ingredient at issue in this invention (just as in the earlier generations of statins) is the anion, which as such cannot exist independently or included in a tablet, but needs a cation “as a carrier”. The essence of the invention does not lie in the precise salts (anion-cation combinations), but in the new active anion. The two examples included in the description only describe the process for preparing two salt forms of rosuvastatin, without comparing these forms or subjecting them to further tests. Subsequently, the experiment was only performed with the sodium salt; the biological activity was not compared with the calcium (or other) salt, but with another statin known from the prior art. Therefore, finding a suitable salt form is not the inventive idea underlying the wording of the claim(s).

Also based on these findings, in contrast to the District Court, the Court of Appeal found that on the priority date, the average skilled person did not have valid reasons to assume that the patent proprietor only wanted protection for the salts of rosuvastatin mentioned in paragraph 7 and waived the broader protection that claim 1 offered according to its literal wording. This means that claim 1 must be interpreted such that the extent of the protection it confers extends to (in addition to the rosuvastatin acid) all non-toxic pharmaceutically acceptable salts of rosuvastatin, including those that are not mentioned in paragraph 7 of the description. Therefore, Court of Appeal did not err & appeals were dismissed.

Added subject matter:

Resolution took the position that claim 1 of EP 471 is invalid under “added subject matter” to the extent that the claim pertains to anything other than rosuvastatin sodium or calcium salt, because the original application allegedly does not directly and unambiguously disclose rosuvastatin acid or other salt forms to the average skilled person. The District Court held that only rosuvastatin acid constitutes added subject matter. However, Court of Appeal reversed & held that no added subject matter is involved, because claim 1 of EP 471 also extends to rosuvastatin acid as well as non-toxic pharmaceutically acceptable salts other than the sodium and calcium salt.” According to the Court of Appeal, the average skilled person reads salts and acids in the disclosure/is reminded of these in the Markush formula at position R4 of the original application. Thus, the Resolution’s appeal regarding added subject matter was dismissed.

Bendmustine - USA

On Jun 11, 2018, Eagle Pharmaceuticals, Inc. announced that the U.S. District Court for the District of Columbia (the Court) has issued a decision requiring the USFDA to grant seven years of orphan drug exclusivity (ODE) for BENDEKA™ (bendamustine hydrochloride injection), a liquid, low-volume (50 mL) and short-time 10-minute infusion formulation.

As a result of the Court’s decision, the FDA will not be able to approve any drug applications referencing BENDEKA until the ODE expires in Dec 7, 2022. Moreover, the Company now does not expect generic TREANDA ® entrants into the market until 2022, rather than November 2019.

On April 27, 2016, Eagle sued FDA in the U.S. District Court for the District of Columbia alleging that FDA violated the Administrative Procedure Act (“APA”) when the Agency refused to grant 7-year of ODE to BENDEKA for Chronic Lymphocytic Leukemia (“CLL”) and indolent B-cell Non-Hodgkin Lymphoma (“NHL”) indications.  Previously, FDA by letter of March 24, 2016 denied ODE because according to FDA, Eagle did not provide sufficient evidences than BENDEKA is superior to TREANDA. Thus, FDA claimed that Eagle had failed to meet the agency’s criteria for a demonstration of “clinical superiority”.

Prevnar 13 - USA

IPR decision (Jun. 08, 2018):

AIA Review	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-00378; &	June 13, 2017	Merck Sharp & Dohme Corp	8,562,999	Claims 1–6, 10, 11, 14, 17, 19, 20 are unpatentable & claim 18 is patentable
IPR2017-00380	June 13, 2017	Merck Sharp & Dohme Corp	8,562,999	Claims 1–6, 10, 11, 14, 17, 19, 20 are unpatentable & claim 18 is patentable
IPR2017-00390	June 13, 2017	Merck Sharp & Dohme Corp	8,562,999	claims 7–9, 12, 13, 15, 16, 21, and 22 are unpatentable

US 8,562,999 claims  formulation comprising (i) a pH buffered saline solution with pKa of about 3.5 to about 7.5, (ii) an aluminum salt and (iii) one or more polysaccharide-protein conjugates, wherein the formulation is comprised in a siliconized container means and inhibits aggregation induced by the siliconized container means.

This patent is related to Pfizer Inc.’s top-selling Prevnar 13 pneumonia vaccine.

Prepopik® – USA

On Jun 08, 2018, the Federal Circuit in one-liner order affirmed a Delaware court's finding that Par Pharmaceutical Inc. infringed two of Ferring Pharmaceuticals Inc.’s patents (US 8,450,338 and US 8,481,083) covering the colonoscopy drug Prepopik.

Previously on Jul 11, 2017 Delaware court issued its opinion (reported on this blog here) & held that Par’s proposed ANDA product infringes claims 1, 4-6, 8, 9-12, and 17-18 of the '338 patent and claims 1 and 7-11 of the '083 patent. Main dispute was whether Defendant's ANDA product comprises a "spray-coated layer of sodium picosulfate coating a potassium bicarbonate core”. Delaware court credited plaintiff’s expert Dr. Davies testimony & said that Defendant is attempting to reargue claim construction. Specifically, Defendant's current proposal is not materially different from the construction it proposed, which court already rejected, at claim construction.

Efinaconazole - USA

IPR decision (Jun. 06, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-00190	11/02/2016	05/01/2017	Acrux DDS Pty Ltd.	7,214,506	Claims 1 and 2 are unpatentable
IPR2017-01429*	05/12/2017	11/13/2017	Argentum Pharmaceuticals LLC

* joined to IPR2017-00190

US 7,214,506 (expiring on Oct. 05, 2021) claims method for treating a subject having onychomycosis by topically administering to a nail a therapeutically effective amount of Efinaconazole.

USFDA approved Jublia® (Efinaconazole) topical solution Jun 6, 2014. NCE would expire on Jun 6, 2019.

Decision summary:

Claim construction:

PTAB by applying BRI standard concluded that the term, “nail” includes “nail plate, nail bed, nail matrix, further side nail wall, posterial nail wall, eponychium and hyponychium which make up a tissue around thereof.” It also concluded on this record that “onychomycosis” is not limited to infections of the nail plate and nail bed, but includes superficial mycosis that involves disease of the skin or visible mucosa.

Obviousness over the Ogura with each of JP ’639, the ’367 patent, or Hay:

PTAB found that Ogura is not prior art to the ’506 patent as Patent Owner has established that the invention was reduced to practice before Ogura was allegedly published. Therefore, PTAB concluded that the Petitioner has not shown by a preponderance of the evidence that claims 1 and 2 are unpatentable.

Obviousness over Kaken Abstracts with JP ’639, the ’367 patent, or Hay:

PTAB agreed with Petitioner that the Kaken Abstracts point to KP-103 as being known to have potent antifungal activity against T. mentagrophytes, one of the major causes of onychomycosis. The Kaken Abstracts showed that KP-103 is effective in vitro and in vivo, at least with respect to skin, in treating fungal infection. As Dr. Walters (Petitioner’s expert) notes, the question is not whether one of ordinary skill in the art would have been led to use efinaconazole because of the particular compound(s) taught by JP ’639, the ’367 patent, and Hay, but whether one of ordinary skill in the art would have been motivated by the disclosures of JP ’639, the ’367 patent, or Hay in combination with the Kaken Abstracts, as a whole, to improve the topical formulations and methods of JP ’639, the ’367 patent, or Hay by using efinaconazole, “a highly potent antifungal compound with broad spectrum activity that is not inactivated by keratin and has high retention in the horny layer, in the topical formulation and method”.

PTAB credited Dr. Walters’ and Dr. Weignberg’s testimony and found that Petitioner has shown sufficient rationale for one of ordinary skill in the art to combine the teachings of the Kaken Abstracts with the teachings of each of JP ’639, the ’367 patent, or Hay with a reasonable expectation of success. Also, because the method for Jublia®’s use is not reasonably commensurate with the claims of the challenged claims, PTAB found that Petitioner has rebutted the presumption of nexus for the secondary considerations relating to Jublia®. PTAB also concluded that the Patent Owner’s evidences of other secondary considerations are weak and insufficient to support the non-obviousness of the challenged claims.

Thus, Petitioner has shown by a preponderance of the evidence that claims 1 and 2 of the ’506 patent are obvious under 35 U.S.C. § 103(a).

Icatibant - USA

On Jun 05, 2018, Delaware district court held that the asserted claims of the patent-in-suit are not invalid under the doctrine of obviousness-type double patenting or prosecution laches in FIRAZYR® Hatch-Waxman litigation.

In this patent infringement action, Shire and Sanofi-Aventis ("Plaintiffs") alleged that Fresenius Kabi USA, LLC, ("Defendant") filed an ANDA with USFDA to manufacture and sell a generic version of FIRAZYR® (icatibant acetate) prior to the expiration of U.S. Patent No. 5,648,333. FIRAZYR® Injection is used for the treatment of acute attacks of hereditary angioedema ("HAE") in adults 18 years of age and older. The court held a four-day bench trial in this matter beginning on January 29, 2018. Plaintiffs have asserted Claim 14 of the '333 Patent. Claim 14 of the '333 Patent claims:

A peptide of the formula H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH or a physiologically tolerable salt of said peptide.

Fresenius asserted that claims are invalid under the doctrine of obviousness-type double patenting ("OTDP") in light of the prior arts including, U.S. Patent No. 5,597,803 & under prosecution Laches.

Obviousness-Type Double Patenting:

The obviousness-type double patenting analysis hinges on whether (1) the removal of the N-terminal modification Fmoc from the peptides of Claim 1 of the '803 Patent results in Claim 14 of the '333 Patent; and (2) whether the N-terminal modifications in the '803 Patent are intended to be permanent and integral components of the final peptide. Claim 14 of the '333 Patent claims a single ten-amino acid peptide known as icatibant and relates to "Peptides Having Bradykinin Antagonist Action." In contrast, the '803 Patent relates to "Bradykinin Peptides with Modifications at the N-Terminus" and covers Fmoc-icatibant. Because Claim 1 of the '803 Patent allows for modifications in the peptide sequence at two positions, the court found that the claims themselves are different under step one of the analysis even though they share some inventors and are assigned to the same company.

Court next considered step 2 inquiry whether the differences in subject matter of the two patents render the claims patentably distinct-i.e., the later claim is not obvious over or anticipated by an earlier claim. In arguing that the claims are not patentably distinct, Defendant made three primary arguments. First, Defendant argued that the only difference between Claim 1 of the '803 Patent and Claim 14 of the '333 Patent is the presence or absence of the extra N-protecting groups-the Z and P groups. Second, Defendant argued that the only difference between Fmoc-icatibant and icatibant is the presence of Fmoc.  Third, Defendant argued it presented clear and convincing evidence demonstrating that a POSA would have been motivated to remove the Fmoc and that they would have had a reasonable expectation that the resulting peptide would be a bradykinin antagonist. 

The court found that persons having ordinary skill in the art would not have removed Fmoc based on the patent itself and the prior art. As of 1989, it was known that the addition of N-terminal modifications could confer significant benefits to the resulting peptide, including reduction of side effects and resistance to enzymatic degradation. Finally, the court found that, contrary to Defendant's assertion, every example of a peptide of formula I contains Z and every peptide evaluated for biological activity has a Z group. The court, therefore, held that a POSA in 1989 using Claim 1 of the '803 Patent as a starting point, would not have been motivated to remove the N-terminal modifications from the peptides of Claim 1 of the '803 patent to result in Claim 14 of the '333 Patent.

Defendant next argued that a POSA would understand that Claim 14 of the '333 Patent does not recite any biological activity and that and Claim 1 of the '803 Patent recites biological activity but does not require it. Specifically, Defendant asserted that the POSA would have reasonably expected the icatibant peptide remaining after Fmoc removal would be a bradykinin antagonist based on its structure and the icatibant peptide would be consistent with the prior art Stewart SAR Data. In contrast, Plaintiffs asserted that Claim 14 of the '333 Patent concerns bradykinin antagonist activity because, among other reasons, every example in the '333 Patent is a bradykinin antagonist. Court held that the specification of the '803 patent contemplates two different functional roles for Fmoc: (1) a protecting group used during synthesis that is removed from a peptide under construction, meaning while that peptide is attached to the resin or still has side chain protective groups, or both; or (2) an integral component of the final peptide product. Therefore, the peptides in the '803 Patent are not under construction and are, therefore, not intermediates. That distinction would have instructed the POSA that the modification was permanent, and would not have motivated the POSA to remove Fmoc.

The court, also considered secondary consideration thought prima facie case of obviousness was not established. Court found that the secondary considerations weigh against a finding of obviousness-type double patenting.

Prosecution Laches:

"The doctrine [of prosecution laches] 'may render a patent unenforceable when it has issued only after an unreasonable and unexplained delay in prosecution' that constitutes an egregious misuse of the statutory patent system under the totality of the circumstances." It also requires a showing of prejudice, which in turn requires "evidence of intervening rights, i.e., that either the accused infringer or others invested in, worked on, or used the claimed technology during the period of delay." The '333 Patent issued from U.S. Patent Application 08/487,442 ("the '442 Application"), which was filed on June 7, 1995. The '442 Application claims priority to five German patent applications and ten U.S. patent applications.

Defendant primarily argued that Plaintiffs' four year delay in prosecuting the patent between 1991 and 1995 was unreasonable and unexplained because, during that time, applicants failed to provide a substantive response to the PTO. Specifically, Defendant asserted that Plaintiffs failed to provide the Patent Office with the in vivo data requested to support utility of the '162 application and, instead, argued the in vitro data was sufficient, which delayed prosecution. Defendant argued Plaintiffs had the in vivo data related to icatibant, as early as March 1989 prior to the original '162 application filing date.

Court held that "there are legitimate grounds for refiling a patent application which should not normally be grounds for a holding of laches, and the doctrine should be used sparingly lest statutory provisions be unjustifiably vitiated." The filing of multiple continuing applications is not per se unreasonable. Novozymes AIS v. Genencor Int'!, Inc., 446 F. Supp. 2d 297, 333-34 (D. Del. 2006). In the instant case, the court found Plaintiffs actively prosecuted without an unreasonable or unexplained delay. The '333 Patent resulted from German priority and U.S. applications of three distinct inventions. In addition to the evidence adduced at trial, prosecution laches has not been applied to an alleged four-year-delay. The court, therefore, found that Defendant did not establish by clear and convincing evidence that there was an unreasonable and unexplained delay in the prosecution of the '333 Patent. Thus, Claim 14 of the '333 Patent is not invalid under the doctrine of prosecution laches.