Trastuzumab - USA

IPR decision (Jul 31, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-02031	08/31/2017	03/29/2018	Boehringer Ingelheim	6,407,213	Terminated-Adverse Judgment
IPR2017-02032	08/31/2017	03/29/2018	Boehringer Ingelheim	6,407,213	Terminated-Adverse Judgment

On US’213 patent, Mylan previously filed IPRs (IPR2016-01693 & IPR2016-01694) on 08/30/2016 which were terminated due to settlement. Celltrion, Pfizer & Samsung Bioepis each filed 2 separate IPRs which were instituted by PTAB in Dec 2017 & Feb 2018.

US 6,407,213 (Genentech; Exp: Jun 18, 2019)

1. A humanized antibody variable domain comprising non-human Complementarity Determining Region (CDR) amino acid residues which bind an antigen incorporated into a human antibody variable domain, and further comprising a Framework Region (FR) amino acid substitution at a site selected from the group consisting of: 4L, 38L, 43L, 44L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, and 92H, utilizing the numbering system set forth in Kabat.

30. An antibody which binds p185.sup.HER2 and comprises a humanized antibody variable domain, wherein the humanized antibody variable domain comprises non-human Complementarity Determining Region (CDR) amino acid residues which bind p185.sup.HER2 incorporated into a human antibody variable domain, and further comprises a Framework Region (FR) amino acid substitution at a site selected from the group consisting of: 4L, 38L, 43L, 44L, 46L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, 75H, 76H, 78H and 92H, utilizing the numbering system set forth in Kabat.

62. A humanized antibody variable domain comprising non-human Complementarity Determining Region (CDR) amino acid residues which bind an antigen incorporated into a consensus human variable domain, and further comprising an amino acid substitution at a site selected from the group consisting of: 4L, 38L, 43L, 44L, 46L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, 75H, 76H, 78H and 92H, utilizing the numbering system set forth in Kabat.

63. A humanized antibody which lacks immunogenicity compared to a non-human parent antibody upon repeated administration to a human patient in order to treat a chronic disease in that patient, wherein the humanized antibody comprises non-human Complementarity Determining Region (CDR) amino acid residues which bind an antigen incorporated into a human antibody variable domain, and further comprises an amino acid substitution at a site selected from the group consisting of: 4L, 38L, 43L, 44L, 46L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, 75H, 76H, 78H and 92H, utilizing the numbering system set forth in Kabat.

64. A humanized variant of a non-human parent antibody which binds an antigen and comprises a human variable domain comprising the most frequently occurring amino acid residues at each location in all human immunoglobulins of a human heavy chain immunoglobulin subgroup wherein amino acid residues forming Complementarity Determining Regions (CDRs) thereof comprise non-human antibody amino acid residues, and further comprises a Framework Region (FR) substitution where the substituted FR residue: (a) noncovalently binds antigen directly; (b) interacts with a CDR; (c) introduces a glycosylation site which affects the antigen binding or affinity of the antibody; or (d) participates in the V.sub.L -V.sub.H interface by affecting the proximity or orientation of the V.sub.L and V.sub.H regions with respect to one another.

66. A humanized antibody heavy chain variable domain comprising non-human Complementarity Determining Region (CDR) amino acid residues which bind antigen incorporated into a human antibody variable domain, and further comprising a Framework Region (FR) amino acid substitution at a site selected from the group consisting of: 24H, 73H, 76H, 78H, and 93H, utilizing the numbering system set forth in Kabat.

79. A humanized variant of a non-human parent antibody which binds an antigen, wherein the humanized variant comprises Complementarity Determining Region (CDR) amino acid residues of the non-human parent antibody incorporated into a human antibody variable domain, and further comprises Framework Region (FR) substitutions at heavy chain positions 71H, 73H, 78H and 93H, utilizing the numbering system set forth in Kabat.

80. A humanized antibody variable domain comprising non-human Complementarity Determining Region (CDR) amino acid residues which bind an antigen incorporated into a human antibody variable domain, and further comprising a Framework Region (FR) amino acid substitution where the substituted FR residue:

(a) noncovalently binds antigen directly;

(b) interacts with a CDR; or

(c) participates in the V.sub.L -V.sub.H interface by affecting the proximity or orientation of the V.sub.L and V.sub.H regions with respect to one another, and wherein the substituted FR residue is at a site selected from the group consisting of: 4L, 38L, 43L, 44L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H, 24H, 36H, 39H, 43H, 45H, 69H, 70H, 73H, 74H, 76H, 78H, 92H and 93H, utilizing the numbering system set forth in Kabat.

Cinacalcet - USA

On Jul 27, 2018, District of Delaware delivered opinion in Sensipar® Hatch-Waxman litigation & found Amneal, Piramal, Watson non-infringing & Zydus infringing.

This is a consolidated patent infringement action in which Amgen accuses multiple Defendants of infringing US 9,375,405 patent by filing ANDA seeking FDA approval to manufacture, use and/or sell generic versions of Sensipar®. These Defendants are Amneal, Piramal, Watson & Zydus. Court bifurcated the infringement claims and invalidity counterclaims and held a four-day bench trial on infringement beginning on March 5, 2018. The ’405 patent relates to “Rapid Dissolution Formulation of Calcium Receptor-Active Compound”. For most of the asserted claims, the parties’ stipulated that a finding of infringement would depend on the findings for claim 1 of the ’405 patent. Claim 1 recites a pharmaceutical composition combining specific excipients in specific amounts with the active ingredient cinacalcet hydrochloride.

Claim 1 of the ’405 patent specifically states:

A pharmaceutical composition comprising:

(a) from about 10% to about 40% by weight of cinacalcet HCl in an amount of from about 20 mg to about 100 mg;

(b) from about 45% to about 85% by weight of a diluent selected from the group consisting of microcrystalline cellulose, starch, dicalcium phosphate, lactose, sorbitol, mannitol, sucrose, methyl dextrins, and mixtures thereof;

(c) from about 1% to about 5% by weight of at least one binder selected from the group consisting of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, and mixtures thereof; and

(d) from about 1% to 10% by weight of at least one disintegrant selected from the group consisting of crospovidine (sic), sodium starch glycolate, croscarmellose sodium, and mixtures thereof;

wherein the percentage by weight is relative to the total weight of the composition, and wherein the composition is for the treatment of at least one of hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated calcium phosphorus product.

On February 27, 2018, court construed the Markush groups for the binder and disintegrant elements as “closed to unrecited binders and disintegrants.” Court concluded that “there could be no literal infringement if the Defendants’ ANDA product contained an unrecited (or unlisted) binder or disintegrant.” Amgen then opposed the court’s construction of the Markush groups by filing a motion for reargument, which was later denied.

Amneal product:

Amneal’s ANDA contains Opadry YS-1-7006 (“Opadry”) as binder. But claim 1 of the ’405 patent does not list Opadry in the Markush group for binders, therefore there was not a clear case of literal infringement. Amgen nonetheless attempted to prove literal infringement by arguing that Opadry is a pseudonym for hydroxypropyl methylcellulose (“HPMC”), which is a listed binder. Alternatively, Amgen argued that infringement is established through the doctrine of equivalents. Court disagreed with Amgen on both of these arguments. Court concluded that for numerous reasons the Opadry is not literally HPMC. The excipients have different chemical structures, physical characteristics, binding mechanisms, and commercial sources.  Amneal also does not infringe the binder limitation under the doctrine of equivalents. Here, Amgen’s expert, Dr. Davies, opined in conclusory fashion that only the HPMC fraction of Opadry functioned as the binder, and “the polyethylene glycol … in the Opadry doesn’t act as a binder.” Dr. Davies never explained it with “function-way-result,” or “substantial/insubstantial differences” test. The court is therefore not obligated to accept the conclusory assertions of an expert. Thus, Dr. Davies’ opinion, given without explanation or corroborating evidence, was not found persuasive.

Amneal’s ANDA discloses the use of the listed disintegrant crospovidone and the unlisted disintegrant pregelatinized starch. The ’405 patent lists “starch” in the Markush groups for diluents, and the parties remaining in this litigation do not dispute that the term “starch” in the ’405 patent covers pregelatinized starch. Accordingly, Amgen argued that the pregelatinized starch in Amneal’s product is not functioning as a disintegrant, but as a diluent. Amgen’s sole support for its argument is Dr. Davies’ opinion that crospovidone is a super-disintegrant which destroys the structure of a tablet so quickly that the pregelatinized starch does not have the opportunity to act as a disintegrant. However, court did not find Dr. Davies’ opinion, as applied to Amneal’s ANDA product, convincing. First, as Dr. McConville (Amneal’s expert) testified, Amneal’s ANDA product does not appear to need another diluent. Amneal’s ANDA product already includes two diluents—microcrystalline cellulose and mannitol—in a large amount; specifically, 67.89% by weight of the accused product. Second, Dr. McConville persuasively testified that, with Amneal’s manufacturing process, the crospovidone cannot usurp the disintegration function of the pregelatinized starch. Here, Amneal uses pregelatinized starch as an intragranular disintegrant and crospovidone as an extragranular disintegrant. And because the pregelatinized starch is the only disintegrant inside the granules, it alone acts as a secondary disintegrant. Third, Amneal’s ANDA contains the results of testing which confirm that the pregelatinized starch in its product functions as a secondary disintegrant.

Thus, Amgen has failed to show by a preponderance of the evidence that Amneal’s accused product infringes the binder and disintegrant limitations of the ’405 patent. For the foregoing reasons, Amneal does not infringe claim 1 of the ’405 patent. This means, pursuant to the parties’ stipulation, Amneal does not infringe claims 2-4, 8-12, and 14-17.

Watson product:

Watson uses unlisted disintegrant, low substituted hydroxypropyl cellulose (“L-HPC”), which under court’s claim construction order means there is no literal infringement. As a result, Amgen argued that L-HPC infringes claim 1 under the doctrine of equivalence. At trial, Amgen took the position that L-HPC is equivalent only to crospovidone and only under the function-way-result test. However, in its post-trial briefs, Amgen took two new positions: (1) L-HPC is equivalent to all three listed disintegrants of claim 1 under the function-way-result test, and (2) L-HPC is equivalent to crospovidone under the insubstantial differences test. Watson correctly pointed out that Amgen did not fairly presented these positions in expert discovery or at trial. For that reason alone, Amgen’s new infringement theories should be disregarded as an unfair surprise. Court however, still found why Amgen’s new theories under the function-way-result test are not persuasive & explained why Amgen’s original theory also would have failed.

Court said that Amgen should have presented through its expert, Dr. Davies, particularized testimony regarding the function, way, and result for each disintegrant to be compared. Dr. Davies, however, did not identify at trial what he considered to be the function, way, or result of the disintegrants being compared. Accordingly, Amgen failed to prove at trial that L-HPC is equivalent under the function-way-result test to all three disintegrants listed in claim 1. Also because L-HPC is not a superdisintegrant, it does not perform substantially the same function as the disintegrants listed in claim 1. In addition, Dr. Davies’ testimony on this point was unclear: He also testified that “there are a number of different mechanisms by which [superdisintegrants] work.” Amgen also argued that L-HPC is equivalent to crospovidone under the insubstantial differences test. Amgen’s expert, Dr. Davies, did not provide an opinion regarding the insubstantial differences between L-HPC and crospovidone. Dr. Appel (Watson;s expert)identified several differences between L-HPC and crospovidone, which were corroborated by scientific literature.

Thus, Amgen has failed to prove by a preponderance of the evidence that L-HPC is equivalent to all of the disintegrants listed in claim 1 under the function-way-result test or that L-HPC is equivalent to crospovidone alone under the insubstantial differences test. Therefore, Watson does not infringe claim 1 of the ’405 patent. This means, per the parties’ stipulation, Watson does not infringe claims 2-4, 8-17, and 19-20.

Piramal product:

The parties disputed whether Piramal’s ANDA product infringes the binder and disintegrant limitations of claim 1. Amgen argued that the unlisted binder in Piramal’s ANDA product—pregelatinized starch—has two components; a native starch fraction that actually functions as a diluent; and a cold water soluble fraction that functions as a binder. Neither pregelatinized starch nor its cold water soluble fraction are listed in the Markush group for binders, which under court’s claim construction order means there is no literal infringement. Accordingly, Amgen argued that cold water soluble fraction is equivalent to povidone. But court found that Amgen is foreclosed by prosecution history estoppel from asserting the doctrine of equivalents against Piramal’s use of pregelatinized starch as a binder.

During prosecution, Examiner did not allow the claims in the 2014 Amendment which included specific 20-100 mg of cinacalcet. Instead, the Examiner proposed the Examiner’s Amendment, which added the Markush groups to the binder and disintegrant limitations. In addition, the Examiner expressly stated that he was allowing the claims as set forth in the Examiner’s Amendment because, inter alia, the closest prior art “fails to specifically disclose or render obvious the combination of components and in the amounts thereof.” For all of these reasons, court found that the Examiner’s Amendment was adopted for substantial reasons related to patentability & hence estoppel applies.

Thus, for the foregoing reasons, Amgen cannot prove that Piramal’s product infringes claim 1 of the ’405 patent. Per the parties’ stipulation, Piramal also does not infringe claims 2-4, 8-17, and 19-20.

Zydus product:

Amgen’s dispute with Zydus comes down to the function of pregelatinized starch. Amgen took the position that it functions as a diluent, as stated in Zydus’ ANDA. Zydus takes the position that it functions as a binder. Zydus’ position adopts an opinion Amgen’s expert has asserted against other defendants. In tablet formulations, pregelatinized starch can, depending on the context, function as a diluent, binder, or disintegrant. The ’405 patent, however, limited itself by claiming pregelatinized starch only as a diluent. On the face of the ANDA, Zydus’ product appears to literally infringe each and every limitation of claim 1. To avoid a finding of literal infringement, Zydus simply adopted Dr. Davies’ opinion that the cold water soluble fraction of pregelatinized starch functions as an unlisted binder. Normally, where literal infringement is unavailable, a patentee can still prove infringement by resorting to the doctrine of equivalents. Here, however, court granted a motion in limine, which bars Amgen from asserting the doctrine of equivalents against Zydus.

Court was not persuaded that Dr. Davies’ opinion regarding pregelatinized starch is scientifically sound. Amgen claims that three defendants literally infringe claim 1, because the fractions opinion applies to Aurobindo and Piramal but not to Zydus. But Dr. Davies could not provide a credible explanation for this variation in treatment. First, he said that the pregelatinized starch in Zydus’ product functioned only as a diluent, because that was how Zydus identified the pregelatinized starch in its ANDA. When it was pointed out that Dr. Davies did not accept how pregelatinized starch was identified in other defendants’ ANDAs, he agreed and said that was why he was also asserting his fractions opinion against Zydus. This shift in infringement theories does not place Amgen in a better position. Amgen acknowledges, Zydus already uses 4.98% of hydroxy propyl cellulose as a binder. If the cold water soluble fraction in Zydus’ product also acts a binder, then that is another 3.97% acting as a binder. Adding 4.98% of hydroxy propyl cellulose to 3.97% of a cold water soluble fraction results in a total 8.95% of binder, which exceeds the “about 5%” weight limitation in the ’405 patent. When Zydus raised this point with Dr. Davies, he shifted infringement theories yet again, stating that Zydus’ product literally infringed the binder limitation, because there was “at least one” binder from the Markush group in Zydus’ product that was within the about 1% to about 5% weight limitation: the 4.98% of hydroxy propyl cellulose. This testimony is not consistent with the court’s controlling claim construction. Ultimately, Dr. Davies consistently asserted, and other experts agreed, that the particular function of pregelatinized starch in any given formulation “depends on the context,” including the amount of pregelatinized starch, the other excipients present, and the manufacturing process. When evaluating the ANDA products for Amneal, Piramal, and Zydus, the percolation theory provides the consistency lacking in Dr. Davies’ opinion. For example, Amneal and Zydus use over 20% by weight of pregelatinized starch which is consistent with the diluent function identified in their ANDAs. Piramal uses 11% of pregelatinized starch which is consistent with the binder function identified in its ANDA. Finally, the Example uses 33.378% of pregelatinized starch which is consistent with a diluent function that would result in the ’405 patent covering the Example.

Given all of the foregoing, Court found that Amgen has not proven by a preponderance of the evidence that pregelatinized starch should be artificially divided into two fractions, with each fraction alone serving a different function. As a result, Zydus cannot defeat Amgen’s assertions of literal infringement by adopting Dr. Davies’ opinion that the cold water soluble fraction of pregelatinized starch functions as a binder. Zydus’ ANDA product literally infringes claim 1 to the extent the claim is found valid and enforceable. Court also found per the parties’ stipulation that Zydus’ ANDA product literally infringes claims 2-4, 8-9, 15-17, and 19, to the extent each claim is found valid and enforceable.

Glycerol phenylbutyrate - USA

IPR decision (Jul 26, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-01159	03/27/2017	09/28/2017	Lupin Ltd.	9,254,278	Terminated-Settled
IPR2017-01160	03/27/2017	09/28/2017	Lupin Ltd.	9,326,966	Terminated-Settled

On US’278 patent, Par Pharma filed IPR (IPR2017-01767) on 07/13/2017, which was instituted on 01/30/2018.

On US’966 patent, Par Pharma filed IPR (IPR2017-01769) on 07/13/2017, which was instituted on 01/30/2018.

US 9,254,278 & US 9,326,966 patents owned by Horizon Therapeutics are expiring on 03/09/2032. These patents claim method of treating & method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate in urea cycle disorder.

Previously, on June 27, Horizon Pharma entered into a Settlement and License Agreement with Lupin Pharmaceuticals relating to RAVICTI Oral Liquid, 1.1 gm/mL. Specifically, the Settlement Agreement pertains to on-going patent infringement litigation against Lupin in the U.S. District Court for the District of New Jersey. The Settlement Agreement also includes the pending IPRs. Under the Settlement Agreement, the License Effective Date is July 1, 2026; however, Lupin may be able to enter the market earlier in certain circumstances.

Tenofovir disoproxil and Emtricitabine - CJEU

On Jul 25, 2018, Court of Justice of the European Union (CJEU) clarified when a product is ‘protected by a basic patent’ within the meaning of article 3(a) of regulation 469/2009 (the SPC regulation) in TRUVADA case & referred lower court to determine whether basic patent protects the combination.

The request was made in proceedings between Teva, Accord, Lupin and Generics (UK) Ltd, concerning the validity of a supplementary protection certificate (‘the SPC’) granted to the Gilead for TRUVADA® product used for the treatment of human immunodeficiency virus (‘HIV’). High Court of Justice (England & Wales), Chancery Division (Patents Court) referred the following question to the Court of Justice for a preliminary ruling:

‘What are the criteria for deciding whether “the product is protected by a basic patent in force” in Article 3(a) of Regulation No 469/2009?’

CJEU answered the question in case of combination product as:

The answer to the question referred is that Article 3(a) of Regulation No 469/2009 must be interpreted as meaning that a product composed of several active ingredients with a combined effect is ‘protected by a basic patent in force’ within the meaning of that provision where, even if the combination of active ingredients of which that product is composed is not expressly mentioned in the claims of the basic patent, those claims relate necessarily and specifically to that combination. For that purpose, from the point of view of a person skilled in the art and on the basis of the prior art at the filing date or priority date of the basic patent:

– the combination of those active ingredients must necessarily, in the light of the description and drawings of that patent, fall under the invention covered by that patent, and

– each of those active ingredients must be specifically identifiable, in the light of all the  information disclosed by that patent.

CJEU’s Analysis:

CJEU said that Article 69 should be interpreted as balanced position which combines a fair protection for the patent proprietor with a reasonable degree of legal certainty for third parties. For the purpose to determine whether that product in fact falls under the invention covered by that patent, the description and drawings of the basic patent must be taken into account, as stipulated in Article 69 of the EPC read in the light of the Protocol on the Interpretation of that provision. Thus for the purposes of the application of Article 3(a) of that regulation, the claims of the basic patent must be construed in the light of the limits of that invention, as it appears from the description and the drawings of that patent.

The claims of a patent are to be interpreted from the perspective of a person skilled in the art and, therefore, the issue whether the product which is the subject of the SPC necessarily falls under the invention covered by that patent must be assessed from that perspective. To that end, it is necessary to ascertain whether a person skilled in the art can understand without any doubt, on the basis of their general knowledge and in the light of the description and drawings of the invention in the basic patent, that the product to which the claims of the basic patent relate is a specification required for the solution of the technical problem disclosed by that patent. Also for the purposes of assessing whether a product falls under the invention covered by a basic patent, account must be taken exclusively of the prior art at the filing date or priority date of that patent, such that the product must be specifically identifiable by a person skilled in the art in the light of all the information disclosed by that patent.

Therefore, for the purposes of determining whether a product which is the subject of an SPC is protected by a basic patent, within the meaning of Article 3(a) of that regulation, that product must be identifiable specifically by a person skilled in the art in the light of all the information disclosed by the basic patent and of the prior art at the filing date or priority date of that patent.

Thus, as regards the present issue whether a claim such as claim 27 of the basic patent in fact covers a combination such as the Tenofovir disoproxil (TD)/emtricitabine, which is the subject of the SPC at issue, it falls to the referring court to determine whether the general expression ‘other therapeutic ingredients’, associated with the term ‘optionally’, satisfies the requirement that the claims of the basic patent must relate necessarily and specifically to the product. It is for the referring court to ascertain, whether from the point of view of a person skilled in the art, the combination of active ingredients of which the product which is the subject of the SPC at issue consists necessarily falls under the invention covered by that patent, and whether each of those active ingredients is specifically identifiable on the basis of the prior art at the filing date or priority date of that patent.

In the present case it is apparent, first, from the information in the order for reference that the description of the basic patent at issue contains no information as to the possibility that the invention covered by that patent could relate specifically to a combined effect of TD and emtricitabine for the purposes of the treatment of HIV. Consequently, it does not seem possible that a person skilled in the art, on the basis of the prior art at the filing date or priority date of that patent, would be able to understand how emtricitabine, in combination with TD, necessarily falls under the invention covered by that patent.

Pemetrexed - Germany

According to press release, on July 17, 2018, the German Federal Patent Court had declared the German section of European patent EP 1313508 for Alimta® (expiring on 2021), invalid in the first instance, on the basis of a suit filed by pharmaceutical companies including STADA Arzneimittel AG, paving the way for generic launch.

Previously in Jun 2016, German Supreme court in Eli Lilly and Company v. Actavis case vacated Court of Appeal‘s (Dusseldorf) decision of non-infringement. The German Supreme Court then returned the case for further proceedings. The case concerned whether Lilly's vitamin regimen patent for Alimta® (pemetrexed disodium) would be infringed by a generic competitor that had stated an intention to market a dipotassium salt form of pemetrexed in Germany.

Testosterone undecanoate - USA

On Jul 13, 2018, Federal Circuit upheld two patents covering testosterone replacement therapy (Aveed®) & rejected a generics maker’s argument that the patents were invalid for obviousness.

Endo Pharmaceuticals Solutions, Inc. holds NDA for Aveed®, a testosterone undecanoate (TU) intramuscular injection. Aveed® is a long-acting injectable testosterone replacement therapy for men suffering from physiologically low levels of testosterone, also known as hypogonadism. Custopharm Inc.’s predecessor-in-interest, Paddock Laboratories, LLC, submitted an ANDA to USFDA for approval of generic version of Aveed®.  Claim 2 of US 7,718,640 patent and claim 18 of US 8,338,395 patent which were the sole issues cover Aveed®’s formulation and injection regimen. Specifically, claim 2 of the ’640 patent covers a 750 mg dosage of TU in the composition & claim 18 of the ’395 patent covers a 750 mg dosage of TU & a vehicle containing castor oil (42% or less) and a co-solvent, benzyl benzoate.

The case proceeded to a bench trial on the sole issues of whether claim 2 of the ’640 patent and claim 18 of the ’395 patent would have been obvious to a skilled artisan in view of the prior art, which consisted primarily of three scientific articles: Behre, Nieschlag, and von Eckardstein (Articles). These Articles describe small clinical studies involving 1000 mg TU injections. The Articles report a composition of 250 mg/ml TU in castor oil. The parties agreed that the Articles do not disclose or describe the use of a co-solvent. District court found that the prior art did not disclose the 750 mg TU injection dosage, and that Custopharm had not shown, by clear and convincing evidence, that a skilled artisan would have been motivated to lower the dosage of TU from 1000 mg to 750 mg due to concerns patients were being overdosed. Further, the district court found that the Articles do not inherently disclose benzyl benzoate as a co-solvent or the particular ratio of solvent to co-solvent claimed by the patents-in-suits. Custopharm appealed.

During appeal, Custopharm contended that a skilled artisan would have recognized that these patients were being overdosed and would have been motivated to reduce the dose from 1000 mg to 750 mg by injecting patients with 3 ml instead of 4 ml of solution at a TU concentration of 250 mg/ml. Court however, rejected the arguments & found that Custopharm had not shown, by clear and convincing evidence, that a skilled artisan would have recognized that patients injected with 1000 mg TU were being overdosed. To meet its burden, Custopharm needed to do more than merely show that the prior art does not preclude lowering the dose of TU. Custopharm needed to affirmatively demonstrate that a skilled artisan would have been motivated to lower the dose of TU despite no clear evidence of overdosing under the FDA Guidelines which disclosed 300 to 1000 ng/dl ranges.

Regarding the vehicle formulation, Custopharm argued that the vehicle formulation was inherently disclosed because the Articles provide a detailed recitation of the TU injection composition’s pharmacokinetic performance, from which a skilled artisan could derive that the vehicle consisted of 40% castor oil and 60% benzyl benzoate. The district court reasonably found that this was not enough “to establish that the Articles barred the possibility of an alternative vehicle being used in the prior art compositions” to meet the rigorous standard of inherency. Because first, Custopharm has not demonstrated that a skilled artisan could extrapolate the vehicle formulation used in the Articles from pharmacokinetic performance data. Second, the prior art was replete with potential co-solvents such that a skilled artisan, reviewing the Articles, would not have necessarily recognized that the Articles’ authors used benzyl benzoate as a co-solvent for their reported clinical studies. Third, the cases Custopharm cited to support their inherency arguments are inapposite.

Thus, Federal Circuit concluded that the district court did not commit reversible error in finding that claim 2 of the ’640 patent and claim 18 of the ’395 patent were not proven to be obvious over the prior art.

Rivaroxaban - USA

On Jul 13, 2018, District court of Delaware found Xarelto compound patent valid in Hatch-Waxman litigation proceeding.

In a consolidated patent infringement action, plaintiffs, Bayer and Janssen alleged infringement of claim 16 of U.S. Patent No. 7,157,456, which claims the compound rivaroxaban. The parties concede infringement. Defendants, Mylan and Sigmapharm Laboratories submitted that the patent is invalid as obvious. Four-day bench trial was held beginning on March 5-9, 2018.

Rivaroxaban, a factor Xa inhibitor is an anticoagulant that prevents blood clot. Factor Xa inhibitors have two key binding sites: the S1 and S4 pockets. The conventional wisdom as of priority date in December of 1999 was that in order to be a potent factor Xa inhibitor a compound required a basic P1 group at S1 pocket and an aromatic or basic P4 group at S4 pocket. Defendants selected linezolid as lead compound for obviousness & asserted that POSA would have made changes to the S1 & S4 pockets to arrive at Rivaroxaban. Specifically, Defendants asserted that a POSA would have selected linezolid as a lead compound because (1) it was the most advanced oxazolidinone in Phase III clinical trials; (2) linezolid had an excellent pharmacokinetic profile and more specifically, 100% oral bioavailability; and (3) linezolid possesses structural motifs characteristic of existing factor Xa inhibitor.

Court however, disagreed & said that it is well established that a lead compound is “a compound in the prior art that would be the most promising to modify in order to improve upon its . . . activity and obtain a compound with better activity.” Therefore, POSA would not have selected a compound which is antibiotic as a lead compound for factor Xa inhibitors. Court agreed that the Linezolid was the most advanced oxazolidinone antibiotic and it was in Phase III trials for antibiotic indications. But the relevant issue here, however, was whether the prior art taught that oxazolidinones were useful in factor Xa inhibitors. It did not.

Defendants next asserted that a POSA would have selected linezolid because it had 100% oral bioavailability. Court said that this argument failed for several reasons. First, 100% oral bioavailability is meaningless without activity against factor Xa. Second, the prior art taught chemists to address bioavailability by incorporating less basic P1 replacements into factor Xa inhibitors to obtain “good” oral bioavailability. Conventional wisdom did not teach the use of compounds with no activity against the target and 100% oral bioavailability.

Defendants next argued that linezolid has structural motifs characteristic of factor Xa inhibitors. Court disagreed & said that Ewing II does not teach using an oxazolidinone or linezolid as a lead. What is more, Ewing provided no reason to use an oxazolidinone core instead of a pyrrolidinone. This argument is further weakened by the fact that Ewing actually discloses data for two pyrrolidinone core structures, and the one closer in structure to an oxazolidinone was 40-fold less potent. A POSA simply would not have selected linezolid as a lead based on this prior art. 

Court further said that even if any one of the three reasons set forth by defendants were supported by clear and convincing evidence, the fact remains that the prior art taught away from the selection of linezolid as a lead compound. First, linezolid is an antibiotic & not factor Xa inhibitor. Second, it had several side effects. Third, antibiotics such as linezolid is used for short term treatment whereas factor Xa inhibitors are used for long term. Thus, defendants failed to prove that POSA would have selected linezolid as lead compound.  

Court further said that even assuming the POSA would have selected linezolid as a lead compound, the POSA would have not made the modifications necessary to arrive at rivaroxaban. Specifically, court held that based on the evidence presented at trial, that the development of rivaroxaban from linezolid was not an obvious path because it did not involve a “finite number of identified, predictable solutions. Instead, “[e]ach layer of decision-making would have required a lengthy research and development process that would not have provided predictable results.” Moreover, secondary considerations put forth by plaintiffs weigh in favor of non-obviousness. Thus, the claim 16 of the ’456 patent is not invalid due to obviousness.

  

Sodium oxybate - USA

On Jul 13, 2018, Federal Circuit upheld PTAB’s decision & found 7 REMS patents covering Xyrem® invalid as obvious.

Background:

Jazz Pharmaceuticals, Inc. appealed from the IPR decisions of the PTAB which held certain claims of Jazz’s U.S. Patents 7,668,730 7,765,106, 7,765,107, 7,895,059, 8,589,182, 8,457,988 and 8,731,963 invalid as obvious. The patents in suit are members of a family of patents owned by Jazz relating to a drug distribution system for tracking prescriptions of a Xyrem® through database. On May 14, 2001, the FDA announced a meeting through the Notice in the Federal Register & and that main focus of the deliberations was on risk management issues associated with Xyrem. The meeting was “open to the public,” and permitted interested persons to “present data, information, or views, orally or in writing, on issues pending before the committee.” The Notice also included a hyperlink to an FDA website where background material from the drug sponsor and the FDA would be posted & furthermore, the Notice provided specific instructions on how to access the meeting materials on the FDA website. The Board determined that the Advisory Committee Art (ACA) materials were publicly accessible on an FDA website listed in the Notice no later than October 4, 2001, over two months prior to the critical date of December 17, 2001. Thus, the Board found that a person of ordinary skill would have been motivated to combine the ACA materials, and that the ACA materials collectively taught or suggested all limitations of the claims. Jazz appealed.

Appeal:

The primary issue on appeal was whether the ACA materials available on FDA website during regulatory review of Xyrem® were sufficiently accessible to the public to constitute prior art.

During appeal Jazz principally argued that the ACA materials are not prior art, so all of the Board’s decisions relying on the ACA materials should be reversed. Emphasizing the substantial length of the annual Federal Register, Jazz asserted that the Board failed to make the requisite finding that a person of ordinary skill exercising reasonable diligence could have located the ACA materials and also argued that Amneal failed to submit any evidence of searchability or indexing of that material. Whether a reference qualifies as a “printed publication” under § 102(b) is a legal conclusion based on underlying factual findings. ‘Public accessibility’ has been called the touchstone in determining whether a reference constitutes a ‘printed publication’ . . . .”[ In re Hall, 781 F.2d 897, 898–99 (Fed. Cir. 1986)]. Federal circuit said that comparing the facts of this case to those in MIT, Klopfenstein, and Medtronic confirms that the ACA materials were disseminated more broadly and for a longer duration to persons of ordinary skill than the materials disclosed at individual meetings in those cases. First, the breadth of the dissemination here to persons of ordinary skill is significant. The Notice in the Federal Register widely disseminated the ACA materials through a hyperlink to a public FDA website where the ACA materials could be accessed. Second, the ACA materials were available online for a substantial time before the critical date of the patents in suit. “[T]he longer a reference is displayed, the more likely it is to be considered a ‘printed publication.’” [Klopfenstein, 380 F.3d at 1351]. Third, the ACA materials were distributed via public domain sources with no possible expectation that the materials would remain confidential or not be copied. In sum, after considering the relevant factors identified in our public accessibility cases, the record here demonstrates that the ACA materials were widely disseminated to persons of ordinary skill for a substantial time with no reasonable expectation of confidentiality. They were “in the possession of the public,” [Wyer, 655 F.2d at 226].

Jazz next asserted that the Board’s finding of public accessibility must be reversed because evidence of “searchability or indexing is required to conclude that the ACA materials are prior art” and Amneal did not submit such evidence. But federal circuit held that neither indexing nor searchability was required for a reference to be a printed publication under § 102(b). Specifically, printed publication ‘need not be easily searchable after publication if it was sufficiently disseminated at the time of its publication.’ Moreover, even assuming that indexing is relevant to this case, the Federal Register was meaningfully indexed.

Jazz also argued that the Board erred by “equating the constructive notice provided by the Federal Register with the legal standard for prior art”. Federal circuit said that….. “we do not interpret the Board’s decision as applying a per se rule that every notice in the Federal Register satisfies the requirements for prior art, nor do we endorse such a rule that would supplant the case-by-case inquiry consistently applied throughout our case law. Nor do we discern any error in the Board’s sensible observation that the purpose of the Federal Register is to provide notice of government action such as the advisory committee meeting here. However, we do reiterate that [i]f accessibility is proved, there is no requirement to show that particular members of the public actually received the information.” Thus, the ACA materials were publicly accessible because they were broadly disseminated to interested persons of ordinary skill for a substantial time with no expectations of confidentiality. Hence, they qualify as printed publications under § 102(b).

Next with respect to obviousness Jazz argued that the Board’s finding that a person of ordinary skill would have been motivated to modify the ACA materials. Federal circuit, however, agreed with Amneal & held that the Board’s decisions on this matter are consistent. The Board made the same essential finding in both decisions that a person of ordinary skill would have been motivated to run the ACA materials’ distribution system over multiple computers, as taught in Korfhage. Court also agreed with Amneal that Jazz misinterprets both the Supreme Court’s decision in KSR and this court’s obviousness precedent. KSR did not impose a rigid requirement to identify both a problem to be solved in the art and a finite universe of potential options. Thus, the Board did not err in concluding that implementing the ACA materials’ centralized database system on multiple computers “would have been a predictable use of a known distributed data system according to its established function.” For these reasons, Federal Circuit affirmed the Board’s decisions & found these REMS patents invalid as obvious.

Fingolimod - USA

IPR decision (Jul 11, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-00854*	02/03/2017	07/18/2017	Apotex	9,187,405	Claims 1–6 are patentable

*Cases IPR2017-01550 (Argentum), IPR2017-01946 (Actavis), and IPR2017-01929 (Sun Pharma) have been joined with this proceeding.

US 9,187,405 (Novartis; Exp: 12/25/2027 with PED)

1. A method for reducing or preventing or alleviating relapses in Relapsing-Remitting multiple sclerosis in a subject in need thereof, comprising orally administering to said subject 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form, at a daily dosage of 0.5 mg, absent an immediately preceding loading dose regimen.

3. A method for treating Relapsing-Remitting multiple sclerosis in a subject in need thereof, comprising orally administering to said subject 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form, at a daily dosage of 0.5 mg, absent an immediately preceding loading dose regimen.

5. A method for slowing progression of Relapsing-Remitting multiple sclerosis in a subject in need thereof, comprising orally administering to said subject 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form, at a daily dosage of 0.5 mg, absent an immediately preceding loading dose regimen.

Ezetimibe + Simvastatin - France

On Jun 26, 2018, Paris Court of Appeal upheld the interim order of Paris Court of First Instance & dismissed the requests for preliminary injunction against Biogaran based on SPC.

As reported on “the SPC blog”, the basic patent EP 0720599 covers in particular ezetimibe in claim 8 and combination of ezetimibe with simvastatin in claim 17. EP’599 patent is the basic patent of a first SPC No. 03C0028 relating to ezetimibe (Ezetrol®) which expired on April 17, 2018 and of a second SPC no. 05C0040 relating to the "ezetimibe optionally in the form of its pharmaceutically acceptable salts in combination with simvastatin" expiring on April 2, 2019 (Inegy®).

In December 2017, Biogaran filed an action on the merits before the Paris Court of First Instance for the invalidation of SPC 0040. By an interim order issued on April 5, 2018, the Paris Court of First Instance dismissed the request for preliminary injunction filed by SPC holder. The Paris Court of Appeal has confirmed the lower court’s order. Specifically, court said that though both the active compounds are specifically mentioned in claims but inventive idea of patent lies in ezetimibe only. The second compound simvastatin was already known.

The case is currently pending on the merits before the Paris Court of First Instance.

Tadalafil - Denmark

On Jun 15, 2018, the Danish Maritime & Commercial High Court granted preliminary injunction against Sandoz’ generic product & rejected invalidity challenges.

As reported on “EP law blog”, the Court found that DK/EP 1173181 patent showed surprising effect that Tadalafil can be used daily and is effective at low doses with a minimum of side effects. The Court specifically found that the use of a unit dosage comprising 1 to 5 mg Tadalafil up to a maximum total dose of 5 mg daily would not have been obvious to the person skilled in the art in view of prior arts.

Thus, Court granted preliminary injunction against Sandoz’ 2.5mg & 5mg strengths but not for 10mg strength because Eli Lilly had not rendered it probable that sale of Sandoz’ 10 mg tablets constituted an indirect infringement.