Dimethyl fumarate - EPO

On Jan 29, 2018, European Patent Office revoked Forward Pharma A/S's EP 2801355 patent in an opposition proceedings filed by several parties. The '355 patent covers a PH-controlled release pharmaceutical composition for oral use that contains dimethyl fumarate (DMF), the active ingredient in Biogen's MS drug Tecfidera.

EP’355 independent claims:

1. A pH controlled release pharmaceutical composition for oral use which consists of dimethylfumarate as the active substance, wherein the composition is provided with an enteric coating wherein the daily dosage is from 480 to 720 mg active substance given in one to three doses for use in the treatment of psoriatic arthritis, neurodermatitis, inflammatory bowel disease, or an autoimmune disease.

9. A pH controlled release pharmaceutical composition for oral use in the treatment of psoriatic arthritis, neurodermatitis, inflammatory bowel disease, or an autoimmune disease which consists of dimethylfumarate as the active substance, provided with an enteric coating wherein the daily dosage is 480 mg active substance given in one to three doses.

Total 11 parties (Zaklady Farmaceutyczne Polpharma;  G. L. Pharma; Strawman Limited; Zentiva; Hexal AG; Laboratorios Liconsa, Interquim S.A ; Biogen MA Inc; Actavis; Generics [UK] Limited and STADA Arzneimittel AG) filed post grant oppositions in Feb 2016. The EPO Opposition Division held oral hearing on Jan 29, 2018 & announced its decision to revoke the patent. The Opposition Division will issue detailed reasons for the decision in written form in due course, and following receipt and review of these, Forward plans to appeal the Opposition Division’s decision to the Technical Board of Appeal.

According to Jan 2017 news, Biogen entered into a settlement and license agreement with Forward Pharma. Upon the effectiveness of the settlement and license agreement, Biogen will provide Forward Pharma a cash payment of $1.25 billion. Biogen will only be obligated to pay Forward Pharma royalties in countries other than the U.S. if Forward Pharma obtains patent rights covering treatment of a human for multiple sclerosis by orally administering 480 mg per day of DMF in the opposition proceeding against Forward Pharma’s European patent EP 2801355.

Darunavir - UK

On Jan 25, 2018, Lord Justice Floyd of court of appeal stayed the appeal proceedings and referred the question to the CJEU in ‘Darunavir SPC’ case.

The SPC in question is “SPC/GB07/038” for a product described in the SPC as “Darunavir or the pharmaceutically acceptable salt, ester, or prodrug thereof”.  The SPC covers a product marketed in Europe by companies associated with the second respondent under the trade mark “Prezista”.  It is a protease inhibitor used in an anti-retroviral medication for the treatment of the HIV virus and AIDS.  The respondents contend that the product described in the SPC was protected by European Patent (UK) No 0 810 209 (“the patent”)

In a decision dated 3 May 2017, Arnold J decided that darunavir was a product protected by the patent. He declined to refer questions to the CJEU on the interpretation of Article 3(a) of the SPC Regulation because he considered that, on all tenable constructions of Article 3(a), darunavir was protected by the patent. Appellants (Sandoz Ltd & Hexal AG) appeal from that decision and his consequent order. 

Below are some Lord Justice Floyd’s comments on the present issue:--

Specifically Lord Justice Floyd of court of appeal said that, “CJEU’s requirement, formulated for the first time in Eli Lilly, that, in order to be protected by the basic patent, the claim must relate to the product implicitly, but necessarily and specifically as “the Lilly requirement”.  If it were possible to say that the Lilly requirement is limited to functional claims, or alternatively, if it applies to all claims, that it is always satisfied by a Markush claim which covers the active ingredient, then it would follow that the appeal must be dismissed.  If the position is not clear, however, we may have to refer a question to the CJEU.”

 “In the case of a SPC with a single active ingredient, the reasoning in Medeva requires that the basic patent protect that active ingredient as such.  The reasoning is not informative as to how specifically the claims must focus on the active ingredient, or what underlies the requirement that they should do so. Also it is not clear that the CJEU's judgment in Eli Lilly takes the matter much further. Eli Lilly was specifically concerned with functional claims. Functional claims and structural claims are fundamentally different in terms of what they require the skilled person to do in order to determine whether a particular product is specified by a claim”. 

“The adoption of the core inventive advance test remains a possibility given the pending references from in Sitagliptin and Teva v Gilead, and the fact that it is becoming clear (see Actavis v Novartis, Actavis v Boehringer) that the possible abuse identified by the Advocate General in Medeva can be dealt with through Article 3(c).  If that test were adopted across the board and applied here, despite Ms May’s (Appellants representative) submissions concerning its application (which I reject), I have no doubt that the SPC would satisfy Article 3(a)”.  

“In case it would assist the Court of Justice I will express my provisional conclusion.  Left to myself, I would have concluded that darunavir was a product protected by the claims of the patent. In the case of a product with a single active ingredient and a patent with a claim which identifies a number of compounds by means of a Markush formula, all of which compounds embody the core inventive technical advance of the patent, the test should be whether the skilled person, considering the claims of the patent on the one hand and the structure of the product in question on the other, would immediately recognise that the active ingredient in question is one of those specified by the formula.  On the facts of the present case as found by the judge, that test is satisfied.  However, for the reasons I have given, it is not clear that this is the correct approach in EU law”.

Lord Justice Floyd therefore proposed that this court should stay the present appeal proceedings and refer the following question to the CJEU:

“Where the sole active ingredient the subject of a supplementary protection certificate issued under [the SPC Regulation] is a member of a class of compounds which fall within a Markush definition in a claim of the patent, all of which class members embody the core inventive technical advance of the patent, is it sufficient for the purposes of Article 3(a) of the SPC Regulation that the compound would, upon examination of its structure, immediately be recognised as one which falls within the class (and therefore would be protected by the patent as a matter of national patent law) or must the specific substituents necessary to form the active ingredient be amongst those which the skilled person could derive, based on their common general knowledge, from a reading of the patent claims?”

Memantine - USA

On Jan 23, 2018, U.S. District Judge Randolph D. Moss upheld the FDA’s decision that Amneal Pharmaceuticals LLC forfeited 180-day exclusivity by failing to win approval within 30 months of seeking approval.

The plaintiff in this case, Amneal Pharmaceuticals LLC ("Amneal"), was the first manufacturer to file an ANDA to market a generic version of Namenda XR (memantine hydrochloride extended release capsules), with P-IV certification. Amneal did not, however, obtain tentative approval for its ANDA within the 30-month window. As a result, Amneal's eligibility for the 180 days of generic market exclusivity turns on whether its failure to obtain timely approval was "caused by a change in or a review of the requirements for approval of the" ANDA. In proceedings before the Food and Drug Administration ("FDA"), Amneal argued (1) that the delay was caused by the FDA's demand for data from a commercial-scale batch of the drug and (2) that this demand constituted a change in a requirement for approval of the ANDA.

On June 10, 2013, Amneal submitted an ANDA seeking approval to market a generic version of Namenda XR-a medication intended to treat moderate to severe dementia of the Alzheimer's type. In its ANDA, for purposes of commercial sales, Amneal proposed to produce much larger batches of 1,000,000 capsules and, in doing so, to blend up to six different lots of ER beads with two different lots of iR beads which are different than that of pilot batches.  On September 10, 2014, the FDA sent Amneal a letter identifying a number of substantive deficiencies with Amneal's ANDA. Specifically FD Asked to submit all the required [chemistry, manufacturing, and controls] information for the production of a 7 mg and 28 mg Memantine HCl lot of the size intended for commercial distribution. Overall, the FDA reviewers concluded that, "[d]ue to the complexity of the proposed process, combined with the deficiencies noted in the review," and because "mixing multiple lots of ER and IR beads could induce additional deviations not observed during the manufacture of the [pilot] lots that may require additional control," Amneal "should submit a scale up batch before approval."

The said process took eight months to complete. But, upon review of the additional data, the FDA noted several issues. Most problematically, Amneal's proposed IR-to-ER bead ratio "was not followed in the newly submitted batches" and, while "some latitude in this ratio [was] required [,] ... the deviation ... was not justified." Acknowledging that combining multiple lots of IR and ER beads introduced additional "complexity" into the production process, which "may result in calculation errors," Amneal proposed an "additional control ... to ensure [that the] accurate dose of the drug product is administered to the patients." The FDA, however, concluded that the additional control was "not acceptable," and it, accordingly, "recommend [ed]" that Amneal "scale down the proposed commercial batch size to a size with a constant, reproducible capsule filling weight as well as a constant bead type composition." Amneal accepted the FDA's recommendation to scale down the proposed commercial-scale batches-from 1,000,000 capsules to 150,000 capsules-thus resolving the issue and clearing the way for approval of its ANDA.

In the meantime, however, Amneal experienced a further delay: an "Import Alert" was issued on October 15, 2015, to the supplier of Amneal's active pharmaceutical ingredient ("API").  Amneal sought approval to use a different API supplier, and sought to amend its ANDA to substitute the new supplier in place of the one that was previously identified. Amneal's troubles continued, however, and, on December 7, 2015, the FDA notified Amneal that its proposal to change its source of API was "not acceptable" because Amneal had yet to demonstrate bioequivalence. Amneal provided the missing data demonstrating bioequivalence using the new source of API on February 25, 2016, but FDA chemistry reviewers raised additional deficiencies in Amneal's product, which were not addressed until August 11, 2016 and September 15, 2016. Finally, on September 28, 2016, the FDA tentatively approved Amneal's ANDA. By that time, however, the 30-month period for approval had expired on December 10, 2015.

On same day Sep 28, 2016 the FDA tentatively approved Amneal's ANDA, the agency issued a 17-page letter decision concluding that Amneal had forfeited the 180-day period of exclusivity. In its appeal, most significantly, Amneal disagreed with the FDA's conclusion that the agency's "demand for commercial-scale data" did not constitute a "change in a requirement for approval of the application." Court under Chevron framework held that the FDA did not violate the plain terms of the statute or act unreasonably in deciding that neither of the regulatory steps identified by Amneal constituted "a change in or review of[a] requirement for approval of' Amneal's ANDA.

Court said that Amneal presumes that the requirements for the FDA to receive an ANDA mirror the requirements for approval. But the FDA has explained and Amneal has not identified any evidence to the contrary-that the two requirements, even if closely related; are distinct. Understood in this light, nothing in the statutory text supports Amneal's reading, much less unambiguously forecloses the FDA's approach. Court further sided with FDA & said that to the contrary, the forfeiture decision makes clear that the FDA's prior requests for data from commercial-scale batches were "application specific" requests "made during the substantive review of the ANDA by the chemistry reviewers," based on the applicant's failure to "demonstrate a good understanding of its product and manufacturing process" and failure to "have appropriate in-process controls." Thus the FDA's prior requests merely represented case-by-case evaluations of whether data from a commercial-scale batch was needed to address a case-specific deficiency. Accordingly, the FDA's conclusion that its request for commercial-scale data did not constitute a "change in ... requirements for approval" such that Amneal was exempt from the 30-month forfeiture date was both reasoned and consistent with agency precedent.

As on today, there are 07 ANDAs have been approved by USFDA including Amneal. With respect to litigation, on December 11, 2017, Federal Circuit affirmed district court’s decision of indefiniteness. [Forest Labs, Inc. v. Teva Pharm. USA, Inc., Nos. 2016-2550, 2016-2553, 2017 WL 6311688 (Fed. Cir. Dec. 11, 2017)]. Although the Federal Circuit's mandate has yet to issue, and a petition for rehearing is pending, a final affirmance in the Teva case would open the door for generic manufacturers with approved ANDAs to market their products.

Dexmedetomidine - USA

On Jan 22, 2018, District court of Delaware issued its ruling in Precedex (dexmedetomidine) injection product. Court found 3 patents invalid & infringed and remaining 1 patent valid & infringed by ANDA filer in Hatch-Waxman litigation.

Plaintiff (Hospira) brought this patent infringement action against Amneal Pharmaceuticals, LLC in 2015. At issue in this case are ready-to-use formulations of the compound dexmedetomidine.  Amneal filed Abbreviated New Drug Application ("ANDA") No. 207551, seeking to engage in the commercial manufacture, use, and sale of generic versions of Hospira's 4μg/mL dexmedetomidine products ("Precedex premix") in 50 mL and 100 mL glass vials. Since its FDA approval in 1999, Hospira's original Precedex product (100 μg/mL dexmedetomidine hydrochloride), also known as Precedex concentrate, has been sold in a 2 mL glass vial. Before Precedex concentrate is administered to a patient, it must be diluted to an appropriate concentration per the instructions on the Precedex concentrate label. The delay in drug administration to patients and increased risks of dosing error and contamination associated with this dilution step led Hospira to develop ready-to-use formulations of Precedex.

The Court held a bench trial from August 21-24, 2017. Plaintiff asserted that Defendant's ANDA submission constitutes infringement of claims 3 and 4 of U.S. Patent No. 8,242,158; claim 4 of U.S. Patent No. 8,338,470; claim 5 of U.S. Patent No. 8,455,527 and claim 6 of U.S. Patent No. 8,648,106. The' 158, '470, and' 106 patents each describe ready-to-use pharmaceutical compositions of dexmedetomidine or a pharmaceutically acceptable salt thereof for parenteral administration, disposed within a sealed glass container. Defendant argued that all the asserted claims are invalid as obvious, and further asserts that claim 3 of the '158 patent, claim 4 of the '470 patent, and claim 5 of the '527 patent are invalid as anticipated. Additionally, Defendant contends that claim 6 of the '106 patent is indefinite under 35 U.S.C. § 112.

OBVIOUSNESS OF THE '158, '470, AND '527 PATENTS:

Defendant argued that in view of pharmaceutical packaging knowledge in the art, the asserted claims are obvious over the prior art Precedex concentrate product in combination with the 2010 label accompanying it, or obvious over Trissel. Plaintiff responded that the asserted claims are not obvious because the prior art did not disclose a ready-to-use 4 μg/mL dexmedetomidine solution or suggest development of such a solution, the USPTO issued the patents-in-suit over the Precedex concentrate product and the accompanying label, and commercial success of the Precedex premix product supports nonobviousness.

The parties did not dispute that the Precedex concentrate product and its accompanying 2010 label taught many elements of the asserted claims. The 2010 label discloses that Precedex concentrate, once diluted to a concentration of 4 μg/mL, is to be administered intravenously to achieve patient sedation. Additionally, the label directs a POSA to prepare 50mL of a 4 μg/mL dexmedetomidine formulation by diluting the Precedex concentrate product with 0.9% sodium chloride. The parties dispute whether a POSA would have been motivated to develop a ready-to-use 4 μg/mL dexmedetomidine formulation disposed within a sealed glass container with reasonable expectation of success.

Court agreed with Defendant that a POSA would have been motivated to develop a ready-to-use dexmedetomidine formulation, and would have combined the Precedex concentrate product with the 2010 label to do so. The 2010 label is a package insert that is included with the Precedex concentrate product with the intent that it be used in combination with the product to ensure its safe and effective use. Cain's disclosure that a hospital pharmacy was routinely making available to physicians for clinical use premixed 10 mL syringes of 4 μg/mL dexmedetomidine demonstrates that at least one large medical institution (Children's Hospital of Pittsburgh) recognized the value of ready-to-use dexmedetomidine formulations. Court also held that Based on the Precedex concentrate product and the 2010 label, a POSA would have known that Precedex concentrate is stable in a sealed glass container.   Because like the inventors, a POSA would have been familiar with the general knowledge that glass was the preferred packaging for small-volume injectables. Even crediting Plaintiff's assertion that glass vials are not interchangeable (which would increase the number of potential packaging options), the prior art supports a finding that a POSA would have reasonably expected to succeed in using a sealed glass container to store a 4 μg/mL ready-to-use dexmedetomidine formulation.

With respect to commercial success, court held that although the direct competition between the invention and the prior art provides evidence of the required nexus, that evidence is weakened by the confounding factor of Plaintiff's aggressive business practices that attempted to shift demand to Plaintiff's premix product before generic concentrate product market entry. Since the '214 blocking patent renders weak any evidence of commercial success, and Plaintiff's business practices further weaken evidence of the required nexus, it concluded that considerations of commercial success do not support finding the asserted patents nonobvious.

Thus considering all of the evidence, court concluded that Defendant has proven by clear and convincing evidence that claims 3 and 4 of the '15 8 patent, claim 4 of the '4 70 patent, and claim 5 of the '527 patent are invalid as obvious.

OBVIOUSNESS OF THE '106 PATENT:

Defendant argued that claim 6 of the '106 patent is obvious because the "no more than about 2% decrease" in dexmedetomidine concentration limitation is inherent in a 4 μg/mL dexmedetomidine formulation in normal saline disposed within a sealed glass container. Plaintiff counters that Defendant's evidence is insufficient to prove inherency. Court held that Defendant offers no expert testimony regarding the scientific principles underlying its inherency argument, and relies on just two examples of stability data covering the claimed 4 μg/mL dexmedetomidine concentration. As Plaintiff notes, Defendant's expert conceded that stability data for a 4 μg/mL dexmedetomidine formulation could not be inferred from the Precedex concentrate label, and that he would have had to confirm any stability hypothesis for a 4 μg/mL dexmedetomidine formulation through testing.

The lack of evidence of degradants or oxidation of dexmedetomidine formulations increases the weight of Defendant's affirmative examples of dexmedetomidine's stability at room temperature in a sealed glass container. It does not, however, provide additional affirmative evidence to support Defendant's contention. Despite this additional support for Defendant's examples, given the absence of supporting expert testimony, court found the examples insufficiently powered to establish inherency by clear and convincing evidence.

INDEFINITENESS OF THE '106 PATENT:

The essence of Defendant's indefiniteness argument is that because the '106 patent discloses concentration measurements performed under both long-term and accelerated conditions and claim 6 does not explicitly specify which condition to use, a POSA would not know whether the "no more than about 2% decrease" limitation should be measured under long-term or accelerated conditions.

Court held that although claim 6 of the '106 patent does not explicitly specify the storage condition under which dexmedetomidine concentration should be measured, the intrinsic evidence demonstrates that the claim is not indefinite. The language of claim 6 indicates that the purpose of the claimed invention is to administer the dexmedetomidine formulation to a patient. (' 106 patent at claim 1 ("A ready to use liquid pharmaceutical composition for parenteral administration to a subject ... ")). Additionally, the detailed description of the invention makes clear that the discovery that dexmedetomidine could be stored long-term contributed to generating the invention. Considering all of the evidence, court found that the '106 patent adequately conveys to a POSA that long-term storage is the condition relevant to claim 6. Defendant has failed to provide clear and convincing evidence that claim 6 of the ' 106 patent is invalid under 3 5 U.S. C. § 112.

INFRINGEMENT OF THE '158, '470, '527, AND '106 PATENTS:

At trial the parties stipulated that Defendant infringes all limitations of the asserted claims except (1) whether Defendant's ANDA covers products disposed within a "sealed glass container," and (2) whether Defendant's ANDA products, "when stored in the glass container for at least five months[,] exhibit[] no more than about 2% decrease in the concentration of dexmedetomidine," as required by the '106 patent.

Plaintiff argued that Defendant's ANDA documents and the testimony of Plaintiff's technical expert, Dr. Linhardt, establish that Defendant's ANDA products are disposed within a "sealed glass container" under any proposed construction of the term. Defendant does not argue in post-trial briefing that its ANDA products do not meet the "sealed glass container" limitation. Therefore, Defendant has conceded that its proposed ANDA products meet this limitation.

Plaintiff asserted that Defendant infringes the "no more than about 2% decrease" limitation of claim 6 of the '106 patent under two separate theories. First, Plaintiff asserts that Defendant infringes the "no more than about 2% decrease" limitation in claim 6 of the '106 patent as a matter of law. Second, Plaintiff argues that Defendant infringes this limitation as a matter of fact.

Defendant's ANDA specification provides that Defendant's proposed ANDA products, as measured by high performance liquid chromatography ("HPLC") assay, will remain within 90-110% of their initial dexmedetomidine concentration claimed on the products' label for the 2-year shelf life also claimed on the label. According to Defendant, the 3-5% variability inherent in the HPLC measurement technique specified by its ANDA precludes its ANDA specification from directly addressing the issue of infringement because the possible 3-5% variability in any concentration measurement exceeds the 2% limit of the claimed concentration loss.

Plaintiff argued that Defendant's proposed ANDA products infringe as a matter of law because the less than or equal to 10% dexmedetomidine concentration loss in Defendant's ANDA specification directly addresses the claim limitation of "no more than about 2% decrease" in dexmedetomidine concentration after at least 5 months of storage. According to Plaintiff, since a concentration loss of no more than 10% includes a concentration loss of no more than about 2%, Defendant's proposed ANDA products infringe under Sunovion. Citing Ferring, Defendant submits that Sunovion does not apply, because the ANDA product specification does not specify a dexmedetomidine concentration for the claimed five-month measurement time point.

Court held that with the knowledge that dexmedetomidine concentrations cannot increase under the relevant storage conditions, however, it becomes clear that a decrease of not more than 10% over 24 months imposes a limitation not just for 24 months, but for all time points less than 24 months as well. The concentration decrease of no more than 10% at 5 months necessarily present in Defendant's ANDA includes the claimed concentration decrease of no more than about 2% at 5 months. Therefore, Plaintiff has proven that Defendant's proposed AND A products infringe claim 6 of the ' 106 patent as a matter of law under Sunovion.

CONCLUSION:

Defendant has proven by clear and convincing evidence that the asserted claims of the '158, '470, and '527 patents are invalid. Defendant has failed to prove by clear and convincing evidence, however, that the asserted claim of the '106 patent is invalid. Plaintiff has proven that Defendant infringes the asserted claims of the’158,’470, and’527 patents as a matter of fact and that Defendant infringes the asserted claim of the’106 patent as a matter of law.

Daptomycin - UK

On Jan 17, 2018 UK court of appeal handed down its decision in Daptomycin case & affirmed the patent court’s decision of finding claimed invention obvious.

This appeal concerns a method of purification of the antibiotic daptomycin. Although at trial the judge, Henry Carr J, was concerned with multiple issues on several patents, the sole issue on this appeal is whether the method claimed in European Patent (UK) 2,264,047 ("the patent") is obvious over an article in the journal Biotechnology Techniques by Sung-Chyr Lin and Horng-Jyh Jiang entitled "Recovery and Purification of the lipopeptide biosurfactant of Bacillus subtilis by ultrafiltration" ("Lin and Jiang"). In his decision dated 10 June 2016 the judge held that the patent was invalid and on 17 October 2016 he made an order for its revocation. The judge found that the skilled team would have known that the formation of micelles was dependent upon a number of factors and that the CMC (critical micelle concentration) might be affected by altering the temperature or by adding solvent or electrolyte. In the end both experts gave evidence to the effect that the CMC could be adjusted by altering the pH and the judge found that it was routine to investigate how changes in pH affected the stability of a solution of a surfactant and the CMC. The proprietor of the patent, Cubist Pharmaceuticals LLC ("Cubist") appealed against that decision and order.

The patent describes a new way to purify daptomycin which relies upon the ability of daptomycin molecules under particular conditions to form into structures called micelles and then, under different conditions, to dissociate. This permits the use of a two stage purification process in which impurities, whether smaller or larger than the daptomycin molecules, are removed. The specification explains that the invention relates to a process for preparing a highly purified form of daptomycin which involves altering the pH of a daptomycin solution to change its CMC. Hospira contended that it would have been perfectly obvious to the skilled team that the purification method described in Lin and Jiang could be used for the purification of daptomycin, and it would have been an entirely routine matter for the team to use the alteration of pH rather than the addition of methanol to adjust the CMC. Cubist responded that it would not have been obvious to the skilled team that the Lin and Jiang method could be applied successfully to the purification of daptomycin because the team would not have expected the method to remove pyrogens, an impurity associated with daptomycin; the team would not have thought it likely that daptomycin was a surfactant which would form micelles; and it would not have been obvious to the team to use pH instead of methanol to adjust the CMC.

During appeal Cubist contended that the trial  judge was not entitled to find that the skilled team would have had a real expectation that daptomycin was likely to be a surfactant which would form micelles, or that the team would have been able to confirm that by straightforward routine testing. Court of appeal affirmed lower judge’s finding & said that the skilled team would have had a real expectation that daptomycin was likely to be a surfactant in view of “shake test”. As a surfactant, it would form micelles under appropriate conditions. Also “electrical conductivity test” would also have confirmed that daptomycin was a surfactant. In this test the change in conductivity of a solution of a material is measured as the concentration of the solution is increased (or another relevant condition such as pH is changed), and the CMC is identified by an inflection in the curve.

On the issue of micelle formation by pH adjustment, Cubist contended that the judge made two errors in reaching his conclusion that the skilled person would replace the methanol used to control micelle formation and dissociation in the process of Lin and Jiang with pH adjustment, namely (a) that he wrongly concluded that pH adjustment was a common general knowledge technique for altering the CMC of a surfactant; and (b) that he failed to consider whether the skilled person would have had the required fair expectation of success that pH adjustment would work as a way of adjusting the CMC. Court of appeal again sided with trial judge on this issue & held that “there can be no doubt that the judge was aware that expectation of success may be a relevant matter to consider in assessing whether an invention was obvious. He expressly directed himself that where it is alleged that a step is obvious to try, the question is whether the skilled person would do so with a fair expectation of success, and that what amounts to a fair expectation of success will depend upon all of the circumstances of the case. Here he carried out his evaluation having regard to all of the evidence before him and all of the material circumstances”.

Finally court of appeal held that claimed invention was obvious in the light of Lin and Jiang and that trial judge’s finding was properly reasoned & he made no error of principle. Thus the appeal was dismissed.

Abiraterone - USA

IPR decision (January 17, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Status
IPR2016-01317 IPR2016-00286 IPR2016-01582 IPR2017-00853 IPR2016-01332	12/04/2015 06/29/2016 06/30/2016 08/10/2016 02/08/2017	05/31/2016 09/19/2016 01/10/2017 01/19/2017 04/12/2017	Amerigen Argentum Mylan Wockhardt Actavis	US 8,822,438	Final Written Decision (claims 1–20 are unpatentable)

PTAB concluded that Petitioner has demonstrated that the preponderance of the evidence of record supports that it would have been obvious to the ordinary artisan at the time of invention to combine Gerber with O’Donnell or Barrie and/or Sartor, with a reasonable expectation of success. The secondary considerations of nonobviousness raised by Patent Owner are neutral or not in favor of the patentability of the challenged claims, and do not outweigh the other Graham factors in obviousness analysis.

US 8,822,438 (expiring on Aug 24, 2027) claims a method for the treatment of a prostate cancer with abiraterone and prednisone.

Everolimus - USA

IPR decision (Jan 11, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Status
IPR2016-00084	10/26/2015	04/29/2016	Par Pharmaceutical, Inc.	US 5,665,772	Final Written Decision (claims 1–3 and 8–10 are patentable)

Roxane, Breckenridge IPRs (IPR2016-01102 & IPR2016-01023) were terminated as they joined above IPR & Par, Breckenridge’s IPRs (IPR2016-01059 & IPR2016-01103) were denied.

US 5,665,772 patent claims compound.

Erlotinib - USA

IPR decision:

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Status
IPR2016-01284	06/28/2016	01/09/2017	Apotex, Inc	US 6,900,221	Final Written Decision (Claims 44‒46 and 53 are Unpatentable)

PTAB concluded that Petitioner has demonstrated that the preponderance of the evidence of record supports that it would have been obvious to the ordinary artisan at the time of invention to combine Schnur with either OSI’s 10-K or Gibbs, with a reasonable expectation of success.

Cyclobenzaprine hydrochloride – USA

On Jan 04, 2018, the Federal Circuit vacated & remanded district court’s infringement decision in Amrix (Cyclobenzaprine hydrochloride) ANDA case.

In this Hatch-Waxman case, Apotex Inc. and Apotex Corp. appeal from the district court’s claim construction of “extended release coating” and its finding that Apotex’s product infringes U.S. Patent Nos. 7,790,199 and 7,829,121. Aptalis Pharmatech, Inc. and Ivax International GmbH own the ’199 and ’121 patents which relate generally to extended release dosage forms of cyclobenzaprine hydrochloride, a skeletal muscle relaxant. Instead of requiring three daily doses of cyclobenzaprine, as in the prior art, the asserted patents disclose an extended release cyclobenzaprine formulation that provides twenty-four hour relief from muscle spasms with a single dose.

The asserted patents teach two different formulations that use a water insoluble polymer coating to achieve an extended release profile. The parties refer to these alternatives as membrane systems and matrix systems. In a membrane system, a water insoluble polymer coating is applied onto an active-containing core. In a matrix system, the water insoluble polymer is mixed together with the drug and compacted into a tablet. Although the specification discloses two different extended release formulations, the claims are not expressly limited to a specific formulation by name (i.e., “membrane system” or “matrix system”). Claim 1 reads:

1. A pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise: an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammoniomethacrylic acid copolymers, and mixtures thereof; wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 30 mg; wherein following a single oral administration of the pharmaceutical dosage form, the pharmaceutical dosage form provides a maximum blood plasma concentration (Cmax) of 19.851±5.8765 ng/mL of cyclobenzaprine HCl and an AUC0-168 of 736.60±259.414 ng·hr/mL.

Apotex argued that it does not infringe because its products contain a matrix-style formulation. Parties stipulated to a construction for part of the disputed term that “a water insoluble polymer membrane surrounding said core” means “a water insoluble polymer covering that surrounds the active core.” The district court subsequently construed “extended release coating,” the remainder of the disputed claim term, as “[a] layer of any substance that is applied onto the surface of another, the purpose of which is to delay the release of a drug in order to maintain the drug at therapeutically effective concentrations over an extended period of time.” Applying this claim construction, the district court found that Apotex’s ANDA product contained an extended release coating and infringed the asserted claims of the ’199 and ’121 patents.

Apotex appealed the district court’s claim construction and its infringement finding. During appeal Apotex contended that the intrinsic evidence would have taught an ordinarily skilled artisan at the time of the invention that an “extended release coating” is limited to a continuous outer film, not simply “[a] layer of any substance that is applied onto the surface of another.” Federal circuit said that a coating that surrounds the core or encloses it on all sides connotes a continuous coating, i.e., one that covers the entire surface of the core. And, because the extended release coating must surround the core, the plain claim language suggests that the coating must be located outside of the core. In other words, the water insoluble polymer membrane is an outer coating relative to the core. This construction reflects these limitations by requiring a “continuous outer film applied onto the surface of the active-containing core.” The specification also bolsters the conclusion that the extended release coating must be a continuous outer film. And the specification’s frequent references to applying the extended release coating “onto” the active-containing core comports with court’s understanding of the spatial orientation required by the claims.

Federal circuit was not persuaded by Aptalis’ arguments in defense of the district court’s contrary construction. Aptalis first argued that the “applied onto the surface of the active-containing core” and “outer” requirements would exclude preferred embodiments. In Example 2, for instance, a seal coat is applied onto the active-containing core before the extended release coating, and an additional coating layer is added after the extended release coating. Because there is a seal coat between the extended release coating and the active-containing core, Aptalis argued that the extended release coating was applied onto the seal coat, not “onto the surface of the active-containing core.” Similarly, Aptalis interpreted “outer” to mean “outermost” and points out that there is a coating layer applied onto the extended release coating in Example 2. Aptalis next asserted that the word “continuous” does not appear in the asserted patents and that a “continuous” extended release coating would not be functional because the coating must be permeable to gastrointestinal fluids. Federal circuit denied all Aptalis arguments & finally held that district court erred in construing the claims. Thus it vacated and remanded the district court’s infringement finding for further proceedings consistent with court’s claim construction.

HAAPY NEW YEAR 2018!!

Pharma IP Circle wishes a very Happy & Prosperous New Year to all readers. May this New Year bring more learning, more knowledge in the field of IP.

And in this New Year now you can follow recent drug litigation updates at Twitter handle- @pharmaipcircle. Stay updated on the go!!