Estradiol - USA

On Dec 22, 2017, District court of Delaware held that a patent related to Estradiol (Minivelle®) ER film is valid but not infringed because of prosecution history estoppel.

Noven is the holder of New Drug Application ("NDA") No. 203752, for the manufacture and sale of an estradiol transdermal delivery system (Minivelle®), with dosages of 0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day and 0.1 mg/day. Minivelle® is indicated for treatment of moderate to severe vasomotor symptoms (also known as "hot flashes") due to menopause and for the prevention of post-menopausal osteoporosis. On March 20, 2015, Plaintiff Noven Pharmaceuticals, Inc. ("Noven" or "Plaintiff') filed suit against Defendant Actavis Laboratories UT, Inc. ("Actavis" or "Defendant") alleging infringement of U.S. Patent No. 8,231,906 (the "'906 patent"), which is directed to a transdermal product for the delivery of the hormone estradiol. The Court held a claim construction hearing on May 3, 2016 and issued a claim construction opinion on July 5, 2016. The Court conducted a three-day bench trial in January and February of 2017 and heard closing arguments on May 8, 2017. At trial and in its post-trial briefing, Noven claimed that Actavis infringed the asserted claims of the '906 patent literally and under the doctrine of equivalents. Actavis, in turn, claimed that prosecution history estoppel barred Noven from asserting infringement under the doctrine of equivalents and that the asserted claims of the '906 patent were invalid as obvious.

Infringement under DOE & prosecution history estoppel:

Noven asserted that Actavis's proposed generic product and/or manufacturing process infringe claims 1-14 of the '906 patent. Claim 1 reads:

1. A monolithic transdermal drug delivery system for estradiol, comprising a single polymer matrix layer defining an active surface area and comprising a polymer matrix comprising estradiol as the only drug, wherein the polymer matrix layer has a coat weight selected from the group consisting of 12.5 mg/cm2 and 15 mg/cm2 , includes greater than 0.156 mg/cm2 estradiol, and achieves an estradiol flux that is greater than 0.01 mg/cm2 /day, based on the active surface area.

On May 29, 2012 during prosecution, claim 1 did not contain a quantitative coat weight limitation. On May 29, 2012, the PTO issued a Final Office Action, rejecting certain claims under 35 U.S.C. § 103 over certain prior arts such as Kanios, Nuwayser & Rovati. With respect to the rejections, the Examiner stated that although Rovati "does not teach that the system achieves an estradiol flux that is greater than 0.01 mg/cm2 /day," "[i]t would have been obvious to one of ordinary skill in the art at the time that the invention was made to utilize the matrix taught by Kanios II in the monolithic patch of Rovati ... to achieve the instantly claimed estradiol flux." On May 30, 2012, in response to the May 29, 2012 Final Office Action, Applicant amended claim 1 & argued that amended claim 1 was patentable over Rovati in view of Kanios II because both prior art references did not "teach or suggest a polymer matrix coat weight as recited in the instant claims." Applicant also argued that "Rovati does not recognize any criticality of the coat weight of the polymer matrix" and that "Rovati's example appears to have a coat weight of about 9.8 mg/cm2 which is significantly lower than the 12.5 or 15 mg/cm2 recited in the claims."

Actavis contended that prosecution history estoppel bars Noven from asserting infringement of claim 1 under the doctrine of equivalents. Actavis's arguments focused on the "coat weight" limitation of claim 1. In Actavis's view, the Applicant "added the 'coat weight' limitation to distinguish the claims from" Rovati. Actavis further contended that Noven cannot establish "the narrow tangential relation exception to prosecution history estoppel," "[b]ecause both the reason for the amendment and the asserted equivalent relate to [the coat weight of the polymer matrix layer]." Noven asserted that the "coat weight" amendment "was not made for reasons of patentability or to narrow the claims in view of the prior art" but, instead, was made "to claim two specific embodiments." Moreover, even if estoppel would presumptively apply, Noven contends that the coat weight amendment "was only tangentially related to the equivalent in question" because "[t]he amendment rewrote the limitation into the independent claim."

Court said that the '906 patent's prosecution history demonstrates that the Applicant added the coat weight limitation to overcome a § 103 rejection based on Rovati in view of Kanios II. For example, in its response to the PTO's rejection, the Applicant stated that "Rovati does not recognize any criticality of the coat weight of the polymer matrix" and that "Rovati' s example appears to have a coat weight of about 9 .8 mg/cm2 [,] which is significantly lower than the 12.5 or 15 mg/cm2 recited in the claims." The Applicant further stated that Rovati "does not teach or suggest a polymer matrix coat weight as recited in the instant claims" and that "Kanios II does not provide any teachings regarding the coat weight of its polymer matrix." From these statements (and the entirety of the prosecution history), the Court concludes that the Applicant used the coat weight amendment to distinguish the amended claim over Rovati, making the coat weight amendment substantially related to patentability.

For the reasons explained above, the Court concluded that the coat weight amendment was a narrowing amendment made to distinguish the claim over prior art and further concluded that the reason for the amendment was not tangentially related to the equivalent in question. Consequently, prosecution history estoppel bars Noven from asserting infringement of the coat weight limitation under the doctrine of equivalents.

Invalidity:

Actavis argued that the asserted claims are obvious over the prior art because: (1) a POSA would have been motivated to make a smaller estradiol transdermal delivery system; (2) the specific size reduction in making a smaller transdermal estradiol delivery system would have been a design choice; (3) a POSA attempting to modify Vivelle-Dot® would have been motivated to keep the polymer matrix weight ofVivelle-Dot® the same and would, therefore, arrive at the claimed coat weight limitation; (4) a POSA attempting to modify Vivelle-Dot® would have been motivated to use the same amount of estradiol as Vivelle-Dot®, thereby increasing the amount of estradiol per unit area; and (5) a POSA attempting to modify VivelleDot® would have been motivated to increase flux.

Court after hearing both the parties held that the Court is not persuaded that a POSA would have been motivated by the prior art to develop a transdermal estradiol system smaller than Vivelle-Dot®. Although Actavis correctly observed that its cited "prior art [references] ... disclose[] that patients preferred smaller estradiol transdermal drug delivery systems," none of the references indicates that patients preferred a transdermal estradiol patch smaller than Vive/le-Dot® Further the Court agrees with Noven that "a POSA would not have had a reasonable expectation of success in implementing any chosen size reduction" because a "POSA would have had to test numerous combinations ... to determine if flux could be increased enough" to allow for that size reduction. Additionally, although certain techniques were known to be beneficial in increasing flux, a POSA would recognize that those same techniques could also deleteriously impact other aspects of the drug's profile. Accordingly, the Court concluded that the specific size reduction in designing a smaller patch would not have been "an obvious design choice." Given this conclusion and the evidence cited above, Actavis has failed to prove that the claimed size limitations would have been obvious to a POSA in July 2008.

Accordingly, again, Actavis has failed to prove that the polymer matrix weight limitation, estradiol limitation, flux limitation would have been obvious to a POSA at the priority date of the '906 patent. Also there is a nexus between Minivelle®'s commercial success and the invention claimed in the '906 patent. Minivelle®'s size - a feature claimed by the '906 patent - has been a central theme of promotion since Minivelle®' s launch and is crucial to its success. Accordingly, Noven has proven a causal nexus. The secondary consideration of commercial success further demonstrates the nonobviousness of the asserted claims of the '906 patent.

CONCLUSION:

Pursuant to Federal Rule of Civil Procedure 52(a), and having considered the entire record with respect to prosecution history estoppel and invalidity, the Court concluded that:

(1) Prosecution history estoppel bars Noven from asserting infringement of the coat weight limitation of the '906 patent under the doctrine of equivalents; and

(2) Actavis has failed to prove, by clear and convincing evidence, that the asserted claims of the '906 patent are invalid as obvious.

Pemetrexed - Denmark

On Dec 08, 2017, Danish Maritime and Commercial High Court held that Fresenius generic drug with pemetrexed tromethamine infringes EP1313508 patent.The case concerns the infringement of Lilly’s patent DK/EP’508 which relates to the use of the active ingredient pemetrexed in combination therapy with vitamin B12 and optionally folic acid.

Initially, the Court noted that the product "Pemetrexed Fresenius Kabi" does not constitute a literal infringement of the patent, as pemetrexed disodium is not used in this product. With respect to infringement under equivalence  court said that the amendment of the patent claims from pemetrexed to pemetrexed disodium was due to the EPO's preliminary objection to added matter for "pemetrexed" in accordance with Article 123(2) EPC. The reason for this preliminary objection and the resulting amendment was not lack of novelty or inventive step. Therefore there was no clear estoppel.

Court further held that based on both the wording and the description in the patent, It is undisputed that the pemetrexed anion, i.e. the diacid, is the active ingredient of the medicinal products and that the counterion is not important to the efficacy of the medicinal product. Also it was obvious to this skilled person that the invention could be carried out by using other salts than the specific salt pemetrexed disodium. Therefore the skilled person could expect to find another counterion for the pemetrexed diacid based on the most commonly used salt formations, including tromethamine.

Based on this, the Court found that infringement by equivalence was rendered probable & asked Fresenius Kabi to pay legal costs to Eli Lilly.

Brimonidine & Timolol – USA

On Dec 22, 2017, The Federal Circuit affirmed Eastern District of Texas' earlier decision that that each of three Allergan patents are valid but reversed the district court's decision of infringement of one patent in Combigan® (Brimonidine & timolol) case.

Allergan holds the approved new drug application for Combigan®, which is used to lower intraocular pressure in glaucoma and ocular hypertension patients. Combigan® is a “fixed combination” ophthalmic solution consisting of 0.2% brimonidine tartrate and 0.68% timolol maleate for twice-daily dosage. Allergan Sales, LLC sued Sandoz under the Hatch-Waxman Act, alleging infringement of U.S. Patent Nos. 7,030,149, 7,320,976, and 8,748,425. In particular, Allergan claims that claim 4 of the ’149 patent, claim 1 of the ’976 patent, and claims 1–8 of the ’425 patent protect Combigan® and its administration. The U.S. District Court for the Eastern District of Texas found the asserted claims not invalid but only claims of the ’425 patent infringed. Sandoz appealed the district court’s no-invalidity and infringement determinations. Allergan cross appealed the finding of non-infringement.

With respect to invalidation, Sandoz argued that the district court erred because the asserted claims merely recite the inherent results of administering an obvious combination. Federal circuit however disagreed & said that each asserted claim, expressly recites an additional efficacy limitation that further restricts the method of administering the composition twice daily: (1) “without loss of efficacy” in claim 4 of the ’149 patent, (2) “a therapeutically effective amount” in claim 1 of the ’976 patent, and (3) “reducing the incidence of one or more adverse events” in claim 1 of the ’425 patent. Those efficacy limitations are not disclosed by any prior art reference in the record. To the contrary, the prior art shows that the combination dosed twice daily produces a loss of efficacy in the afternoon. In light of the foregoing, the district court did not err by finding that Sandoz failed to present clear and convincing evidence to overcome the presumption that the asserted claims are valid.

With respect to infringement, Sandoz argued that the district court erred in finding infringement of claims 1–8 of the ’425 patent. Allergan asserted only literal infringement of those claims. The district court found that the proposed generic contains 0.5% timolol free base and therefore infringed the claims of the ’425 patent. That finding is erroneous for two related reasons. Claims 1–8 are narrowly and specifically drawn, reciting administration of 0.2% brimonidine tartrate and 0.5% timolol free base. Both Combigan® and the proposed generic, however, contain 0.68% timolol maleate, an ophthalmic compound distinct from 0.5% timolol free base. The district court relied on the equivalency of the two compounds in finding literal infringement—that is, 0.5% timolol free base recited in claims 1–8 as chemically equivalent to 0.68% timolol maleate contained in the proposed generic. Because chemical equivalency is not sufficient for literal infringement of these claims, the court clearly erred. Here, Combigan® contains a 0.2% brimonidine tartrate and 0.68% timolol maleate solution, as its FDA-approved label makes clear. But claims 1–8 of the ’425 patent expressly recite 0.5% timolol free base, not 0.68% timolol maleate. Therefore, as a matter of law, Combigan® is not the “drug claimed in” the ’425 patent, and Sandoz’s ANDA does not infringe under § 271(e)(2)(A). In sum, the district court erred by finding that Allergan showed literal infringement of claims 1–8 of the ’425 patent.

Allergan argued on its cross-appeal that the district court erred in finding that Sandoz’s proposed generic does not infringe claim 4 of the ’149 patent and claim 1 of the 976 patent. Allergan again asserted only literal infringement with respect to those claims. Both the claims specifically recite 0.2% brimonidine. But the proposed generic contains 0.2% brimonidine titrate, a distinct pharmaceutical compound that reduces to 0.132% brimonidine—indeed, Allergan’s expert confirmed so. As such, the district court did not err by finding that Allergan failed to show literal infringement of claim 4 of the ’149 patent and claim 1 of the ’976 patent.

Federal circuit finally affirmed that district court’s finding of no invalidity of the asserted claims and non-infringement of the claims of the ’149 and ’976 patents, but reversed the finding of infringement of claim 1 of the ’425 patent.

Cabazitaxel - USA

By an order of Dec 17, 2017, New Jersey district court found claims 7, 11, 14, 15, 16, 21, 26, and 30 of U.S. Patent No. 8,927,592 (expiring on 04/27/2031) are invalid & claims 1 and 2 of U.S. Patent No. 5,847,170 (expiring on 09/26/2021) are valid and are infringed by Defendants’ proposed generic products.

This consolidated action arises under the patent laws of the United States (Sanofi-Aventis US LLC et al v. Fresenius Kabi USA, LLC NJD-3-14-cv-07869). The Court conducted an eight-day bench trial on September 18-20 and September 25-29, 2017. The parties submitted post-trial briefs on October 31, 2017 and the Court heard closing arguments on November 8, 2017. The parties filed supplemental correspondence on November 17, 2017, December 4, 2017, and December 11, 2017. Pursuant to Court order, the parties filed supplemental legal briefs on December 13, 2017. The Court has set forth its Findings of Fact and Conclusions of Law in an accompanying Opinion pursuant to Federal Rule of Civil Procedure 52(a)(1).

The Patent Trial and Appeal Board in Sep 2017 also held the US’592 patent invalid, rejecting arguments that the drug’s success weighed against finding various claims were obvious in an inter partes review (IPR) filed Mylan Laboratories Ltd.

Plerixafor – USA

On Dec 18, 2017, The Federal Circuit affirmed a Delaware judge's decision that ANDA filers Dr Reddy’s & Teva Pharmaceuticals failed prove the obviousness of Mozobil (Plerixafor) patent since there was no reasonable expectation of success.

This consolidated set of appeals arises from a Hatch-Waxman action brought by Genzyme Corporation and Sanofi-Aventis U.S. LLC (collectively, Genzyme) against Dr. Reddy’s Laboratories and Teva Pharmaceuticals (collectively, DRL). After a bench trial, the district court held that DRL failed to prove that claim 19 of U.S. Patent No. 7,897,590 (the ’590 Patent) is invalid for obviousness. The ’590 Patent makes use of a regimen comprising a combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor to increase the number of stem cells in the blood for collection. Claim 19 of the ’590 Patent was the only claim at issue in this set of appeals. It recites a “method to obtain progenitor and/or stem cells” by (1) administering G-CSF to a subject; (2) administering plerixafor or a pharmaceutically acceptable salt thereof to the subject, in an amount effective to mobilize the progenitor and/or stem cells; and (3) harvesting the progenitor and/or stem cells.

As part of its obviousness challenge, DRL presented the following prior art: (1) Hendrix et al., (2) International Patent Application Publication No. WO 00/45814 (WO ’814); and (3) U.S. Patent No. 5,824,304 (the ’304 Patent). Hendrix disclosed “binding of [plerixafor] to CXCR4 may inhibit the chemotactic effects of SDF-1α, causing release of WBCs from the endothelium and/or stem cells from bone marrow.” The ’304 Patent teaches a method for increasing the number of stem cells in the peripheral blood by administering a blocking agent of VLA-4 antigens. DRL argued that the only difference between the claimed invention and the ’304 Patent is that the ’304 Patent does not teach that the blocking agent can be plerixafor. But that would have been obvious, DRL argued, because Hendrix expressly suggested that plerixafor could function as a blocking agent for releasing stem cells from the marrow. The district court, however, found that Hendrix was not analogous art. Whereas Hendrix focused on HIV treatment, the ’590 Patent focused on mobilizing stem cells for subsequent harvest and transplantation. But even if Hendrix were deemed analogous art, the district court found that Hendrix would not have rendered claim 19 obvious. The district court expressly rejected DRL’s position that it was “reasonably predictable in October 2000 that plerixafor would mobilize stem cells in sufficient numbers for harvesting and transplantation.” It also found that the evidence established a “history of failure in the field”.

Federal circuit carefully considered the findings and all of the parties’ arguments, & discussed principally the parties’ dispute over whether a person of skill in the art would have had a “reasonable expectation of success” in achieving the claimed invention. The district court’s finding that stem cell mobilization was highly unpredictable at the time of the invention runs counter to an expectation of success. In particular, there was great uncertainty about the role of SDF-1 or CXCR-4, if any, in the process of stem cell mobilization. CXCR-4 antagonists were only studied in the HIV field, and there was a history of failure resulting from the investigation of more than a dozen candidates in the search for a better stem cell mobilization agent. No one had ever mobilized stem cells with any CXCR-4 antagonist, let alone plerixafor. DRL’s alternative basis for invalidating the ’590 Patent is the combination of the WO ’814 Patent and the ’304 Patent. Like Hendrix, “WO ’814 does not disclose information about using plerixafor to mobilize stem cells, but instead reveals the relationship between plerixafor and white blood cell elevation.” Ultimately, the deficiency regarding the combination of Hendrix and the ’304 Patent also undercuts the combination of WO ’814 and the ’304 Patent. As noted, sufficient evidence supported the district court’s finding of a lack of a reasonable expectation of success.

Federal circuit after reviewing the record surrounding the prior art and analyzing the arguments of the parties, finally held that the district court’s factual conclusions regarding an insufficient reasonable expectation of success were not clearly erroneous. Thus Federal circuit affirmed the district court’s holding that the ’590 Patent is not invalid.

Everolimus - USA

On Dec. 14, 2017, Judge Richard G. Andrews of district of Delaware issued a trial opinion in Everolimus (Afinitor) case & found method of treatment patents valid in Hatch-Waxman litigation.

Plaintiffs brought this patent infringement action against Roxane Laboratories, Inc. Roxane (now West-Ward) filed Abbreviated New Drug Application ("ANDA") No. 207486, seeking to engage in the commercial manufacture, use, and sale of generic versions of Novartis's Afinitor product. The parties have stipulated that this ANDA infringes claims 1-3 of U.S. Patent No. 8,410,131 ("the '131 patent") and claim 1 of U.S. Patent No. 9,006,224 ("the '224 patent"). The Court held a bench trial on September 13-15, 2017. Defendant argues that the asserted claims of the '131 and '224 patents are invalid as obvious. Asserted claims 1-3 of the '131 patent require administering a therapeutically effective amount of everolimus to inhibit the growth of solid excretory system tumors, including advanced solid excretory system tumors and kidney tumors. Asserted claim 1 of the '224 patent relates to method for treating pancreatic neuroendocrine tumors wherein the tumors are advanced tumors after failure of cytotoxic chemotherapy. At issue in this case are methods for using everolimus to treat advanced renal cell carcinoma ("RCC") and advanced pancreatic neuroendocrine tumors ("PNETs").

VALIDITY OF THE '131 PATENT:

Defendant contended that administration of a therapeutically effective amount of everolimus to treat advanced RCC would have been obvious to a POSA. The essence of Defendant's obviousness argument was that knowledge in the art about the biology of advanced RCC, mTOR3 inhibitors, and safe dosing ranges of everolimus, alongside phase I temsirolimus clinical trial results in advanced RCC, would have given a POSA a reasonable expectation of success of effectively treating advanced RCC with everolimus, as both everolimus and temsirolimus are mTOR inhibitors. Defendant asserted that "the prior art established a strong scientific rationale for using an mTOR inhibitor to treat advanced RCC”. Plaintiffs countered that many different agents were under investigation for the treatment of advanced RCC, and that the relative success of immunotherapies would have motivated a POSA to investigate immunostimulants rather than immunosuppressants like everolimus.

The prior art disclosed general antiproliferative properties of everolimus, and that oral administration of everolimus was safe and tolerable in treating renal and liver transplant patients. Defendant's expert, Dr. Cho, opines that a POSA would have been motivated to administer therapeutically effective amounts of everolimus to inhibit the progression of advanced RCC with a reasonable expectation of success. According to Dr. Cho, the claimed invention would have been obvious over the teachings of Hidalgo 2000 or Hutchinson in combination with the '973 patent or the '772 patent, in view of the general knowledge in the art. Plaintiffs assert that because Dr. Cho restricted his review and analysis to art regarding mTOR inhibitors, he failed to consider the full scope of the relevant prior art, and Defendant has failed to prove obviousness because it has failed to prove a motivation to select everolimus over other compounds.

Court found that the relevant prior art would have included art relating to treatments beyond mTOR inhibitors. Against the backdrop of a strong desire to find an effective advanced RCC treatment and the general preference for orally-administered cancer treatments, promising temsirolimus phase I data, and shared properties of temsirolimus and everolimus, a POSA would have been motivated to pursue everolimus as one of several potential treatment options for advanced solid tumors, including advanced RCC. But even if a POSA would have been motivated to select everolimus to treat advanced RCC, court found that the asserted combinations would not have provided a POSA a reasonable expectation of success in using everolimus to treat advanced RCC. Here, no prior art reference disclosed the use of everolimus to treat advanced RCC. The prior art does not disclose all elements of the asserted claims. Thus considering the evidence as a whole, Defendant has not shown by clear and convincing evidence that claims 1-3 of the '131 patent are invalid as obvious.

VALIDITY OF THE '224 PATENT:

Defendant contended that administration of a therapeutically effective amount of everolimus as a monotherapy to treat patients with advanced PNETs after the failure of cytotoxic chemotherapy would have been obvious to a POSA. The essence of Defendant's obviousness argument was that the prior art teaches that mTOR inhibitors were demonstrated to be safe and effective to treat advanced PNETs in phase II and preclinical models, including after the failure of cytotoxic chemotherapy, and that everolimus would have been an obvious substitute for temsirolimus because both drugs are mTOR inhibitors with shared properties. Defendant's expert, Dr. Yu, opined that a POSA would have been motivated to administer a therapeutically effective amount of everolimus as a monotherapy to treat advanced PNETs after the failure of cytotoxic chemotherapy. Dr. Yu stated that a POSA would have been motivated to combine the prior art references Duran, Dancey, and Tabemero because they all deal with using mTOR inhibitors to treat cancer.

Court held that given the incomplete knowledge of the molecular biology of PNETs and the mTOR pathway, along with the high number of potential therapeutic targets both within and outside the mTOR pathway, I find that Defendant has failed to establish by clear and convincing evidence a motivation to select everolimus. Even if Defendant had established such a motivation, however, Defendant has failed to prove by clear and convincing evidence that any one of the asserted prior art combinations would give a POSA a reasonable expectation of success of administering a therapeutically effective amount of everolimus as a monotherapy to treat advanced PNETs after the failure of cytotoxic chemotherapy.

CONCLUSION: Defendant failed to prove by clear and convincing evidence that the asserted claims of the '131 and '224 patents are invalid as obvious.

Prasugrel - USA

On Dec 12, 2017, The Federal Circuit upheld a Patent Trial and Appeal Board decision that invalidated Daiichi Sankyo’s patents US 8,404,703 and US 8,569,325 for anti-blood clot drug Effient (Prasugrel). In a one-line order (Rule 36 judgment), the Federal Circuit affirmed the Board’s decision after hearing arguments in the case on Friday. This was an appeal from the United States Patent and Trademark Office, Patent Trial and Appeal Board in Nos. IPR2015-00864, IPR2015-00865, IPR2015-01881, IPR2015-01882. The Board had found in September 2016 that Daiichi Sankyo’s US’703 and US’325 patents, which claim the combination of anti-clotting agent prasugrel and aspirin are invalid as obvious over Coniglio, Bernat, Asai, and Koike prior arts.

Memantine – USA

On Dec 11, 2017, The Federal Circuit affirmed a Delaware judge's decision that Forest Laboratories’ six patents on the Alzheimer's drug Namenda are invalid as indefinite in a win for Teva Pharmaceuticals. During claim construction, Delaware district court determined that all of the asserted patent claims are invalid for indefiniteness and on that basis entered judgment against Forest. During appeal CAFC agreed with district court’s finding that the Delaware Court’s construction was reasonable and as such, the claims were indeed indefinite.

Forest Laboratories, Inc., holds New Drug Application No. 22–525 covering Namenda XR® (Namenda Extended Release formulation), a memantine hydrochloride formulation “indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.” Adamas is the owner, and Forest Laboratories Holdings, Ltd., is the exclusive licensee, of six related patents: U.S. Patent No. 8,168,209; U.S. Patent No. 8,173,708; U.S. Patent No. 8,283,379; U.S. Patent No. 8,329,752; U.S. Patent No. 8,362,085; and U.S. Patent No. 8,598,233. The patents describe and claim pharmaceutical compositions, and methods of administering pharmaceutical compositions, that contain extended-release formulations of memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist. According to the specification, the rate that the memantine in a particular formulation enters a patient’s bloodstream is measured in terms of a ratio: “dC” designates the change in concentration of memantine in blood during a specified time; “dT” designates the length of the specified time.

In December 2013, Teva filed an abbreviated new drug application seeking approval to sell a generic version of Namenda XR® and provided Forest with its Paragraph IV certification stating that the six patents were invalid or will not be infringed by Teva’s generic. Forest then sued Teva & the parties addressed issues of claim construction. The parties agreed that the language in claim 1 of the ’209 patent is representative & claim 1 reads:

1. A solid pharmaceutical composition in a unit dosage form for once daily oral administration comprising an extended release formulation of 5 to 40 mg memantine or pharmaceutically acceptable salt thereof, wherein administration of a dose of the composition to a human subject provides a plasma memantine concentration profile, as measured in a single-dose human PK [pharmacokinetic] study, characterized by a change in memantine concentration as a function of time (dC/dT) that is less than 50% that of an immediate release dosage form comprising the same dose of memantine as the composition, wherein the dC/dT is measured between the time period of 0 to Tmax of the immediate release form of memantine.

Forest proposed that the highlighted language either be left unconstrued or be construed to mean a “change in plasma memantine concentration of the extended [sustained] release dosage form as a function of time (dC/dT) that is less than 50% that of an immediate release dosage form comprising the same dose of memantine as the extended [sustained] release dosage form.” Teva contended that the claim term is indefinite under 35 U.S.C. § 112. According to Teva, the term requires the comparison of a concentration profile of an immediate-release formulation and a concentration profile of an extended-release formulation, as measured in human pharmacokinetic studies. Teva asserted, neither the claim language nor the specification adequately describes how to conduct the studies to obtain those concentration profiles, and differences in study design lead to variable results in the claim-required comparison. Forest argued that, under the claim language, the dC/dT of the extended-release formulation is to be derived from a human study, and then compared to the dC/dT from the computer-derived curve of the immediate-release formulation shown for Namenda 20 mg in Figures 1A and 2D of the specification.

The district court construed the claim to require that the concentration profile of the extended-release formulation and the concentration profile of the immediate-release formulation be measured in human pharmacokinetic studies. The court concluded that the intrinsic evidence does not disclose a specific human-study design or provide guidance as to how to design a human study. The court also found that the extrinsic evidence of how a person of skill in the art would understand the language at issue, including undisputed expert testimony, showed that “measurements from human [pharmacokinetic] studies vary widely in terms of the concentration profiles they generate” for any particular memantine formulation. Because “[a] person of ordinary skill in the art would not know, with reasonable certainty, which ‘human [pharmacokinetic] study’ on which to rely when considering whether a formulation of memantine might infringe” and because human-study results are so variable, the court ruled, claim 1 and the other claims it represented are indefinite. Thus Delaware court entered a final judgment of invalidity based on indefiniteness.

CAFC reviewed de novo a district court’s determination of indefiniteness, but reviewed for clear error any of the district court’s underlying findings of fact based on extrinsic evidence. Forest contended that the district court erred by construing the claim to require that both of the concentration profiles being compared—the profiles of the extended- and immediate-release formulations—be derived from measurements in human pharmacokinetic studies. CAFC agreed with the district court & rejected Forest’s argument. Court said that language of claim 1 requires “a plasma memantine concentration profile”, as measured in a single-dose human PK [pharmacokinetic] study. The specification describes Figures 1A and 2D as showing concentration profiles of a 20 mg memantine immediate-release formulation and a 20 mg memantine extended-release formulation generated by a predictive pharmacokinetic software program called GastroPlus. The descriptions of the figures are no more than what they purport to be: descriptions of the figures. They do not constitute a definition and are not even directed to the meaning of the claim terms. Elsewhere, the specification does expressly define terms, such as “dC/dT”. Indeed, the merely illustrative character of the figures is confirmed by the fact that the figures show profiles only for particular doses, not profiles for the full range of doses covered by the claims—for which immediate-release profiles are needed but not found in those figures. The prosecution history also provides no support for Forest’s proposed construction. The inventor declaration submitted during prosecution describes the results of a human pharmacokinetic study from which both immediate-release and extended-release profiles were derived. The inventor compared those two profiles measured in the human study; he did not compare the extended-release profile from the human study to the immediate-release profile in Figures 1A and 2D.

Moreover the district court’s indefiniteness ruling is supported by precedents that hold claims indefinite in particular circumstances where the claims require measured quantities (absolute or relative), different techniques for such measurements are known in the art and some produce infringing results and others not, the intrinsic evidence does not adequately specify the technique or techniques to use, and extrinsic evidence does not show that a relevant skilled artisan would know what technique or techniques to use. Thus finally CAFC affirmed the judgment of the district court & found patents invalid as indefinite.

Sofosbuvir - Australia

On Dec 07, 2017, Federal court of Australia upheld the invalidity decision of lower court in Sofosbuvir case and dismissed the appeal of Idenix.

The appellants (Idenix) are the registered owners of patent no. AU2003247084, titled “Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections” (the Idenix patent). The Idenix patent relates to compounds for the treatment of flaviviridae infections, including the hepatitis C virus (HCV) infection. The respondents (Gilead) are the registered owners of patent no. AU2004253860 (the Clark patent). Gilead has sought to sell in Australia a pharmaceutical drug containing or comprising an effective amount of a compound called sofosbuvir to treat HCV. Gilead commenced proceedings in this Court against Idenix seeking a declaration that claims 7 to 41 (inclusive) of the Idenix patent were invalid. It contended that the Idenix patent was invalid on the grounds that the patent did not disclose a manner of manufacture, lacked novelty, lacked fair basis, lacked utility, and lacked sufficiency. In turn, Idenix brought a cross-claim alleging that Gilead threatened to infringe various claims of the Idenix patent through the supply of pharmaceutical compositions containing the compound sofosbuvir. Gilead conceded, subject to its invalidity assertions, that sofosbuvir infringed claims 7 and 8 as well as dependent claims 10 and 13 of the Idenix patent. The primary judge found the Idenix patent to be invalid on the grounds of insufficiency in respect of claims 7 to 41 (Gilead Sciences Pty Ltd v Idenix Pharmaceuticals LLC (2016) 117 IPR 252; [2016] FCA 169).

Idenix then appealed the primary judge’s decision on the basis that her Honour erred in her conclusions as to insufficiency, certain aspects of fair basis and inutility. Further and consequentially, Idenix contended that the primary judge erred in dismissing its cross-claim given that her Honour premised that dismissal on relevant claims of the Idenix patent being invalid. Gilead has filed a notice of contention in which it challenges the primary judge’s conclusions that the Idenix patent was not invalid on the grounds of lack of novelty and other aspects of lack of fair basis.

With respect to lack of sufficiency, Gilead contended that the Idenix patent did not identify which of the compounds within claim 7 were effective for the treatment of flaviviridae infections or HCV and did not describe how to identify such compounds. It was common ground that a compound that is within claim 7 is the 2'-methyl-“up”-2'-fluoro-“down” nucleoside. The principal issue on this aspect was whether at the priority date a person skilled in the art who was armed with the Idenix patent and relying only upon common general knowledge could have synthesised a compound of claim 7 without new invention or addition or a prolonged study of matters presenting initial difficulty. Federal Court found no error in primary judge’s analysis and held that there was clear and compelling evidence before the primary judge justifying her finding that the requirement was not met. Indeed, part of the evidence before her Honour was material demonstrating that Idenix was unable to obtain a claim 7 compound despite having a team of skilled scientists and external expert consultants engaged in a prolonged attempt to do so for a period of nearly three years.

Thus court finally dismissed Idenix’s appeal and also Gilead’s other grounds of contention. 

Rosuvastatin - Netherlands

On Nov 24, 2017, Dutch Supreme Court issued its ruling in Rosuvastatin case & affirmed most of appeal court’s arguments of finding infringement, validity & dismissed the appeals of Resolution Chemicals Limited.

           

Shionogi is the holder of the supplementary protection certificate 300125 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, EP0521471 has been exclusively licensed to Astrazeneca & it markets rosuvastatin calcium under the brand name Crestor®. The SPC expires on 29 June 2017, unless the application for paediatric extension of the SPC is granted. In that case, the duration of the SPC will be extended to 29 December 2017. EP’471 claims compound rosuvastatin acid or a “non-toxic pharmaceutical salt thereof”. Resolution obtained a marketing authorization for the marketing of rosuvastatin zinc and intends to put that product on the market in the Netherlands.

On 17 April 2014, Resolution initiated proceedings against AstraZeneca 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 based on ground of added subject matter.

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 non-toxic 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 (which was also in the original application), i.e. 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” and would take this to be a limiting definition and understand that the proprietor only wanted to confer protection for those salts for use with rosuvastatin. The District Court further held that rosuvastatin salts - other than the calcium or sodium salt - do not constitute added subject matter, while the rosuvastatin acid does. The declaratory judgment of non-infringement claimed by Resolution was awarded.

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. The question to be answered was how the claim feature ‘or a non-toxic pharmaceutically acceptable salt thereof’ in claim 1 of EP’471 must be interpreted. AstraZeneca’s point of view was that the paragraph [0007] would only be regarded as a non-exhaustive list & should not be construed as limiting definition. While Resolution took the position that in light of paragraph [0007] of the description, this feature must be interpreted such that ‘salt’ only comprises one of the salts mentioned in paragraph [0007]. The Court of Appeal did not find Resolution’s approach as correct. Appeal court further said that although this further description must be taken into account as part of the description in interpreting the patent claim, this is without prejudice to the fact that the question regarding whether such description must be taken to be restrictive depends on the question of how the average skilled person would understand this further description, taking into account the description and his general professional knowledge on the priority date. Based on the 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.

Court of appeal further held that in interpreting a claim in light of the description, the inventive idea underlying the words of the claim must be taken into account as a point of view. As found before, this inventive idea can be formulated as finding a new group of statins, specifically including rosuvastatin, with an HMG-CoA reductase inhibitory effect. After all, as the average skilled person knows on the priority date, the salt form in which statins are administered is irrelevant for their biological activity, because the anion of the statin is the active ingredient and the salt only serves to administer the rosuvastatin anion in tablet form. To the extent that Resolution intended to contend that according to the Protocol, the claims must be interpreted in light of the description, so that there is no room for taking the inventive idea underlying the words of the claim into account, or at least that the wording of the description must prevail, this point of view is dismissed. After all, an interpretation of the patent claims in light of the description must always start from the perspective of the average skilled person on the priority date, taking into account his general professional knowledge. This perspective is in part determined by the inventive idea.

With respect to added subject matter Resolution took the position that claim 1 of EP’471 is invalid due to breach of Section 75 (1) c ROW (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. Appeal court held that the rosuvastatin is disclosed in the application, the average skilled person would also read – or, in other words, be reminded of – the possible choices for R4 other than sodium or calcium, i.e. the acid form and other salt forms, as well. Because this choice is not relevant for the biological activity of rosuvastatin, this does not provide any (technical) information that cannot be directly and unambiguously inferred from the original application. Position R4 determines the acid or salt form. Hydrogen (meaning the hydrogen ion that the acid form produces) and cations that can form non-toxic pharmaceutically acceptable salts with a statin are already explicitly mentioned in the original application as belonging to the group from which the parameter for the R4 position can be selected. The explicitly disclosed sodium and calcium salts from this group are examples of this – which the skilled person takes to be non-exhaustive. For this reason, the average skilled person understands that he can vary the R4 position with one of the other ions mentioned, without this having any impact on the biological activity of the explicitly disclosed rosuvastatin. Based on the above, the Court of Appeal believed that no added subject matter was 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.”

Thus Supreme Court dismissing the various appeals of Resolution held that:

 ü  Complaints in cassation directed against Court of Appeal’s interpretation that definition given in paragraph 7 of the description is not a limiting definition, is incomprehensible and in breach of Article 69 EPC, do not hold.

 ü  Court also feels that the complaints directed against the Court of Appeal’s interpretation of the grounds for appeal and the finding that no added subject matter is involved are unsuccessful.

Thus, Court concludes that the appeals in cassation are dismissed.

This opinion was delivered by AG G.R.B. Van Peursem, where he said that the Supreme Court could use this case to clarify whether the waiver doctrine from Van Bentum/Kool is still valid law. This is a difficult disputed point in the patent practice (and in the case at issue, as well), which would benefit from clarity regarding this point.

“I believe that the waiver doctrine stems from the era of the abandoned protective scope doctrine of the essence and does not fit (or no longer fits) within the correct application of Article 69 EPC according to the Protocol on the interpretation of this article, as this has also been almost fully worked out in the Netherlands. Because according to prevailing Dutch patent law, the inventive idea is no longer the starting point in determining the protective scope, but is a point of view that may play a role in this, I believe that in practical terms, it is possible to arrive at a system that comes close to the waiver doctrine: in my opinion, in the scope of the point of view of the inventive idea, in conformance with Article 69 EPC, it is possible to include this when considering whether according to the average skilled person, the intention was to limit the extent of the protection. On balance, this is the method that the Court of Appeal used in the ruling that is challenged in the case at issue. This differs slightly (not radically) from the waiver doctrine as we know it, but in practice, this will rather frequently produce similar results in terms of outcome”.

Rotigotine - USA

On Nov. 14, 2017, Chief Judge Leonard P. Stark of district of Delaware issued a decision in Rotigotine (Neupro®) case & found one patent valid & infringed while another patent invalid in a Hatch-Waxman proceeding challenged by Actavis.

This patent infringement action was brought by Plaintiffs UCB, Inc., UCB Manufacturing Ireland Limited, UCB Pharma GMBH, and LTS Lohmann Therapie-Systeme AG (collectively, "UCB" or "Plaintiffs") under the Hatch-Waxman Act. Plaintiffs filed suit against Defendants Watson Laboratories, Inc. and Actavis Laboratories UT, Inc. (collectively, "Actavis" or "Defendants"), which submitted an Abbreviated New Drug Application ("ANDA") to market a generic version of Neupro®, a patch for transdermal delivery of rotigotine for treatment of Parkinson's disease. Plaintiffs assert U.S. Patent Nos. 6,884,434 and 8,232,414. The '434 patent is listed in the Orange Book and generally describes and claims transdermal systems containing rotigotine as a free base for treatment of Parkinson's disease. The '414 patent claims a certain polymorphic form of rotigotine. In June 2017, the Court held a four-day bench trial.

With respect to US’434 patent, the only difference between the disputed element and Actavis' matrix is the use of a polyisobutylene-based polymer adhesive system instead of an acrylate- or silicone-based polymer adhesive system as literally claimed. Court having considered the purpose for which the polymer is used in the patent, the qualities it has when combined with the other ingredients and the scaffold function that it is intended to perform, (Graver Tank. 339 U.S. at 609) the Court found that polyisobutylene and the recited silicone and acrylate polymers are not substantially different in the context of these claims. Accordingly, the Court concluded that UCB has proven by a preponderance of the evidence that Actavis infringes claim 1 of the US’434 patent. Having found Actavis' ANDA products to infringe claim 1 of the '434 patent, the Court further finds that the ANDA products also infringe the asserted dependent claims. Court also concluded that Actavis has failed to meet its burden to prove by clear and convincing evidence that the asserted claims are invalid for anticipation or obviousness.

The US'414 patent claims a new polymorphic form of rotigotine, Form II. Actavis contends that the claims of the '414 patent are invalid because: (1) the invention was derived from LTS scientists not named as inventors, (2) prior art inherently discloses Form II, and (3) Form II was used in the United States before the date of the invention. Court concluded that Actavis has failed to meet its burden to prove invalidity by clear and convincing evidence under its derivation and inherent anticipation theories, but has met its burden to prove by clear and convincing evidence that the claims of the '414 patent are invalid because the invention was in use in this country before the patent's priority date. Because on November 30, 2007, just two days after the priority date, a female patient experienced an adverse event while being treated with Neupro from lot no. 47808. The Report indicated that the patient was on the lot 47808 patches for "one week," before she experienced adverse event. Further, it is reasonable to infer that the 47808 patches used by the patient contained Form II rotigotine. By November 12, 2007, the vast majority of patches tested from this lot contained visible snowflake crystals corresponding to Form II. Thus, the Court found that Form II rotigotine, the invention of the '414 patent, was used in this country before the priority date by at least one patient

CONCLUSION: Pursuant to Federal Rule of Civil Procedure 52(a), and after having considered the entire record in this case and the applicable law, the Court concludes that: (1) Actavis infringes claims 1 5, 7, 14, and 15 of the '434 patent; (2) claim 1 of the '434 patent is not invalid due to anticipation; (3) claims 1, 5, 7, 14, and 15 of the '434 patent are not invalid due to obviousness; (4) claims 1-3 of the '414 patent are not invalid due to derivation or inherent anticipation; and (5) claims 1-3 of the '414 patent are invalid under§ 102(a) because the claimed invention was in use in the United States before its priority date.

Buprenorphine - Norway

On Sep 08, 2017, Oslo District Court of Norway issued a decision in buprenorphine transdermal patch case & found patents-in-suit invalid under lack of inventive step.

The case concerns the validity of the Norwegian patents NO 334290 (NO’290), NO 332248 (NO’248), & alternative sets of claims A and B, and NO 333139 (NO’139). The defendant, Mundipharma AS (Mundipharma), is the holder of the patents-in-suit in the case. One of Mundipharma's products is a transdermal patch for the administration of buprenorphine over a period of seven days. The transdermal patch marketed by the above companies has the commercial name of Norspan in Norway, while in certain other countries it is marketed under the commercial name of BuTrans.

The plaintiff, Orifarm Generics A/S, Orifarm Generics AS and Orifarm AS (Orifarm) is the holder of three marketing authorisations for a transdermal patch containing buprenorphine under the trade name of Buprefarm. The marketing authorisations encompass three products of different strengths; 5 micrograms/hour, 10 micrograms/hour and 20 micrograms/hour, respectively. On the basis of their marketing authorisations, Orifarm planned to enter the Norwegian market with Buprefarm. On 17 June 2016 Mundipharma petitioned for an interim injunction to stop Orifarm's sale of Buprefarm. On 20 June 2016, Oslo Court of Execution and Enforcement issued a ruling whereby the petition was accepted. On 19 August 2016, Orifarm issued a writ of summons before Oslo District Court, with the prayer for relief that all three patents should be declared invalid and that Mundipharma should be ordered to pay compensation for the loss Orifarm suffered as a consequence of the interim injunction. The main hearing in the case was held from 19 to 28 April 2017.

All three of the patents-in-suit concern a transdermal delivery device that includes buprenorphine for the treatment of pain. A shared feature of the patents is that they according to the patent description make it possible to produce a medicament that enables reduced plasma concentrations of buprenorphine over a longer period of time than what is possible according to prior art, while at the same time causing effective pain relief. Orifarm submits that all of the patents-in-suit are invalid. None of the patents-in-suit fulfill the requirement of inventive step and do thus not fulfill the requirements of section 2 of the Patents Act. The ground for patent for all of the patent claims is the dosing time period described in claim 1 of the patents. At the priority date, it is obvious to the skilled person to use transdermal delivery devices for buprenorphine as described in the patents for both 5 and 7 days, and the skilled person would have had a reasonable expectation of success.

Court defined technical problem as obtaining a more convenient and effective pain relief/pain treatment by means of the transdermal administration of buprenorphine. Court further held that it can be seen from the referenced literature that the patent concerns a problem of a nature that those skilled in the art were generally focused on solving. A dosage interval of one week was considered an advantage, both to make the medicinal product user friendly and economical to use. Other advantages are also described, like constant plasma values over an extended period of time, which would lead to fewer side effects. With respect to the reasonable expectation of success there are no indications to suggest that it will not work. In the literature there are also suggestions that one might simply increase the amount of active ingredient, possibly also adjuvants in the same proportion, to obtain a longer period of effect. It will only be by trying that the skilled person will be able to find any possible adjustments that must be made to the formulation to obtain an extended duration, but the Court finds it clear that the skilled person would have done this with a reasonable expectation of success.

Finally court held that based on an overall assessment to the skilled person it was obvious to solve the problem of finding a more effective and suitable transdermal administration of buprenorphine by choosing the solutions indicated in the patent. Thus Patents NO334290, NO332248, including the alternative sets of claims A and B, and NO 333139, are ruled invalid.

Testosterone – USA

On Nov 22, 2017, the Federal Circuit upheld a district court’s decision finding one patent for Axiron (testosterone solution) invalid in Perrigo, Actavis & Lupin case & other patent valid & infringed in cross appeal by Amneal.

This litigation relates to Abbreviated New Drug Applications filed by the defendants for generic equivalents of Eli Lilly’s Axiron® testosterone applicator. Eli Lilly, in turn, sued the defendants for patent infringement. After a nine-day bench trial, the district court issued a thorough, well-considered opinion over 200 pages long. Eli Lilly appeals the district court’s opinion that claim 20 of U.S. Patent No. 8,435,944 (the ’944 patent) is invalid for obviousness under 35 U.S.C. § 103. Claim 20 of the ’944 patent recites a transdermal delivery method of applying testosterone to the axilla of a patient. Amneal cross-appeals the district court’s opinion that claims 9 and 10 of U.S. Patent No. 8,807,861 (the ’861 patent) are (1) not invalid; and (2) infringed by Amneal’s applicator.

The ’944 Patent:

Federal circuit agreed with the district court that the prior art (e.g. the Aschkenasy ’268 publication and the Cutter 2000 and 2001 references) teach and suggest that applying testosterone to the axilla will increase a patient’s testosterone level with a reasonable expectation of success. Eli Lilly’s arguments against those references lack merit and/or are based on a misreading of the lower court’s opinion. Eli Lilly argued that the prior art teaches away from applying testosterone to the axilla due to concerns over causing an undesired elevated level of dihydrotestosterone (DHT); and the claimed method yielded unexpected results. As the district court noted, Eli Lilly’s teaching away theory rested on a position that the scrotal skin and the axilla have comparably high 5-alpha reductase activity, which can result in an elevated DHT level. But Lilly’s reference to support that assertion, Takayasu, did not include measurements from the scrotal area in its study. Thus, even if the prior art sought to avoid areas that had the same level of 5-alpha reductase activity as scrotal skin, Lilly did not present any evidence that the axilla and scrotal skin have comparably high activity. Thus, the district court correctly found, on this record, that the only teaching relating to DHT levels in the axilla was by Cutter, which reported a normal DHT level after application of testosterone to the axilla.

On unexpected results, Federal circuit held that Eli Lilly made no meaningful argument contesting the district court’s rejection of Lilly’s theory of unexpected results. On review, we see no error in the district court’s explanation that Lilly’s asserted ‘seven-fold increase’ in skin permeability was based on a flawed extrapolation of data reported in a prior art reference. In sum, the lower court correctly found that Lilly’s objective indicia lacked weight. As a result federal circuit uphold the district court’s judgment of invalidity.

The ’861 Patent:

Claims 9 and 10 of the ’861 patent are directed to an applicator with a “resiliently deformable wall” used to administer a testosterone solution to the axilla. Federal circuit detected no error in the district court’s conclusions that the claims, as construed, are not invalid over the asserted prior art (e.g. Gueret ’187 and Gueret ’986) and were infringed by Amneal’s applicator. As to Amneal’s argument that its applicator does not infringe because it does not deform in a “blade-like manner,” the phrase “blade-like manner” appears nowhere in the claims and appears only in the context of a specific embodiment in the specification. Thus, federal circuit agreed with the district court that the claims require only that the applicator wall be “resiliently deformable” and do not require a specific mode of resilient deformation.

Federal circuit finally considering entire appellant’s and cross-appellant’s other arguments affirmed the district court's decision.

Teduglutide - USA

On Nov 15, 2017, Court of appeal for the federal circuit in a non-precedential opinion affirmed the decision of paten trial & appellate board (PTAB) which found formulation patent of Teduglutide (Gattex) invalid. Previously PTAB found NPS pharmaceutical’s U.S. Patent Number 7,056,886 invalid under obviousness in two IPR proceedings (IPR2015-00990 & IPR2015-01093).

US’886 claims GLP-2 (teduglutide) composition with histidine, phosphate buffer &  mannitol /sucrose. PTAB in its decision held that use of histidine & mannitol was well known in protein formulation and experimentation needed to confirm successful application with GLP-2 analog was nothing more than routine practice.

Treprostinil - USA

On Nov 14, 2017, Court of appeal for the federal circuit in a non-precedential opinion affirmed the decision of paten trial & appellate board (PTAB) which found product by process patent of Treprostinil (Remodulin) invalid. In Mar 2017, PTAB found UTC’s U.S. Patent Number 8,497,393 invalid for lack of novelty and obviousness in IPR proceeding (IPR2016-00006) filed by SteadyMed.

PTAB in its decision on novelty held that US’393 patent claims are product by process claims and prior art “Phares” discloses every element of the claims. UTC argued that prior art compound and instant compound are different in terms of purity. However, PTAB held that compound was known and process claims do not add any significant structural or functional characteristics to the claims. Moreover, difference in impurity is because of other factors such as time, solvent used during process of preparation. Therefore, Treprostinil was disclosed in prior art & process steps do not confer novelty to the claims. Hence, claims lack novelty over prior art.

With respect to obviousness, PTAB held that it was obvious to modify “Moriarty” prior art which discloses steps a & b of US’393 patent in view of “Phares” which discloses step c.  Person skilled in that art would have motivated to do so with reasonable expectation of success because by adding ethanolamine to tresprostinil one would eliminate the unnecessary step of purification.

Lacosamide - UK

On Nov 07, 2017, England and Wales High Court (Patents Court) rejected Accord’s invalidity argument & found Lacosamde compound patent valid.

The patent in suit is EP (UK) 0888289, which covers an anti-epileptic drug called lacosamide. The patent expired on 18th March 2017.  There is a supplementary protection certificate (SPC/GB09/007) which extends protection for lacosamide until 2022. Accord contended that the patent is invalid on two grounds viz. lack of priority & obviousness.

With respect to lack of priority, Accord challenged the patentee’s legal entitlement to claim priority from the 1996 priority document.  Accord contended that the assignment of 4^th February 1997 from Prof. Kohn (inventor) to RCT (patent holder) only took effect as an assignment of the bare legal title to the invention and priority claim.  What it did not do was assign the equitable or beneficial title to that property to RCT.  Court after analysing the relevant case laws held that all the indications available to RCT were that the university was aware of what was going on and that Professor Kohn was executing the assignment because he was obliged to do so pursuant to his obligations to the university.  Those indications do not only derive from Professor Kohn but also from the university itself. Court found that on 4^th February 1997 RCT was not on notice of any possible conflicting interest held by the university.  Therefore, RCT acquired good title to the invention including any priority right. 

Accord’s second challenge was on obviousness.  It was based on the state of the art before the priority date, which included a number of papers and other publications from Prof Kohn’s group relating to their work on anticonvulsant compounds.  Accord relies on mainly master’s thesis by a student called Philipe Le Gall. It is entitled 2-Substituted-2-acetamido-N-benzylacetamides Synthesis. Accord argued that given the Le Gall thesis in 1996, the first thing the skilled team would do is a literature search & identification few lead compounds such as LY274959. Court however disagreed & held that the skilled team would not predict that an aliphatic compound mentioned in arts would have good activity. That was because so much of the data related to aromatic rather than aliphatic compounds. Court finally held that putting it all another way, there are just too many uncertainties to justify a finding of obviousness.  Even if the team got as far as deciding to make and test lead compound they would know that the uncertainties meant that either outcome, good or bad, could just as easily be rationalised after the event as the other.  That is not a fair prospect of success.

Ribavirin - Netherlands

On Nov 03, 2017, Supreme Court of the Netherlands reversed the decision of Hague Court of Justice & found Teva’s label indirectly infringing the second medical use patent in Ribavirin case.

MSD is the holder of European Patent EP0956861. Claim 1 relates to use of ribavirin for the preparation of a pharmaceutical composition for the treatment of a patient with chronic hepatitis C infection, together with an active amount of alpha interferon wherein the subject is an anti-viral treatment naive patient with an HCV genotype 1 infection. MSD releases capsules and tablets according to EP’861 on the market under the trade names 'Rebetol' and 'Copegus', respectively. In June or October 2011, Teva introduced its generic ribavirin tablets on the Dutch market. MSD sought declaration of right that Teva generic products fall within the scope of EP 861, and claimed damages for state or profit. Teva counterclaimed in reconciliation (among other things) a declaration of non-infringement of the Dutch part of EP 861, and subject to the assumption of infringement, the destruction of the patent for the Dutch part.

Lower court held that Teva does not infringe the Dutch part of EP 861 as no acts of Teva fall within the scope of the claimed Swiss-type claims. Teva has adequately managed to ensure that it is out of scope for the Swiss-type claims of the patent by a so-called 'carve-out'. Teva has excluded the MSD-claimed patient category (naive and genotype 1 infection). That is enough to fall outside the scope of the patent. Based on the mentioned SmPCs and leaflets, therefore, there is no direct or indirect patent infringement by Teva, whether or not doctors or pharmacists prescribe Teva’s generic ribavirin (treatment of the G1N subgroup) and whether naive genotype 1 patients use that drug. In its action against unlawful action, MSD has not found any other facts than its claims for direct and indirect patent infringement. Merck appealed.

Supreme Court assumed that indirect infringement of a Swiss-type claim is conceivable. According to Art. 73 if a person offers or supplies resources for the use of the patented invention in or for his business, provided that person knows or is aware of the circumstances are clear that those means for that application are appropriate and intended. Court finally held that the manufacturer of a generic drug may indirectly infringe a patent for a second medical indication, namely if he offers or supplies the medicine to persons not entitled to use the invention and he know whether it is clear to him that the medicine is suitable and will be used for the patented second medical indication. Thus Supreme Court reversed the decision of Hague Court of Justice & referred the case for further consideration & decision.

Dronedarone – USA

On Nov 09, 2017, Court of Appeal for Federal Circuit affirmed the district court’s judgment of infringement & validity of two patents against Watson & Sandoz in Multaq (Dornedarone) case.

Sanofi owns U.S. Patent Nos. 8,318,800 and 8,410,167, which describe and claim compositions and uses of the cardiovascular (specifically, antiarrhythmic) drug dronedarone. The ’800 patent, which expires in 2019, claims pharmaceutical compositions containing dronedarone. The ’167 patent, which expires in 2029, claims methods of reducing hospitalization by administering dronedarone to patients having specified characteristics. After a three-day bench trial, the district court ruled that Watson’s and Sandoz’s sale of their proposed generic drugs, with their proposed labels, would induce physicians to infringe asserted claims and they did not prove that any of the asserted claims were invalid for obviousness. Watson and Sandoz appealed.

Federal circuit reviewed the district court’s finding of inducement based on encouragement and inferred intent for clear error. Federal circuit did not find error. It held that the reference to the Clinical Studies section (14) of the label expressly directs the reader to that section for elaboration of the class of patients for whom the drug is indicated to achieve the stated objective, i.e., reduced hospitalization. Section 14 leads with and features a subsection on the ATHENA study, which sets forth the positive results, relating to reduced hospitalization, for patients having the risk factors. There was considerable testimony that this label encourages—and would be known by Watson and Sandoz to encourage—administration of the drug to those patients, thereby causing infringement.

With respect to obviousness, Watson and Sandoz initially argued that the district court committed legal error by applying too high a standard for proving a reasonable expectation of success. Federal circuit however disagreed. Federal circuit held that Watson and Sandoz did not carry their burden of showing that a person of ordinary skill in the art in February 2008 would have had a reasonable expectation that dronedarone would succeed in reducing cardiovascular hospitalization in the ATHENA patient population.

Budesonide - USA

On Oct. 27, 2017, Chief Judge Leonard P. Stark of district of Delaware issued an order granting Defendants' (Teva & Alvogen) motions for judgment of non-infringement of the US 8,784,888 patent in Uceris (Budesonide ER tablet) case. Claim 1 of US’888 patent reads:

“A controlled release oral pharmaceutical composition consisting essentially of: (1) a tablet core consisting essentially of: a) budesonide in an amount effective to treat intestinal inflammatory disease; and b) a macroscopically homogeneous composition comprising at least one lipophilic excipient, at least one amphiphilic excipient, and at least one hydrogel-forming hydrophilic excipient other than a gum, wherein said budesonide is dispersed in said macroscopically homogeneous composition; and (2) a coating on said tablet core, said coating consisting essentially of a gastro-resistant film”.

Cosmo filed suit against Actavis/ Teva and Alvogen in February 2015, after the companies sent notice with P-IV certification that their products would not infringe US’888 patent & other patents. Plaintiffs at one time asserted a number of patents and decided to drop patents at various stages of this litigation. Bench trial was completed on May 23, 2017. Court found that Plaintiffs did not meet the threshold to establish infringement. As the opinion was sealed, the court asked parties to sort out the final judgment, including other stipulations and orders about the other patents. Thereafter, the Court will issue a public version of its Memorandum Opinion.

Tadalafil - UK

On Nov. 01, 2017, the England and Wales Court of Appeal issued a decision in CIALIS (tadalafil) case & found that the patent for treatment of male erectile dysfunction is invalid for obviousness.

The patent, EP (UK) 1,173,181 relates to the use of tadalafil in a dosage form and is entitled "Compositions comprising phosphodiesterase inhibitors for the treatment of sexual dysfunction". The claimants, Actavis, Teva and Mylan, began these proceedings to revoke the EP’181 patent on various grounds and so clear the way for the marketing of their own products. Birss J handed down judgment on Aug 10, 2016 ([2016] EWHC 1955 (Pat)) where he found that patent is valid & infringed by claimants. Claimant appealed.

Three claims were at issue, namely claims 1, 7 and 10. Claims relate to pharmaceutical unit dosage composition comprising 1 to 5mg of tadalafil wherein maximum total daily dose is 5 mg per day for treatment sexual dysfunction. Critical issues before the court of appeal were whether the subject matter of each of claims 7 and 10 was derivable directly and unambiguously, using common general knowledge from the priority document & whether there was enablement. Court of appeal held that skilled person would not have had any difficulty making the compositions the subject of claims 7 and 10 based on disclosure of the priority document. With respect to added matter & novelty court of appeal agreed with Judge Birss J and held that patent is novel & there is no added matter.

Obviousness:

Primary reference, Daugan teaches the use of PDE5 inhibitors for the treatment of ED. Tadalafil (compound A) is specifically disclosed, its IC50 against PDE5 is given and examples of a tablet containing a 50mg dose are described. It explains that doses of tadalafil will generally be in the range of from 0.5 to 800mg daily for the average adult patient.  The differences between the disclosure of Daugan and the subject matter of claims 7 and 10 are that Daugan does not specifically disclose a 5mg daily dose of tadalafil or that such a dose is an effective treatment for sexual dysfunction.

Court held that at the start of the programme and given Daugan, the skilled team would have had no idea whether or not a 5mg daily dose of tadalafil would be a safe, tolerable and effective treatment of sexual dysfunction, still less that it would be both efficacious and have minimal PDE5 related side effects. Summarizing the position in relation to the skilled team's expectations, Judge Bliss J found that they would not have a reasonable expectation that a dose of 5mg per day (on demand) would provide a useful treatment for ED, nor any expectation at all that this would produce a clinically relevant effect but with minimal side effects. However, they would discover that this dose is both effective and has reduced side effects and this would be a surprise.

Court of appeal overturning the decision held that the claimed invention lies at the end of the familiar path through the routine pre-clinical and clinical trials' process. The skilled but non-inventive team would embark on that process with a reasonable expectation of success and in the course of it they would carry out Phase IIb dose ranging studies with the aim of finding out, among other things, the dose response relationship. It is very likely that in so doing they would test a dose of 5mg tadalafil per day and, if they did so, they would find that it is safe and efficacious. At that point they would have arrived at the claimed invention. Therefore claims 7 and 10 of EP’181 are invalid.

Pemetrexed - Europe

The dispute all over Europe is basically related to Eli Lilly’s European patent EP1313508 B1 (“EP ‘508”) entitled “Combination containing an antifolate and methylmalonic acid lowering agent”.  The EP’508 patent protects the drug marketed by Eli Lilly under brand name “ALIMTA” (Pemetrexed disodium). Generic filers have sought declaration of non-infringement with respect to their product which utilizes salt other than disodium.

Herein below is the quick snapshot of recent proceedings/decisions in major countries across Europe.

Netherlands: By judgment of 24 October 2017, the PI judge of District Court of the Hague held that Fresenius and Teva’s  generic drug with pemetrexed diacid infringes EP’508 patent.

Switzerland: By judgment of 20 October 2017, The Swiss Federal Supreme court overturned the previous declaratory judgment of non-infringement of the Swiss Federal Patent Court and found Actavis’ generic pemetrexed diacid product, Amtiris, to directly infringe Eli Lilly’s patent E’508.

Italy: By judgment of 10 September 2017, The Milan court ruled that Fresenius, with its pemetrexed product, does not infringe EP’508.

United Kingdom:  By judgment of 12 July 2017, The UK Supreme Court has ruled that the scope of EP’508 patent extends to other salts than pemetrexed disodium, so that the pemetrexed products mentioned by Actavis directly infringes EP’508.

Germany: By judgment of 14 June 2016, The Federal Court of Justice (Bundesgerichtshof – BGH) referred the case back to the Oberlandesgericht Düsseldorf, since BGH held that the Oberlandesgericht (which found non-infringement of pemetrexed dipotassium) had not properly applied the German equivalent theory. The case is pending before Oberlandesgericht Düsseldorf court.

Portugal, Sweden and Finland:  Lilly and Actavis also have procedures in Portugal, Sweden and Finland. None of these matters have yet been decided.

Vardenafil – USA

On Nov. 01, 2017, Federal circuit reversed the Delaware court’s decision of non-obviousness in Staxyn® (Vardenafil) & found that Bayer’s patent is invalid as obvious handing a win to generics maker Teva (Actavis). Federal circuit held that Delaware federal judge “clearly erred” when he found that the patent was not invalid.

Watson Laboratories, Inc. appealed the District of Delaware’s final judgment holding Watson failed to prove by clear and convincing evidence that claims 9 and 11 of U.S. Patent No. 8,613,950 (“the ’950 patent”) would have been obvious. The US’950 patent is directed to a formulation of vardenafil “in the form of an uncoated tablet which disintegrates rapidly in the mouth comprising vardenafil hydrochloride trihydrate, and at least two sugar alcohols.” Two sugar alcohols are a mixture of sorbitol and mannitol.  The parties agree that claim 8’s requirement that the formulation “releases the drug in the mouth” means it is an immediate-release formulation.

The district court held a six-day bench trial to consider the validity of the ’950 patent. Watson argued the claimed formulation of vardenafil would have been obvious to a person of ordinary skill in the art based on multiple exemplary references showing a motivation to: (1) create an ODT formulation of vardenafil; (2) select mannitol and sorbitol as sugar alcohols; and (3) make the ODT formulation immediate-release. The district court rejected each of Watson’s arguments. It found a person of ordinary skill in the art would not have been motivated to create an ODT formulation of vardenafil and would not have used mannitol and sorbitol as excipients. It found the prior art taught away from formulating vardenafil ODT as immediate-release. The district court also addressed Bayer’s objective evidence of nonobviousness and found it supported its conclusion that Watson failed to prove by clear and convincing evidence that claims 9 and 11 would have been obvious. This determination rested largely on the court’s finding the testimony of Bayer’s expert, Dr. Wicks, more persuasive than the testimony of Watson’s expert, Dr. Jacobs.

Federal circuit on appeal said that the clear error in the district court fact finding that there was no motivation to formulate ED drugs in ODTs & that the record did not contain an indication that ED drugs would be good candidates for ODT formulations. Watson relied on nine prior art references to support its assertion that there would have been a motivation to create an ODT formulation of vardenafil. Dr. Jacobs testified that the Chang reference states “drugs for [ED] would be good candidates for ODT formulation.” He testified the Boolell and Fryburg references each disclose formulating vardenafil as an ODT. He testified that numerous companies had already begun formulating ODT versions of ED drugs: Pfizer filed the Bell-Huff patent application directed to sildenafil ODT; Eisai filed the Furitsu patent application claiming an ODT formulation of phosphodiesterase inhibitors; and Lavipharm filed the Chen international patent application, identifying ODT versions of sildenafil. These six references—Chang, Boolell, Fryburg, BellHuff, Furitsu, and Chen—are absent from the district court’s decision. These references are highly relevant to whether a person of ordinary skill in the art would have been motivated to formulate ODT vardenafil. And their express disclosures cause the district court fact finding regarding motivation to combine to be clear error.

Bayer argued that Watson’s arguments concerning many of its references, such as Chang, Boolell, and Fryburg, were insignificant and the district court did not clearly err by failing to address them. It argued that while Watson asserted on appeal that the district court ignored its key prior art, Watson flooded the district court with references without adequately addressing them. Federal circuit however disagreed. Court held that while it may at times be unwise for a party to rely on numerous prior art references when challenging a patent on obviousness grounds, Watson’s approach were not untenable here. Watson produced these nine references to support a narrow point: they each “disclosed formulating vardenafil and other approved ED drugs into ODTs.” Also Dr. Wicks’ testimony does not cast doubt on the weight of Watson’s evidence regarding the vardenafil ODT limitation. Many of the references Watson relied on for this limitation were unchallenged by Dr. Wicks. Therefore the district court’s finding that ODTs were not considered applicable to ED drugs is clearly erroneous in light of Watson’s evidence.

The remainder of the district court’s findings underlying the motivation to formulate vardenafil ODT focused too heavily on the commercial availability of ODT formulations of ED drugs as of the ’950 patent’s priority date. It is unclear why the district court found it important that no ODT ED drug had gained FDA approval as of ’950 patent’s priority date. The motivation to combine inquiry is not limited to what products are forthcoming or currently available on the market. Particularly given the lengthy FDA approval process, the pharmaceutical industry is no exception. Any motivation, “whether articulated in the references themselves or supported by evidence of the knowledge of a skilled artisan, is sufficient.” Here, the motivation to formulate an ODT version of vardenafil is plainly evident from the face of multiple prior art references disclosing ODT formulations of ED drugs. No further rationale for developing vardenafil ODT was necessary. Therefore here also district court clearly erred when it found there would not have been a motivation to formulate vardenafil ODT.

With respect to combination of mannitol & sorbitol in a formulation District court found Dr. Wicks’ testimony persuasive that “every ODT on the market in the relevant prior art time frame contained only a single sugar alcohol: mannitol,” and that “there were no known problems with the use of mannitol in the existing ODTs.” It found “there was nothing in the prior art that would have given the [person of ordinary skill in the art] a reason to use sorbitol in addition to mannitol in an ODT. Federal circuit held that we do not question the district court’s credibility determinations. However, the district court’s analysis for the sorbitol and mannitol limitation again focused on the commercial availability of products while failing to address relevant prior art. Upon consideration of the entire record and under a proper analysis, we conclude that the district court clearly erred in finding a person of ordinary skill in the art would not have been motivated to formulate an ODT with sorbitol and mannitol.

Federal circuit further held that the district court did not clearly err in its fact finding that a person of ordinary skill in the art would have had concerns using an immediate-release formulation due to vardenafil’s expected bitter taste and bioavailability; however, it clearly erred when it concluded that those findings taught away from the immediate release. The fact that there may be reasons a skilled artisan would prefer one over the other does not amount to a teaching away from the lesser preferred but still workable option. The district court’s finding that a person of ordinary skill in the art would have first pursued a delayed-release formulation over an immediate-release formulation is insufficient to support a finding of teaching away.

Federal circuit held that Bayer presented evidence of copying and unexpected results that weigh in favor of a conclusion of nonobviousness. But weighing all four Graham factors, court concluded that claims 9 and 11 of the ’950 patent would have been obvious & reversed the district court’s holding.