Ivermectin - USA

Claim Construction (District of Delaware): Oct 22, 2019

Presently before the Court is the issue of claim construction of a term in U.S. Patent No. 10,206,939 ("the '939 patent"). The patent relates to methods and compositions for topical treatment of rosacea with ivermectin. The parties dispute a term recited in claims 8, 9, 20, 21, and 22 of the '939 patent.

CONSTRUCTION OF DISPUTED TERMS:

1. "wherein the subject has no adverse reaction, [wherein/and] the adverse reaction is skin burning sensation or skin irritation"

a. Plaintiffs' proposed construction: "wherein the treatment results in a low incidence of skin burning sensation or skin irritation"

b. Defendant 's proposed construction: "wherein the pharmaceutical composition is well tolerated with a low incidence of skin burning sensation or skin irritation"

c. Court 's construction: "wherein the treatment results in a low incidence of skin burning sensation or skin irritation"

Diclofenac - USA

On Oct 10, 2019, Federal Circuit affirmed district court’s decision which prohibited Actavis from marketing generic version of PENNSAID 2% till Oct 2027.

Horizon is the assignee of U.S. Patent Nos. 8,217,078; 9,132,110; 8,618,164; 8,546,450 (method of use patents); and US 9,168,304; 9,168,305; 9,101,591; 8,563,613; 9,220,784; 8,871,809; 8,252,838; 9,066,913 (formulation patents). These patents are listed in orange book for PEENSAID 2% (diclofenac topical solution). It is used for trating knee pain. Actavis sought to market a generic version of PENNSAID 2% and filed ANDA.Horizon then sued Actavis in New Jersey court.

Claim 10 of the ’450 patent is illustrative of the asserted claims of the method-of-use patents:

10. A method for applying topical agents to a knee of a patient with pain, said method comprising: applying a first medication consisting of a topical diclofenac preparation to an area of the knee of said patient to treat osteoarthritis of the knee of said patient, wherein the topical diclofenac preparation comprises a therapeutically effective amount of a diclofenac salt and 40–50% w/w dimethyl sulfoxide; waiting for the treated area to dry; subsequently applying a sunscreen, or an insect repellant to said treated area after said treated area is dry, wherein said step of applying a first medication does not enhance the systemic absorption of the subsequently applied sunscreen, or insect repellant; and wherein said subsequent application occurs during a course of treatment of said patient with said topical diclofenac preparation.

Claim 49 of the ’838 patent is illustrative of the asserted claims of the formulation patents:

49. A topical formulation consisting essentially of: 1–2% w/w diclofenac sodium; 40–50% w/w DMSO; 23–29% w/w ethanol; 10–12% w/w propylene glycol; hydroxypropyl cellulose; and water to make 100% w/w, wherein the topical formulation has a viscosity of 500–5000 centipoise.

New Jersey court in its deciosn found certain terms indefinite, noninfingement with respect to ANDA label & finally nonobviouness of particular claim. Horizon appealed and Actavis cross-appealed the district court’s final judgment.

I Claim construction:

During claim construction, the district court found that the term “the topical formulation produces less than 0.1% “impurity A” after 6 months at 25°C and 60% humidity” was indefinite the identity of “impurity A” is unknowable to a person of ordinary skill in the art (“POSITA”). Second, the district court found that the term “the formulation “degrades” by less than 1% over 6 months” was indefinite because neither the claims nor the specification disclose the means to evaluate degradation. Third, the district court found that the term “consisting essentially of” was indefinite.

Upon appeal, Federal Circuit with respect to term “impurity A” agreed with district coiurt & said that POSITA would not know, with reasonable certainty, the identity of the substance as claimed. The term “impurity A” only appears in claim 4 and Example 6 of the ’913 patent. Court daid that Horizon does not cite to any part of the specification, the claims, or the prosecution history that defines or directly connects “impurity A” to USP Compound A which Horizon attemped to connect. Because the specification omits the details of the HPLC experiment—such as the column, the mobile phase, and the flow rate—a POSITA faced with this specification would not reasonably presume that Example 6 was undertaken using a pharmacopoeia chromatographic system. This outcome undermines Horizon’s reliance on the pharmacopoeias to extrapolate meaning into “impurity A.”

With respect to “degrades” term, federal circuit said that district court’s finding that the claims reciting the “degrades” term are indefinite follows from the indefiniteness determination about “impurity A.” Since “impurity A” is indefinite, it logically follows that another term, such as the “degrades” term, which relies on “impurity A” for its construction, must also be indefinite.

With respect to “Consisting Essentially Of” term, federal circuit said that district court properly considered this term in accordance with legal meaning: “consisting of only the specified materials and those that do not materially affect the basic and novel properties of the claimed invention.” Parties’ dispute focuses on the basic and novel properties of the formulation patents. Court said that the specification of the formulation patents identified five basic and novel properties: (1) better drying time; (2) higher viscosity; (3) increased transdermal flux; (4) greater pharmacokinetic absorption; and (5) favorable stability.

Horizon argues that the Nautilus definiteness standard focuses on the claims and therefore does not apply to the basic and novel properties of the invention. Court further said that Supreme court’s Nautilus definiteness standard applies to the basic and novel properties of an invention. Because by using the phrase “consisting essentially of” in the claims, the inventor in this case incorporated into the scope of the claims an evaluation of the basic and novel properties. Having determined that the basic and novel properties of an invention are part of the scope of the claims in this case, it follows that those basic and novel properties, “when read in light of the specification and the prosecution history, must provide objective boundaries for those of skill in the art.” Now with respect to drying time, court found that the two different methods for evaluating “better drying time” do not provide consistent results at consistent times. Court also found persuasive the testimony of Actavis’s expert that a POSITA would not know under what standard to evaluate the drying rate. Therefore, court concluded that the phrase “consisting essentially of” was indefinite based on its finding that the basic and novel property of “better drying time” was indefinite on this record.

II. Summary Judgment of non-infringement:

On January 27, 2017, after the district court reaffirmed its claim constructions and related indefiniteness determinations, Actavis filed a motion for summary judgment of noninfringement. Actavis argued that there was no dispute that Actavis did not directly infringe the patents-atissue, and that, while Horizon premised its allegations of induced infringement upon the labeling of Actavis’s ANDA product.

Court said that Actavis’s ANDA product, diclofenac sodium topical solution 2%, is a generic version of Horizon’s PENNSAID®2%. Both products are directed to the treatment of osteoarthritis pain on the knees.

Main disputed part of the label was following warning portion which states:

“Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution”.

Court evaluated Actavis’s label vis-à-vis the claims of the method-of-use patents and noted that the dispute between the parties centered around the warning in Actavis’s label to wait until the treated area is dry before covering it or applying another substance.  Although Horizon recognizes that not every user will need to apply sunscreen, insect repellant, or another topical medication, it contends that, when such need arises, Actavis’s instruction will lead to an infringing use.  Actavis argues that its proposed label does not induce infringement because, unlike the method-of-use patents, its label does not promote the application of a second topical agent after application of the diclofenac sodium gel. Actavis maintains that its label never affirmatively instructs the patient to apply anything after the diclofenac sodium gel; the label merely permits applying a second topical agent after the patient waits for the diclofenac sodium to dry. Its label, therefore, does not contain any instruction that induces infringement.

Court said that the patented method here requires three distinct steps. The user must: (1) apply the inventive formulation, (2) wait for the area to dry, and (3) apply sunscreen, insect repellant, or a second topical medication. The instructions in Actavis’s label, however, only require the first step of this method, nothing else. The warning, then, operates in an “if/then” manner: if the user wants to cover the treated area with clothing or apply another substance over it, then the patient should wait until the area is dry. This does not encourage infringement, particularly where the label does not require subsequent application of sunscreen, insect repellant, or a second medication. Court thus held that “Actavis’s proposed label does [no] more than simply permit, rather than require or direct, the post-product application of sunscreen, insect repellant, or a second topical medication.”  The fact that Actavis’s label does not require subsequent application of other products reflects that the product has “substantial noninfringing uses, [and] intent to induce infringement cannot be inferred even [if Actavis] has actual knowledge that some users of its product may be infringing the patent.”

III. Trial on obviousness:

The district court’s Markman and summary-judgment orders disposed of most of the asserted claims of the patents-at-issue. At trial, only one claim remained—claim 12 of the ’913 patent. Actavis maintained that claim 12 of the ’913 patent was invalid as obvious. Actavis stipulated that if the claim was found not invalid at trial, its ANDA product would infringe the claim. On May 12, 2017, the district court found that Actavis had not shown, by clear and convincing evidence, that claim 12 of the ’913 patent is invalid for obviousness.

During appeal, Actavis argued that the district court erred by requiring that the prior art predict the exact formulation of the asserted claim. For obviousness arguments Actavis relied on previous formulation i.e. PENNSAID 1.5% which differes qualitatively with respect to HPC & quantitatively  with respect to certain excipients when compared to PENNSAID 2%. Federal Circuit sided with district court which credited Horizon’s expert’s (Dr. Bunge’s) testimony that the inventive formulation was complex and that a POSITA would be challenged to predict relative ratios in order to achieve the desired goal of PENNSAID® 2%. Court also found that the combination of changes to the PENNSAID® 1.5% formulation were not obvious optimizations of result-effective “variables that would produce a predictable result, particularly as to the formulation’s absorption, thickness, and drying time.” Court also found that the variables involved in this case, including the components of the inventive formulation, interact in an unpredictable or unexpected way, such that the results emanating into PENNSAID® 2% were not obvious. Court found that nothing in the prior art allowed a POSITA to find “the schematic or roadmap to a diclofenac gel effective at two doses a day compared to prior art’s four doses a day.” Court thus held that claim 12 of the ’913 patent was nonobvious.

Doxycycline - USA

On Oct 04, 2019 (unsealed opinion), Delaware court found infringement of formulation patents & rejected Sun’s argument that the patents were obvious.

Galderma sued Sun pharma over Oracea® Capsules patents, US 8,206,740; US 8,394,405; US 8,470,364 and US 7,749,532. Sun seeks to bring to market a new drug (NDA) which is bioequivalent to Galderma's Oracea Capsules, a once-daily 40mg administration of doxycycline for the treatment of the papules and pustules of acne rosacea. In December 2018, the Court held a three-day bench trial. At trial, Galderma asserted infringement of claim 1 of the '740 patent, claims 1 and 3 of the '405 patent, and claims 1 and 2 of the '364 patent.

Claim 1 of the '740 patent recites:

An oral pharmaceutical composition of doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum ofO.l ~g/ml and a maximum of 1.0 ~g/ml, the composition consisting of (i) an immediate release (IR) portion comprising 30 mg doxycycline; (ii) a delayed release (DR) portion comprising 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.

Claim 1 of the '405 patent recites:

An oral pharmaceutical composition comprising about 40 mg of total doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 J.Lg/ml and a maximum of 1.0 J.Lg/ml, wherein the composition consists of 70 to 80 percent of the doxycycline formulated as an immediate release (IR) formulation and 20 to 30 percent of the doxycycline formulated as a delayed release (DR) formulation.

Claim 1 of the '364 patent recites:

An oral pharmaceutical composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; a delayed release formulation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.

Claim 2 of the '3 64 patent recites:

An oral pharmaceutical composition comprising doxycycline, which at a once-daily dosage will give blood levels of the doxycycline of a minimum of 0.1 J.Lg/ml and a maximum of 1.0 J.Lg/ml, the composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; as [sic] a delayed release formulation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.

Sun's NDA Product is a once-daily doxycycline bilayer tablet consisting of two distinct layers as an immediate release ("IR") layer and a modified release ("MR") layer, each of which contains doxycycline. IR layer contains 26.4 mg of doxycycline & releases all 26.4 mg of its doxycycline immediately upon administration without any enhanced, delayed, or extended effect. MR layer contains 13.6 mg of doxycycline out of which 3.6 mg doxycycline get released in the first 30 minutes after administration, and remaining 10 mg doxycycline releases later than 30 minutes after administration. This dual release from MR layer is because of use of two hypromellose polymers.

Main dispute was regarding "IR Portion" and "DR Portion". The parties agreed at trial that "immediate release" (IR ), as defined in the patents, is "a dosage form that is intended to release substantially all of the active ingredient on administration with no enhanced, delayed, or extended release effect." Court construed "delayed release" (DR) to mean "release of a drug at a time other than immediately following oral administration." The case was tried without any specific construction of "portion" as the parties agreed throughout trial (and even for some time after trial) that the term would be given its "plain and ordinary meaning."

Galderma contends that the "immediate release portion" limitations are met by the combination of: (1) the Sun NDA Product's IR layer; and (2) the part of the Sun NDA Product's MR layer that dissolves in the first 30 minutes after administration. Under Galderma's theory, the Sun NDA Product's IR portion, therefore, has about 30 mg of doxycycline, consisting of: (1) the entire 26.4 mg of doxycycline in the IR layer, and (2) the about 3.6 mg of doxycycline that is released from the MR layer in the first 30 minutes after administration. Similarly, on Galderma's view, the "delayed release" portion of Sun's NDA Product is the remaining 10 mg of doxycycline- all from the MR layer- which is released following the first 30 minutes after administration.

Sun counters that its NDA Product's "immediate release portion" includes only the 26.4 mg of doxycycline in the IR layer. Thus, because the IR layer has less than the about 30 mg of doxycycline claimed by the patents, Sun's view is that its NDA Product does not meet the IR portion limitations. Sun contends that its NDA Product also does not meet the "delayed release portion" limitations, for two reasons: (1) the MR layer is not "delayed release" because it releases doxycycline starting immediately after administration and the amount of doxycycline released "continuously increases over time, with no plateau or stoppage of release" and (2) even if the MR layer were a "delayed release portion," the MR layer has 13.6 mg of doxycycline, which is greater than the about 10 mg of doxycycline required by the claims.

After careful review, the Court concluded that the parties' dispute over whether the IR portion and DR portion limitations are met by Sun's NDA Product turns on the meaning of "portion." If "portion" is a functional term - such that the "IR portion" limitation is satisfied if a formulation dissolves in a manner in which 30 mg (or about 30 mg) of doxycycline is released immediately after oral administration, regardless of where in the product that doxycycline comes from- then the Sun NDA Product infringes. If, alternatively, "portion" is a structural term - such that each part of an accused product must be analyzed for its structure and then characterized as either an IR or DR structure - then the Sun NDA Product does not infringe.

In this case parties never asked the Court to construe the disputed claim term, “potion”. This is because in previous Amneal case, court issued claim construction where "portion" had its "plain and ordinary meaning”.  In present case it became apparent when Court reviewed the parties' post-trial briefs.  It was only during closing argument, which the Court heard on the last day of trial, that it began to appear as if Sun was, in fact, seeking additional claim construction. Throughout the case the understanding of portion was like plain and ordinary meaning.  Court said that it is now clear, has always been Sun- that has desired for the Court to modify its understanding of what constitutes a DR portion (as well as an IR portion). Therefore, it was incumbent on Sun somehow to have asked the Court to alter its understanding of the scope of the asserted claims by construing the portion terms. Sun has now done so, but it is far too late.

Nevertheless, court said that it will,  address the claim construction dispute and apply this construction to the evidence presented at trial. With respect to claim language, court said that it supports Galderma’s position. The absence of an explicit structural requirement in the asserted claims suggests that the inventors intended "portion" by itself not to impose a structural requirement. With respect to specification, court said that it too does not provide strong support for either side's proposed construction. The term "portion" is used four times in the specification and none of those uses indicates that the term is being used in a restrictive or narrowing manner. Nothing in this usage of "portion" indicates that the patent is using the term to refer to a physically or structurally discrete part of the composition. Prosecution History and Amneal IPR supports Sun's proposed construction. But court said that for purposes of determining the proper construction of the "portion" terms to apply in the instant litigation, the IPR provides some limited- but not dispositive, and, ultimately, not sufficiently persuasive- support for Sun's proposed construction. Court also looked into extrinsic evidences & said that the definitions provide support for Galderma's proposed constructions and none for Sun's, as they do not suggest that "portion," in general usage, is narrowly limited to structurally discrete parts. Hence, court concluded that that a POSA would understand the "portion" terms to have a broad, functional meaning, rather than a narrow, structural meaning.

Court therefore held that under this construction Sun's NDA Product satisfies immediate release & delayed release portion limitations of claim. Moreover, Sun has not proven by clear and convincing evidence that the asserted claims of the patents are invalid due to obviousness.

Erlotinib - USA

On Oct 04, 2019, Federal Circuit reversed PTAB’s decision & found method of treatment claims valid in Tarceva® case.

This appeal concerns OSI’s patents, U.S6,900,221. Specifically Claims 44–46 and 53 are at issue.

44. A method for the treatment of NSCLC (non small cell lung cancer), pediatric malignancies, cervical and other tumors caused or promoted by human papilloma virus (H[P]V), Barrett's esophagus (pre-malignant syndrome), or neoplastic cutaneous diseases in a mammal comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprised of at least one of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, or pharmaceutically acceptable salts thereof in anhydrous or hydrate forms, and a carrier.

45. The method of claim 44, wherein the treatment further comprises a palliative or neo-adjuvant/adjuvant monotherapy.

46. The method of claim 44, wherein the treatment further comprises blocking epidermal growth factor receptors (EGFR).

53. The method of claim 44 for the treatment of non-small cell lung cancer (NSCLC).

PTAB determined that  these claims would have been obvious over Schnur in view of Gibbs or OSI’s 10-K.

Schnur – relates to compound family where erlotinib is listed as preferred compound. It also discloses that these compounds inhibits EGFR receptors & therefore useful for treatment of various cancers including lung cancer.

Gibbs  - is review article & discusse s various signaling mechanisms in the cell and how they are associated with tumor malignancy. This article discusses generally EGFR as one of the target & erlotinib is one of those compounds. Cross reference 13 refers to Moyer, which discloses how erlotinib inhibits EGFR in mouse liver tumors and in human HN5 tumors. Moyer however, does not discuss NSCLC.

OSI’s 10-K  - states that erlotinib has entered phase II trials & is potent inhibitor of EGFR receptor. OSI’s 10-K discloses no data regarding erlotinib’s effect on NSCLC.

The Board found that the disclosures in OSI’s 10-K that erlotinib targeted a variety of cancers including NSCLC, and that erlotinib had entered Phase II clinical trials, would have provided a person of ordinary skill with a reasonable expectation of success in light of Schnur’s teachings. Although nothing in the record indicated that any preclinical data related to NSCLC existed, the Board concluded that an ordinary artisan would understand from the commencement of Phase I studies that “preclinical animal efficacy data” had been submitted to the FDA. It found similarly with regard to Gibbs, focusing on Gibbs’s disclosure that “[ZD-1839 and erlotinib] appear to have good anti-cancer activity in preclinical models, with an acceptable therapeutic index particularly in patients with non-small cell lung cancer.”

Federal Circuit on appeal said that as an initial matter, in reaching its conclusion, the Board misinterpreted the asserted references to teach more than substantial evidence supports. When the references are properly read, the Board’s finding that the asserted references provide a reasonable expectation of success also is not supported by substantial evidence. To be clear, the claims require only treatment of a mammal with erlotinib—efficacy in humans is not required. But the asserted references do not disclose any data or other information about erlotinib’s efficacy in treating NSCLC. The record does not contain any clinical (human) data or preclinical (animal) data. It does not even include in vitro (test tube) data regarding erlotinib’s effect on NSCLC. At the same time, it is undisputed that NSCLC treatment was highly unpredictable with an over 99.5% rate of failure for drugs entering Phase II clinical studies. On this record, we are not persuaded that a reasonable factfinder could conclude that a person of ordinary skill would have reasonably expected success based on the combination of Schnur and Gibbs or Schnur and OSI’s 10-K.

PTAB’s reading of Gibbs is erroneous because cross reference, Moyer discloses erlotinib but it does not disclose NSCLC. Instead other cross reference, Woodburn mentions NSCLC but it does not mention erlotinib at all. Thus, Board’s finding that there is a “clear inference” in Gibbs that “erlotinib has anti-cancer activity against non-small cell lung cancer” is thus not supported by substantial evidence.

With respect to reasonable expectation of success,CAFC concluded that, properly read, these combinations do not provide substantial evidence supporting the Board’s findings of reasonable expectation of success. Schnur in view of Gibbs, the asserted references do not disclose any information about erlotinib’s efficacy in treating NSCLC in a mammal. There is no dispute that Schnur fails to disclose any in vitro or in vivo efficacy data for erlotinib for NSCLC. The lack of erlotinib-NSCLC efficacy data or other indication of success here is significant because of the highly unpredictable nature of treating NSCLC, which is illustrated by the over 99.5% failure rate of drugs entering Phase II. Moreover, EGFR is involved in many types of cancers & therefore drug’s success in treating one type of cancer does not necessarily translate to success in treating a different type of cancer.

Federal Circuit, however cautioned & said that-

“To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring “absolute predictability of success.” We conclude only that, on these particular facts, a reasonable fact finder could not find a reasonable expectation of success. The Board’s finding is thus not supported by substantial evidence, and accordingly we reverse its obviousness determination.”