Thursday, May 14, 2020

Paliperidone - Canada


On May 05, 2020, Federal Court of Canada found dosage administration patent of INVEGA SUSTENNA valid & non-infringing with respect to certain claims.

In this litigation, Plaintiff (Janssen) sued Defendant (Teva) for filing Abbreviated New Drug Submission  (ANDS) with Health Canada to market generic version of INVEGA SUSTENNA.  Janssen is the owner of Canadian Patent No. 2,655,335 (US equivalent – US 9,439,906) which is titled, “Prolonged-Release Injectable Suspensions of Paliperidone Palmitate, and Dosage Forms and Delivery Systems Incorporating Same.” The invention relates to dosing regimens for long acting injectable paliperidone palmitate formulations for treatment of schizophrenia by administering two loading doses on day 1 (150 mg-eq) & day 8 (100 mg-eq) and then administering monthly maintenance dose (75 mg-eq) in deltoid or gluteal muscles with provided kit containing prefilled syringes.

CA’335 contains 63 claims, and Janssen alleges infringement of claims 1 to 48.

The Asserted Claims of the 335 Patent break down into three sets:

i. claims 1 to 16 relate to prefilled syringes adapted for administration according to the claimed dosing regimens;
ii. claims 17 to 32 relate to a use of a “dosage form” according to the claimed dosing regimens; and
iii. claims 33 to 48 relate to use of paliperidone as paliperidone palmitate in the manufacture/preparation of a “medicament” adapted for administration according to the claimed dosing regimen.

Obviousness:

Teva argued that inventive concept of the asserted claims is to provide  a dosing regimen for a depot formulation of paliperidone palmitate for the treatment of schizophrenia. Janssen on the other hand argued that the inventive concept is “standardized and optimized” dosing regimen of depot formulations of paliperidone for psychiatric patients in need of treatment for schizophrenia, which quickly and safely reaches and maintains potentially therapeutic plasma concentrations of paliperidone. But court said that “standardized and optimized” sets the bar for the inventive concept too high, and is not supported by the claim language or the disclosure. Court found that the inventive concept is a safe and effective dosing regimen using a depot formulation of paliperidone designed to quickly attain, and maintain, therapeutic plasma concentrations of paliperidone for treating patients with schizophrenia.

Teva primarily relied on the CA 2,309,629 Patent (discloses long acting formulation of paliperidone) and the Citrome article as relevant prior art for obviousness. Citrome summarizes information about ongoing and completed paliperidone clinical trials. Data in the paper was compiled from the clinicaltrials.gov website, and included information from 15 studies using an extended release oral formulation, and 7 studies using depot intramuscular formulations. Specifically, Citrome disclosed paliperidone depot injection with doses of 25, 50, 75, 100, and 150 mg-eq; fixed dosing (same dose administered on each dosing day) in the gluteal on days 1, 8, 36, 64 and One phase 3 trial was investigating monthly dosing. Thus, the difference with respect to asserted claims were: specific dose amounts as loading or maintenance dose at specific injection site; dosing windows of ± 2 days (second loading dose) and ± 7 days (maintenance doses); and an adjusted regimen for patients with renal impairment.

Teva argued that the prior art discloses dosing regimens for paliperidone palmitate depot formulations that include five dose amounts (25, 50, 75, 100, and 150 mg-eq), two injection sites (deltoid and gluteal), and two dosing schedules (monthly, or days 1, 8, and monthly thereafter). To get from here to the claimed dosing regimen, the POSITA would simply undertake routine testing to arrive at the claimed combinations of dose amount, dose schedule, and injection sites. Experts agreed that the POSITA would have needed to understand the pharmacokinetic profile of the paliperidone depot formulation in order to design a dosing regimen. As of the relevant date, the necessary pharmacokinetic data in humans was not disclosed in the prior art. Determining the rate of release of paliperidone from the depot formulation would at least require testing in animal models followed by testing in humans to confirm and adjust the dosing as necessary. Court said that even if the POSITA decided to pursue a loading dose regimen, they would have to run clinical trials to evaluate the safety and efficacy of a large number of variables including fixed doses, variable doses, and injection sites. Though the number of dosing regimen variables is finite, but based on the state of the art there were a not finite number of identified, predictable solutions. In fact, the only study disclosed in Citrome where a loading dose regimen was definitely being used had a fixed dosing regimen, that is, each loading and maintenance dose amounts were the same. Nothing in Citrome points the POSITA towards a variable dosing regimen such as that claimed in the 335 Patent. Court held that the POSITA would have had to carry out prolonged and arduous experimentation to the point that the trials would not be considered routine. Therefore, claimed dosing regimen elements is inventive, and the Asserted Claims of the 335 Patent are not obvious.

Infringement:

Janssen submitted that Teva will directly infringe claims 1 to 16 and 33 to 48 by selling its paliperidone palmitate product. Janssen’s position is that both of these claim sets are product claims and therefore no active use is required to support a finding of infringement. Teva submits that because it does not prescribe or administer medications, it cannot infringe these claims, as they all require administration in accordance with the claimed dosing regimens. Court agreed with Janssen.

With respect to other claims, parties agreed that Teva will not directly infringe “use” claims 17 to 32, and the Court need only consider inducing infringement in respect of these claims.

With respect to the dosing schedule, dose amounts, and injection sites, Janssen submits that the Teva’s label specifies the approved indications and dosage and administration instructions, which include administration according to the claimed dosing regimens of the 335 Patent. Janssen submitted that Teva will induce infringement of all three claim sets if it comes to market with its paliperidone palmitate product. Teva argued that Janssen has no evidence that there will be any actual infringement and speculation cannot establish infringement. Court said that IMS data and the expert evidence indicate that a large number of patients on INVEGA SUSTENNA receive 100 mg-eq or 150 mg-eq as their maintenance dose while very low patients receive maintenance dose of 75 mg-eq. Therefore, while acts of infringement may be few, at least some physicians will prescribe and administer paliperidone palmitate injections that fall within the scope of the claimed dosing regimens in the 335 Patent. Janssen argued that Teva’s label goes beyond mere encouragement, and contains clear and explicit instructions that the Teva product is approved to be used in an infringing manner. The 75 mg-eq maintenance dose is one of the “recommended” maintenance doses for non-renally impaired schizophrenia patients. However, Teva’s experts gave evidence that prescribing physicians do not look at generic labels once they are sufficiently familiar with label and subsequent use of the brand products. Teva’s label recommends that the prescribing physician select the maintenance dose for patients based on individual patient characteristics & not because of Teva’s label influence. The appropriate maintenance dose is determined individually for each patient, and in most cases the starting maintenance dose is 100 mg-eq. Court said that this evidence is also consistent with statements made by Janssen in a document submitted to Health Canada that “[g]ood clinical practice is to individualize treatment based upon clinical symptoms” and “[i]ndividualization of the dose of paliperidone palmitate can begin as early as day 36, the time corresponding to the third injection.” Therefore, label itself does not actually result in prescription and use of the 75 mg-eq maintenance dose of paliperidone palmitate.

Court thus held that Teva will not induce infringement of claims 17 to 32 of the 335 Patent if it comes to market with its paliperidone palmitate product. Teva must be aware that at least some infringement by third parties will occur, but this infringement is the result of prescribing physicians’ skill and judgment applied to specific patient characteristics, rather than influence exercised by Teva via its label.

Tuesday, May 12, 2020

Efinaconazole - USA


Claim Construction (District of New Jersey): May 07, 2020

[VALEANT PHARMACEUTICALS NORTH AMERICA LLC et al v. ZYDUS PHARMACEUTICALS (USA) INC. et al.;
Case : 3:2018cv13635]

This case arises out of an action for infringement of Plaintiffs’ patents1 by Defendants’ filing of an Abbreviated New Drug Application (“ANDA”) seeking U.S. Food and Drug Administration (“FDA”) approval to market a generic version of Plaintiffs’ product Jublia®—an efinaconazole topical solution, 10%. The parties dispute the proper construction of a single term, “nail,” used in eight of the nine patents-in-suit.

Claim Language
Asserted Claims
Plaintiffs’ Proposed Construction
Defendants’ Proposed Construction
“nail”
’494 patent claim 1; ’978 patent claims 1, 2, 21, 41; ’009 patent claim 1; ’272 patent claim 1; ’698 patent claims 2, 11; ’955 patent claims 1, 12, 14; ’444 patent claims 2, 9; ’394 patent claim 11
“nail plate”
Plain and ordinary meaning, i.e., “nail unit”

The parties did not dispute that “nail unit” has an ordinary meaning which includes, among other components, the nail plate and nail bed. The nail plate is a rigid outer portion, and the nail bed is the dermis directly beneath the nail plate. However, the present issue is whether the term “nail” as asserted in the patents-in suit refers to merely the nail plate or encompasses the entire nail unit—inclusive of the nail plate, nail bed, and other structures.

Plaintiffs first contend “nail” means “nail plate” because the claims consistently use the phrase “treatment of a disorder of the nail or nail bed”. Plaintiffs argued the use of the word “or” indicates the “nail” is distinct from the “nail bed.” Because the nail bed is part of the nail unit, Defendants’ proposed construction would render the phrase “or nail bed” superfluous and redundant. Defendants contended that their construction would not make “or nail bed” superfluous because a person of ordinary skill in the art (“POSA”) would understand a topical fungal treatment such as Jublia® could be applied to either: 1) the nail unit in its entirety; or 2) the nail bed after removal of the nail plate. Defendants also contended the use of “nail” above should be construed as “nail unit” because the nail unit is primarily composed of hard keratin. Court, however, said that the specifications supports Plaintiff’s construction as it reads:

"The nail plate is thick, hard, and dense, and represents a formidable barrier to drug penetration. Although nail material is similar in various ways to the stratum corneum of the skin, the nail is composed primarily of hard keratin which is highly disulfidelinked and is approximately 100-fold thicker than stratum corneum."

Saturday, May 9, 2020

Bendamustine - USA


On May 08 2020, Federal Circuit affirmed district court’s judgment on pleadings that Slayback's NDA does not infringe Eagle’s patents under Doctrine of Equivalents (DOE).

Eagle is the holder of NDA for BALRAPZO® (bendamustine) that was approved by FDA to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma. Eagle sued Slayback Pharma alleging infringement under the doctrine of equivalents of four patents: U.S. Patent Nos. 9,265,831, 9,572,796, 9,572,797 and 10,010,533 (all expiring on 01/28/2031). Eagle initiated lawsuit in response to Slayback's submission of NDA No. 212209 for approval to manufacture and sell before the four asserted patents expire. Eagle’s four asserted patents share essentially the same written description and all independent claims recite essentially the same limitations.

Claim 1 of U.S. Patent No. 9,572,796 is representative.

1. A non-aqueous liquid composition comprising: bendamustine, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable fluid comprising a mixture of polyethylene glycol and propylene glycol, wherein the ratio of polyethylene glycol to propylene glycol in the pharmaceutically acceptable fluid is from about 95:5 to about 50:50; and a stabilizing amount of an antioxidant…….;

Slayback conceded that its product literally infringes all claim limitations except for the “pharmaceutically acceptable fluid” limitation. Eagle asserted that Slayback’s product infringes the “pharmaceutically acceptable fluid” limitation under the doctrine of equivalents. Specifically, Eagle asserted that the “ethanol” in Slayback’s product is insubstantially different from the propylene glycol (“PG”) in the claimed composition. On January 4, 2019, Slayback moved for a judgment of non-infringement on the pleadings under Federal Rule of Civil Procedure 12(c). Slayback argued that the disclosure-dedication doctrine barred Eagle’s claim of infringement under the doctrine of equivalents because the asserted patents disclose, but do not claim, ethanol as an alternative solvent to PG. On May 9, 2019, the district court granted Slayback’s motion for judgment of non-infringement on the pleadings. You can read the summary “reported here” on this blog.

Eagle appealed.

During appeal, Eagle argued that the district court committed two errors. First, Eagle contended that the district court erred when it concluded that the asserted patents disclose, but do not claim, ethanol—and therefore dedicated ethanol to the public. Second, Eagle contended that the district court improperly applied the dedication-disclosure doctrine at the pleadings stage, in the presence of factual disputes and without drawing all inferences in Eagle’s favor.

With respect to first point, Eagle contended that the asserted patents disclose three distinct “categories” of bendamustine formulations: (i) chloride salt formulations; (ii) antioxidant formulations; and (iii) dimethyl sulfoxide (“DMSO”) formulations. Skilled artisan would recognize that the three separate categories “have separate ingredients and work in different ways.” Eagle asserted that the specification only discloses ethanol as an alternative to PG when discussing the unclaimed chloride salt formulations; it never discloses ethanol as an alternative to PG when discussing the claimed antioxidant formulations. Federal Circuit said that the disclosure-dedication doctrine does not require the specification to disclose the allegedly dedicated subject matter in an embodiment that exactly matches the claimed embodiment. Instead, the disclosure dedication doctrine requires only that the specification disclose the unclaimed matter “as an alternative to the relevant claim limitation.” [Pfizer, Inc. v. Teva Pharm. USA, Inc., 429 F.3d 1364, 1378 (Fed. Cir. 2005)]. The  asserted patents disclose ethanol as an alternative to PG in the “pharmaceutically acceptable fluid” claim limitation. The specification repeatedly identifies—without qualification—ethanol as an alternative pharmaceutically acceptable fluid. This is sufficient for the disclosure dedication doctrine here & thus ethanol is dedicated to public.

With respect to second point, Eagle argued that at the time the district court entered judgment of non-infringement on the pleadings, a factual dispute existed. District court erred by improperly ignoring Dr. Amiji’s declaration & resolving the factual dispute at the pleadings stage without drawing all reasonable inferences in Eagle’s favor. Specifically, Eagle argued that the district court was required to infer that a “skilled artisan would not have understood that ethanol was an alternative to PG in the claimed ‘PEG/PG/Antioxidant’ category of formulations.” Federal Circuit said that when ruling on a Rule 12(c) motion, district courts have discretion to consider evidence outside the complaint for purposes of deciding whether to accept that evidence and convert the motion into one for summary judgment. And district court here did not abuse its discretion when it set aside Dr. Amiji’s declaration. The district court reviewed Dr. Amiji’s declaration and determined that it was merely an “attempt to manufacture a factual dispute.” Moreover, patents themselves provided “sufficient context to decide” the legal issue at hand & therefore, there was no need to refer to the declaration. Only reasonable inference that can be made from the patent disclosures is that a skilled artisan would understand the patents to disclose ethanol as an alternative to the claimed PG. As a result, even when viewing the pleadings in the lightmost favorable to Eagle, there is no material issue of fact to resolve and Slayback is entitled to judgment in its favor as a matter of law.

Friday, May 8, 2020

Carfilzomib - USA


On May 07, 2020, in an unsealed opinion,  Delaware court found Kyprolis® patents valid in a Hatch-Waxman litigation challenged by Cipla.

Plaintiff (Onyx Therapeutics Inc) sued Defendants (Apotex, Aurobindo, Breckenridge, Cipla, Dr. Reddy’s, Fresenius Kabi, Innopharma, MSN, Qilu Pharma and Sagent) as they sought to bring to market generic versions of Plaintiffs' Kyprolis ® (Carfilzomib), a drug indicated for the treatments for relapsed multiple myeloma. Carfilzomib is a novel epoxyketone-based irreversible proteasome inhibitor. All of the defendants other than Cipla entered into consent judgments with Onyx and thus cases were dismissed. Cipla stipulated that its proposed ANDA product infringes Onyx’s U.S. Patent Nos. 7,417,042 and 8,207,125 (Compound Patents) expiring on Jul. 20, 2026 & Apr. 14, 2025 respectively as well as Onyx’s U.S. Patent No. 7,737,112 (Formulation Patent) expiring on Dec. 07, 2027. Cipla, however, contends that the Asserted claims are invalid. In May 2019, the Court held a five-day bench trial.

Onyx asserted claims 23 and 24 (specific compound or its salt) of the ’042 Patent. Onyx asserted claims 1 (specific compound) and 25 (composition with cyclodextrin) of the ’125 patent. Onyx also asserted claims 31 (composition with SBECD and 10 mM citric acid adjusted to pH 3.5) and 32 (composition with SBECD in lyophilized form) of the ’112 Patent.

1. Compound patents:

Obviousness

Cipla sought to invalidate the asserted claims of the Compound Patents as obvious in view of YU-101 (lead compound under development by Proteolix) disclosed in the US 6,831,099 Patent. The addition of a morpholine ring to the N-terminus of YU-101 made it more soluble & thus new compound Carfilzomib was produced. It was known in the art that morpholino acts as a solubilizing substituent.

Court said that lead compound analysis (Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1291; Fed. Cir. 2012) is applied while determining the obviousness of a new chemical compound. A lead compound is a compound in the prior art that would be “most promising to modify in order to improve upon its activity and obtain a compound with better activity. Once a lead compound has been identified, a party seeking to invalidate a patent must then show the reason or motivation for modifying the lead compound, which “may come from any number of sources and need not necessarily be explicit in the prior art.”

Court said that POSA would not have viewed YU-101 as a lead compound for developing a carfilzomib drug. Because, POSA looking for a lead compound would have preferred a compound that had human potency data and not just test tube data. YU-101 is an irreversible epoxyketone proteasome inhibitor and the early 2000s were a period of strong industry aversion to irreversible inhibitors. If an irreversible inhibitor like YU-101 inadvertently binds to an off-target site, a patient may suffer catastrophic side effects that cannot be alleviated. Thus, there was significant pressure in the industry to focus only on reversible inhibitors. Cipla argued that YU-101’s chymotrypsin-like activity (“CT-L”) specificity was so overwhelming that it would have outweighed general industry concerns of off-site toxicity. But court said that this contention is not supported by the record evidence. Cipla has not shown that POSAs in the industry would have correlated proven CT-L site specificity with increased safety. Nor has Cipla proven that a POSA would have believed YU-101 would not bind off-tissue and would not cause an adverse immune response.

Instead, POSA looking to develop a new drug product would have much more likely pursued modifying other known reversible inhibitors, such as bortezomib which was approved by USFDA as first proteasome inhibitor in May 2003. The FDA approval of bortezomib not only validated the CT-L site as a therapeutic target, but also proved to the industry that proteasome inhibition could provide high-impact therapeutic uses. POSA would also have known that bortezomib had an established data package, had been safely and effectively administered to humans, and was the most clinically-advanced proteasome inhibitor at the pertinent time. Therefore, court held that Cipla has failed to prove that a POSA would have viewed YU-101 to be a lead compound for a POSA looking to develop a carfilzomib drug product.

Court further said even assuming that a POSA would have selected YU-101 as a lead compound, Cipla has not proven by clear and convincing evidence that a POSA would have modified YU-101’s N-terminus with a morpholino methylene. Cipla argued that morpholino methylene would have been an obvious modification to improve YU-101’s solubility because it was well known in the art. But, court said that Cipla’s contention that a POSA designing a drug product would have been motivated to increase YU-101’s solubility improperly rests on hindsight reasoning. In this case, Cipla has shown that numerous potential modifications were available to a POSA who desired to increase YU-101’s solubility, but the record does not demonstrate that a POSA would have been motivated specifically to place a morpholino methylene on the N-terminus. Cipla has not proven even that the N-terminus was the obvious location to modify YU-101 to increase solubility. On the contrary, Onyx presented unrebutted evidence that a POSA would have had numerous options, including prodrugs or other side-chain or N-terminal modifications, at her disposal as mechanisms for trying to increase solubility. Further, while adding a morpholino methylene to the N-terminus may have increased solubility, it is undisputed that substantial uncertainty surrounded the biological implications of any modification to YU-101, and it was unknown whether the morpholino methylene N-terminus modification would actually produce a better drug product. Given the uncertainty and relative lack of data surrounding YU-101 as a whole, the Court was persuaded by Onyx’s expert that modifying the N-terminus of YU-101 with a morpholino methylene was not obvious.

Incorrect Inventorship

Cipla sought to invalidate the asserted claims of the ’042 and ’125 Patents as being invented by another, pursuant to 35 U.S.C. § 112(f). Cipla relied on Dr. Bunin’s purported conception of carfilzomib. Dr. Bunin was chemistry consultants hired by Proteolix to generate ideas for possible analogs of YU-101. In September 2003, Dr. Bunin emailed some proposals for creating epoxomicin/YU-101 analogs. The 2003 Research Plan does not describe the synthesis of any specific compound, but instead lists approaches for potentially modifying epoxomicin and YU-101 at multiple locations. Cipla relied on the September Memoranda, in which Dr Bunin proposed a Markush group in which “R=morpholino.” But, court found that Dr. Bunin’s proposal of “R=morpholino” is ambiguous. The Court was persuaded by Onyx’s expert, Dr. Lipinski, that a POSA would interpret “R=morpholino” in the September Memoranda as referring literally to a urea linkage (a morpholino carbonyl), and not carfilzomib (a morpholino methylene).


Court said that clear and convincing evidence required to demonstrate that Dr. Bunin had the idea for carfilzomib “that was definite and permanent enough” that a POSA could have understood it. To the contrary, the September Memoranda show merely that Dr. Bunin had “just a general goal or research plan” he (and Proteolix) hoped to pursue, which is insufficient to constitute conception. The documents and associated communications repeatedly refer to the September Memoranda as research plans or proposals. At the time of the September Memoranda, Dr. Bunin had conducted no testing and had no particular expectation of success. For at least these reasons, Cipla has failed to prove that Dr. Bunin conceived of every modification he proposed, and, most pertinently, has failed to prove, by clear and convincing evidence, that he conceived of carfilzomib.

Obviousness-Type Double Patenting

Cipla sought to invalidate claims 23 and 24 of the ’042 Patent and claim 1 of the ’125 Patent as being an obvious double-patenting (OTDP) of claim 15 of the ’099 Patent, which claims YU-101. Court said that while double patenting does not per se require a complete overlap of inventors or common ownership, there must be some commonality between the earlier and later patents. It is undisputed that the ’099 Patent does not share any common inventors with the Compound Patents, Nor does Onyx own the ’099 Patent, Yale does. Cipla argued that Onyx’s exclusive license with Yale gave Onyx “all substantial rights” to the ’099 Patent, such that Onyx is effectively an owner of the ’099 Patent. Specifically, Cipla points to Onyx’s “first right to sue for infringement” as evidence of Onyx’s effective ownership. Court, however, said that Cipla is asking the Court to extend the effective ownership doctrine from the realm of standing to non-statutory double patenting. The Court is not persuaded to do so, as Cipla’s position ignores the fundamental nature and purpose of the non-statutory double patenting doctrine. Court said that the licensed patent will always be made by another who is not the licensee (e.g., the licensor) and the licensed patent will, therefore, constitute § 102 prior art to the licensee’s patent. The licensee cannot take advantage of the gap which OTDP is directed at filling, so there is no reason to extend OTDP in the manner Cipla proposes.
Here, the ’099 Patent lists different inventors and different assignees/owners than the Compound Patents and, thus, will always constitute § 102 prior art, even without invoking the doctrine of OTDP. The Compound Patents are not invalid based on OTDP.

2. Formulation patents:

Obviousness

Court held that given the conclusions already stated above in connection with the Compound Patents, it follows that Cipla’s contention that the ’112 Patent, the Formulation Patent, is invalid due to obviousness must also fail. This is because both asserted claims of the Formulation Patent, claims 31 and 32, have as a claim limitation that the active ingredient of the claimed formulation is carfilzomib. Because carfilzomib was not obvious, for the reasons explained above, a formulation containing carfilzomib also cannot have been obvious.

Obviousness-Type Double Patenting

Cipla also sought to invalidate claims 31 and 32 of the ’112 Patent as being an obvious double-patenting of claim 25 of the ’125 Patent.

The substantive differences between claim 31 of the ’112 Patent and claim 25 of the ’125 Patent are that the carfilzomib of claim 31 is: (1) complexed with a specific cyclodextrin, SBECD, at 10% w/v, (2) at a pH of 3.5, (3) with 10mM citric acid, (4) in a single formulation. 

With respect to 10% SBECD court said that there is no patentably distinct difference between claiming substituted or unsubstituted beta cyclodextrin, as claim 25 of the ’125 Patent and claiming 10% w/v SBECD, as claim 31 of the Formulation Patent. It would have been obvious to a POSA formulator at least to start with SBECD, given its proven track record with the FDA. With respect to pH of 3.5, court said that there is a patentably distinct difference between claiming carfilzomib in a formulation with no specific pH, as does claim 25 of the ’125 Patent, and a formulation with carfilzomib with a pH of 3.5. The record contains substantial evidence that a POSA would have had concerns with whether carfilzomib could be stable at a pH of 3.5. With resepct to 10mM of Citric Acid limitation, court said that there is also a patentably distinct difference between claiming carfilzomib and claiming a specific formulation with 10mM of citric acid. And court finally said that even if all the elements of claim 31 of the Formulation Patent were obvious and patentably indistinct from the elements of claim 25 of the ’125 Patent (which they were not), Cipla has not shown that the combination as a whole was obvious.

The only substantive differences between claim 32 of the ’112 Patent and claim 25 of the ’125 Patent are that claim 32: (1) is directed at a “pharmaceutical composition” (rather than just a “composition”); (2) recites SBECD instead of substantiated or unsubstantiated β-cyclodextrin; and (3) requires lyophilization. 

Court said that Onyx does not argue that there is a difference between the claimed “pharmaceutical composition” of claim 32 and the “composition” of claim 25 of the ’125 Patent. The Court has also found in connection with claim 31 that there is no patentably distinct difference between claiming substantiated or unsubstantiated beta cyclodextrin and SBECD. So, all that is left as potentially patentably distinct between claim 32 of the Formulation Patent and claim 25 of the earlier ’125 Patent is lyophilization. With respect to this, Cipla has also shown that a POSA would have had a reasonable expectation of success in lyophilizing proteasome inhibitors, as evidenced approbed Bortezomib. Cipla has further proven that a POSA would have had a reasonable expectation of success that SBECD complexes may be lyophilized. For these reasons, claim 32 of the ’112 Patent is invalid due to obviousness-type double patenting, in view of claim 25 of the ’125 Patent.


Wednesday, May 6, 2020

Zoledronic acid/ Neridronic acid - USA


PGR decision: May 05, 2020

AIA Review #
Filing Date
Institution Date
Petitioner
Patent
Respondent
Status
PGR2019-00003
10/16/2018
05/07/2019
Grunenthal GmbH
9,867,839

Antecip Bioventures II LLC
Some Challenged Claims Unpatentable

US 9,867,839 (ANTECIP BIOVENTURES II LLC; Exp: Mar. 27, 2035)

1. A method of treating pain associated with a joint comprising: administering neridronic acid in an acid form or a salt form to a patient who has suffered for at least 3 months with 1) pain associated with a joint and 2) a pain intensity of 5 or greater measured using the 0-10 numerical rating scale (NRS) or 5 cm or greater using the 10 cm visual analog scale (VAS).

15. A method of treating pain associated with a joint comprising: orally administering zoledronic acid in an acid form or a salt form to a patient having 1) pain associated with a joint and 2) a pain intensity of 5 or greater measured using the 0-10 NRS or 5 cm or greater using the 10 cm VAS, wherein a total of about 400 mg to about 600 mg of zoledronic acid is administered in 2 or 3 individual doses within a period of about a month.

ORDER:
Claims 1–14 of the ’839 patent are unpatentable; and
Claims 15–30 of the ’839 patent are not shown to be unpatentable.

Friday, May 1, 2020

Sitagliptin - CJEU


On Apr 30, 2020, The Court of Justice of the European Union (CJEU) has handed down its decision in Royalty Pharma case on interpretation of Article 3 (a) of SPC regulation.

This request was made in the course of proceedings between Royalty Pharma and the Deutsches Patent- und Markenamt (German Patent and Trademark Office, DPMA) on the latter's refusal to issue a SPC for sitagliptin used for the treatment of diabetes mellitus.

Background of the case:

Royalty Pharma is the holder of the European patent (DE) EP 1084705. This patent discloses a method of reducing the blood glucose level of mammals by injecting inhibitors of the enzyme dipeptidyl peptidase IV ('DPP IV'), which contributes to the regulation of blood sugar levels. Sitagliptin is one of the DPP IV inhibitors. On 17 December 2014, Royalty Pharma filed a SPC request for sitagliptin with the DPMA, on the basis of this basic patent and a marketing authorization Issued on March 21, 2007 by the European Medicines Agency (EMA) to Merck for theproduct,  Januvia®. That application was dismissed on April 12, 2017 by the DPMA on the grounds that the requirement in Article 3 a) of Regulation No o  469/2009 was not met. This office considered that, if sitagliptin meets the functional definition of the DPP IV inhibitor given by the claims of the basic patent at issue, the patent does not contain any specific disclosure of this product, so that the concrete active ingredient has not been known to the skilled person. Thus, according to the DPMA, the subject-matter of the protection of that patent does not correspond to the medicinal product subsequently developed and marketed under the name of Januvia. It would therefore be contrary to the objectives of Regulation No o  469/2009 issuing an SPC for a product that has not been disclosed by the basic patent at issue.

Royalty Pharma appealed against this decision to the Bundespatentgericht (Federal Patent Court, Germany). It argued that the description of the functional characteristics is sufficient for the grant of SPC. It submitted that sitagliptin meets the functional definition of a DPP IV category of active principle referred to in the basic patent at issue. According to Royalty pharma, any DPP IV inhibitor for treating diabetes mellitus falls within the “heart of the patented invention”, which covers all of the specific compounds meeting this definition. The Bundespatentgericht (Federal Patent Court) decided to stay the proceedings and to refer the following questions to the CJEU:

Questions:

"1) A product is it protected by the basic patent in force in accordance with Article 3 a) of Regulation No o  469/2009, which falls when the object of protection defined by the claims of the patent thus being delivered to the skilled person as a concrete embodiment?

2) The requirements in Article 3 a) of Regulation No o  469/2009 are they therefore not sufficiently fulfilled when the product in question certainly has the general functional definition that patent claims to give 'a category of active principle without being individualized as a concrete embodiment of the education protected by the basic patent?

3) A product is it already protected by the basic patent in force in accordance with Article 3 a) of Regulation No o  469/2009, certainly falls when the functional definition in the patent claims but was not developed until after the filing date of the basic patent application in an independent inventive step? "


CJEU analysis:

Court said that by its first and second questions, which should be examined together, the referring court asks, in essence, whether Article 3 a) of Regulation No o  469/2009 must be interpreted as meaning that a product is protected by a basic patent in force, within the meaning of this provision, when it meets a general functional definition used by one of the claims of the basic patent and necessarily falls under the invention covered by this patent , without being individualized as a concrete embodiment to be learned from the teaching of said patent. To this end, two cumulative conditions must be met as set out in “Teva V Gilead, 25 july 2018”. First, the product must necessarily fall in the light of the description and drawings of the basic patent, of the invention covered by patent. Second, the person skilled in the art must be able to identify this product specifically in the light of all the elements disclosed by the said patent, and on the basis of the state of the art at the date filing or priority of the same patent.

In the main proceedings, it is apparent from the order for reference that, if sitagliptin is not explicitly mentioned in the claims of the basic patent, it meets the functional definition used by one of the claims of that patent . In those circumstances sitagliptin necessarily falls, as a DPP IV inhibitor, from the invention covered by the basic patent and, therefore, the first condition is met. In order to determine whether the second condition is satisfied, it is more particularly for the referring court to verify whether the subject-matter of the SPC concerned is within the limits of the personskilled in the art, on the date of filing or priority of the basic patent, to deduce directly and unequivocally from the specification of this patent as it was filed, based on its general knowledge in the field considered the filing or priority date and in the light of the state of the art at the filing or priority date. It follows from the foregoing that the answer to the first two questions that Article 3 a) of Regulation No o 469/2009 must be interpreted as meaning that a product is protected by a basic patent in force, within the meaning of this provision, when it meets a general functional definition employed by one of the claims of the basic patent and necessarily relates to the invention covered by this patent, without being individualized as a concrete embodiment to be learned from the teaching of said patent, since it is specifically identifiable, in the light of all the elements disclosed by the same patent, by a person skilled in the art, on the basis of his general knowledge in the field considered on the date of filing or priority of the basic patent and of the state of the art on this same date.

By its third question, the referring court asks whether Article 3 a) of Regulation No o  469/2009 must be interpreted as meaning that a product is not protected by the basic patent in force , within the meaning of this provision, when, although falling within the functional definition contained in the claims of this patent, it was developed after the filing date of the application for the basic patent, at the end of an autonomous inventive step. In this regard, it should be recalled that, for the purposes of applying the condition set by Article 3 a) of Regulation No o  469/2009, the purpose of the protection conferred by the patent base must be determined on the filing date or priority date of this patent. Indeed, if it could be taken into account the results of research carried out after the filing date or priority date of said patent, a SPC could allow its holder to unduly benefit from protection for these results, even though these these were not known on either of these dates. It follows that a product subject to a SPC or a request for a SPC which has been developed, after the filing or priority date of the basic patent, at the end of an autonomous inventive step , cannot be considered to fall within the object of the protection conferred by this patent.

CJEU thus, has now expressly clarified that its interpretation of Article 3(a) endorsed in Teva v. Gilead does not accord any relevance to the “core inventive advance” of the basic patent. Therefore, “core inventive advance” concept has no place in interpretation of Article 3 (a) of SPC.

For these reasons, the Court held that:

1)       Article 3 a) of Regulation (EC) n o 469/2009 of the European Parliament and of the Council of 6 May 2009, concerning the supplementary protection certificate for medicinal products, must be interpreted as meaning that a product is protected by a basic patent in force, within the meaning of this provision , when it meets a general functional definition used by one of the claims of the basic patent and necessarily relates to the invention covered by this patent, without being individualized as a concrete embodiment to be drawn from the teaching of said patent, as soon as it is specifically identifiable, in the light of all of the elements disclosed by the same patent, by a person skilled in the art,on the basis of his general knowledge in the field considered on the date of filing or priority of the basic patent and the state of the art on this same date.

2)       Article 3 a) of Regulation No o  469/2009 must be interpreted as meaning that a product is not protected by a basic patent in force within the meaning of that provision where, although that falling under the functional definition given in the claims of this patent, it was developed after the filing date of the application for the basic patent, at the end of an autonomous inventive step.

Tuesday, April 28, 2020

Bendamustine - USA


On Apr 27, 2020, Delaware court found Eagle pharmaceuticals patents valid & infringed by ANDA filers.

Plaintiffs (Teva, Cephalon and Eagle Pharmaceuticals) sued Defendants (Apotex, Fresenius Kabi, Mylan, and Slayback Pharma) as they sought to bring to market generic versions of Plaintiffs' Bendeka®, a drug indicated for the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell nonHodgkin lymphoma (NHL). Plaintiffs alleged infringement of U.S. Patent Nos. 9,265,831, 9,572,797 (formulation patents) and  9,144,568, 9,597,399, 9,572,887 (administration patents). Defendants mostly stipulated to infringement of the asserted claims (except two) and argued that all asserted claims are invalid.

Obviousness:

      1.   Formulation patents:

The main components of the asserted formulation are: a non-aqueous liquid composition that contains (1) bendamustine (or a pharmaceutically acceptable salt thereof); (2) about 5% to about 10% by volume of the solvent propylene glycol (PG); (3) the solvent polyethylene glycol (PEG); (4) one of the following ratios of PEG to PG: about 95:5, about 90:10, about 85:15, about 80:20, and about 75:25; and (5) a stabilizing amount of an antioxidant. Two claims also specify components and quantities: (1) claim 11 of the #797 patent requires that "the antioxidant is thioglycerol or monothioglycerol," and (2) claim 5 of the #831 patent requires that "the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL." Certain claims also recite stability limitations such as "less than or equal to 0.11 % PG esters at about 1 month of storage at about 5°C.

Bendamustine is prone to degradation because of two functional groups (a nitrogen mustard group and a carboxylic acid group). Because water causes bendamustine to degrade at its nitrogen mustard group, the prior art bendamustine formulations used a lyophilized (freeze-dried) form of bendamustine that required a human operator to reconstitute it using water shortly before administering it to a patient. But this reconstitution by human manipulation had two known disadvantages: it increased the risk of contamination and, because bendamustine is a cytotoxic compound, it posed a potential danger to the operator. Inventor of the asserted patents overcame this problem by providing stable non-aqueous bendamustine composition which contains appropriate quantities of PG & PEG solvents.

Defendants argued that five prior art references would have motivated a POSITA to arrive at the asserted formulation claims with a reasonable expectation of success: Olthoff, Drager, Alam, Rowe, and Boylan.

Olthoff (1983) – discloses non-aqueous, ready to use bendamustine formulation (25 and 100 mg/mL) in polyols such as PG & PEG. Olthoff's examples did not use an antioxidant.
Drager (2008) – discloses stable liquid pharmaceutical formulations comprising bendamustine.But Drager determined that the "results described in [Olthoff] were not reproducible." Drager' s data showed that bendamustine in 99% PG degraded almost completely after eight weeks at 25°C and more than 20% at 5°C after one year.  The reason for that degradation, according to Drager, was that (1) PG causes bendamustine to degrade at the nitrogen mustard group and (2) PG's OH groups cause bendamustine to degrade at the carboxylic acid group through esterification. As a solution to the degradation problem, Drager disclosed the use of aprotic solvents (DMA). Drager also taught that protic solvents-i.e., solvents, including PEG and PG, that have OH groups-are acceptable to use with bendamustine but only when combined with aprotic solvents.
Alam (1989) - disclosed stable liquid formulations of cyclophosphamide, a compound that, like bendamustine, has a nitrogen mustard group & tested its stability in 3 polyols (PG, PEG & glycerols). Alam disclosed using PG at a ratio of from about 10% to about 90% and PEG at a ratio of from about 90% to about 10%.
Rowe -  Rowe's Handbook of Pharmaceutical Excipients disclosed that PEG is susceptible to oxidation and that one can use an antioxidant to prevent such oxidation.
Boylan - Boylan disclosed a list of "some of the most commonly used antioxidants in pharmaceutical injectable formulations" including monothioglycerol.

Defendants argued that Olthoff, Drager, and Alam would have motivated a POSITA to use PEG and PG with bendamustine. Court, however, said that Drager teaches away from Olthoffs teaching of using polyols. Specifically, Drager determined that the results described in [Olthoff] were not reproducible & bendamustine degrades completely in PG after 8 weeks. Drager, therefore, suggested use of aprotic solvent as major component. Drager specifically showed that a formulation containing 66% DMA and 34% PG is stable. Drager, thus, teaches away from the use of only protic solvents (PG & PEG). Therefore, Drager would not have motivated a POSA to replace DMA with a low-OH protic solvent. POSA would have given more weightage to Dragger over Olthoff because data is more reliable in Dragger since it used HPLC & Olthoff used TLC method. Moreover, in the decades between Olthoffs publication in 1983 and the priority date in 2010, Olthoffs formulations were never used, suggesting that POSA generally did not rely on Olthoff. Third reference, Alam is related to cyclophosphamide & the structural differences between bendamustine & cyclophosphamide would have discouraged POSA because degradation pathway would be different. Therefore, POS A would not have viewed cyclophosphamide as a relevant comparator for bendamustine reactions, and would not have considered Alam in formulating a stable bendamustine formulation. In sum, Defendants have not proven by clear and convincing evidence that Olthoff, Drager, and Alam would have motivated a POSITA to use PEG and PG to create a non-aqueous liquid bendamustine formulation.

Since, POSA would not have motivated to use PG & PEG, the other claimed limitations such as PEG:PG ratio, use of antioxidant, bendamustine concentration, stability limitations would not have been obvious. With respect to only argued secondary consideration - “commercial success”,  court said that the evidence of $2 billion sales of Bendeka  does not support a finding of nonobviousness. First, Bendeka® sells at a lower price than the prior art lyophilized Treanda® product. Second, Plaintiffs' cluster of exclusivities has blocked others from entering the market. Court finally held that although the evidence of commercial success does not support a finding of nonobviousness, Defendants have not shown by clear and convincing evidence that the prior art they cited would have motivated a POSIT A to reach the claimed formulations.

      2.  Administration patents:

The asserted administration claims recite methods of treating CLL or NHL with a liquid bendamustine composition. Certain claims require administering the bendamustine composition on days one and two of a 21-day cycle for NHL, or on days one and two of a 28-day cycle for CLL. One claim requires a bendamustine dose of"about 25 mg/m2 to about 120 mg/m2”. The asserted administration claims also specify administration times, the longest time being "about 15 minutes or less”.They also specify administration volumes that are all 100 mL or less. Finally, certain claims specify post dilution bendamustine concentrations ranging from 0.05 mg/mL to 12.5 mg/mL.

Defendants argued that eight prior art references would have motivated a POSIT A to combine the elements of the claimed administration with a reasonable expectation of success: Palepu 2011 (Formulation patents as discussed above), the Treanda® Label, Preiss 1985 (PK study with 3 minutes of administration of bendamustine with 280 to 375 mg dose), Preiss 1998 (MTD study with 3 to 10 minutes of administration of bendamustine with 54 to 226 mg/m2 dose), Schoffski 2000a (administration of bendamustine over 30 minutes and compared its results to the three-to-ten-minute infusions disclosed in Preiss 1998), Schoffski 2000b (Schoffski 2000b administered 60 to 80 mg/m2 of bendamustine in 30 minutes), Barth (suggested administering bendamustine in a solvent volume of 100 to 250 mL), and Glimelius (disclosed the administration of 5-Fluorouracil to treat colorectal cancer as an infusion lasting ten to 20 minutes using a 50 to 100 mL mini-bag).

Court said that prior arts would have motivated a POSA to reach the claimed formulation, dose, and dosing schedule. But, the prior arts would not have motivated a POSA to reach the remaining claim limitations (Administration Times, Volumes, and Post-Dilution Concentrations), and thus the claims as a whole are not obvious. All asserted claims require administering bendamustine in 15 minutes or less, with some requiring ten minutes or less. All asserted claims also require administering bendamustine in a volume of 100 mL or less, with some claims requiring about 50 mL. Finally, all but one of the asserted administration claims require post-dilution bendamustine concentrations ranging from 0.05 to 12.5 mg/mL. Defendants argued that the Preiss studies support a finding that the claimed administration times, volumes, and concentrations are obvious. Court, however,found that Preiss studies would not have motivated a POSA to reach the claimed administration times, volumes, or concentrations because (1) a POSA would not have relied on the Preiss studies to determine a safe and effective infusion time, volume, or concentration for bendamustine because those studies were not designed to evaluate safety, (2) subsequent prior art taught away from Preiss's three-to-ten-minute infusions, instead, it would have considered later prior art references that used 30 to 60 minute infusions and a 500 mL volume and (3) Defendants only hypothesize that the Preiss studies used volumes and concentrations similar to those in the claimed administrations, such speculations about Preiss's infusion rate and volume, however, are only based on "conclusory and unsupported expert testimony" and they do not support a finding of obviousness by clear and convincing evidence.

With respect to secondary consideration, Plaintiffs offered at trial evidence of four secondary considerations that bear on the administration claims: skepticism, long-felt need, commercial success, and industry praise. Court, however, did not find this evidence to be probative indicia of nonobviousness.

Indefiniteness:

Defendants argued that the asserted formulation claims are invalid because they each require "a stabilizing amount of antioxidant"-a requirement Defendants contend is indefinite. Specifically, Defendants argued that the term is indefinite because "[t]he specification does not explain how to determine whether stability has been 'increased' or 'enhanced.’ Court, however, disagreed  & said that the patents provide a POSA with a method for measuring stability: using HPLC to compare the amount of overall bendamustine degradation with and without the antioxidant. Example 3 demonstrates that a POSA would compare the amount of bendamustine remaining in the same formulation, stored under the same conditions, with and without the antioxidant. In addition to providing exemplary test methods, the specification also lists "suitable antioxidant amounts" and "antioxidants," and provides examples of "stabilizing" amounts. Court, thus found that the term "stabilizing amount of antioxidant" is not indefinite and court construed it as: any amount of an antioxidant that decreases the amount of bendamustine degradation after any time period and at any temperature.

Enablement:

Defendants asserted that the asserted formulation claims are invalid for lack of enablement because the formulation patents disclosed neither the use of sodium hydroxide (NaOH) or of "other undisclosed variables." Specifically, Defendants argued that the asserted formulation claims are not enabled because the claims do not contain NaOH and "a pH adjuster like NaOH is necessary to obtain the PG ester levels claimed in the [a]sserted [f]ormulation claims. Court said that evidence that some claimed formulations did not result in the PG ester limitations, does not establish that the claims are not enabled. Defendants have not presented any evidence to show that a POSA would have had to undertake undue experimentation to alter the formulation to obtain the PG ester limitations. That some formulations with the claimed ingredients do not satisfy the PG ester limitations does not support non-enablement unless the number of such formulations is significant enough to have required a POSA to experiment unduly. [Atlas Powder, 750 F.2d at 1576-77….Even if some of the claimed combinations were inoperative, the claims are not necessarily invalid ....)]. Accordingly, Defendants failed to establish by clear and convincing evidence that the asserted claims are invalid for lack of enablement.

Lack of written description:

Apotex argued that claim 9 of the #797 patent is invalid for lack of written description. It asserted that "the absence of any mention of a pH adjuster like NaOH in the [#]797 patent demonstrates that the inventors did not have possession of it at that time, as confirmed by their later filing of another patent application that discloses and claims it." Court said that "written description is about whether the skilled reader of the patent disclosure can recognize that what was claimed corresponds to what was described .... ["Alcon Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1191 (Fed. Cir. 2014)]. And Apotex never citeed the intrinsic record to show that the asserted formulation patents claim something that they do not describe in their written descriptions. Instead, Apotex improperly cited extrinsic evidence-the later-filed Eagle patent application. Apotex has thus failed to establish that claim 9 is invalid for lack of written description.

Infringement:

Defendants stipulated to infringement of the asserted claims with two exceptions. Apotex, Fresenius Kabi, and Mylan argued that (1) they do not infringe the asserted formulation claims because their ANDA products do not contain "a stabilizing amount of an antioxidant" as the asserted formulation claims require, and (2) they do not directly infringe or induce infringement of claim 9 of the #797 patent, which requires that the "bendamustine-containing composition ha[ve] less than or equal to 0.43 % total PG esters at about 3 months of storage at a temperature of about 25°C," because their proposed labeling does not direct physicians to store their ANDA products for about 3 months at about 25°C.

With respect to first point, court said that it has construed the term as any amount of an antioxidant that decreases the amount of bendamustine degradation after any time period and at any temperature. Defendants' ANDA products each contain 5 mg/mL of the antioxidant monothioglycerol and the formulation patents' written description shows that 5 mg/mL of monothioglycerol is a stabilizing amount. The written description identifies "5 mg/mL to about 20 mg/mL" as a "preferable" stabilizing amount of antioxidant. Moreover, Example 3 demonstrates that adding "5 mg/m[L] of lipoic acid ... as a stabilizing antioxidant" to 20 mg/mL of bendamustine in PEG decreased the amount of bendamustine degradation after 15 days at 25°C and 40°C as compared to the same formulation without an antioxidant. Moreover, Fresenius Kabi and Mylan represented to the FDA that 5 mg/mL monothioglycerol was sufficient to ensure that the amount of bendamustine in their ANDA products did not fall below specification limits.

With respect to second point,  Defendants stipulated that their ANDA Products have "less than or equal to 0.43% total PG esters at about 3 months of storage at a temperature of about 25° C," but contend that they do not directly infringe or induce infringement of claim 9 because their proposed labeling does not recommend storing their ANDA Products for "about 3 months" at "a temperature of about 25° C." Court, however, said that even though Defendants' labeling does not mention storage, Defendants' ANDA products directly and indirectly infringe claim 9 because the PG ester limitation does not require the user to store the products for three months at 25°C. Claim 9's PG ester limitation describes a characteristic of the claimed formula; it is not a method step and thus, does not require action to infringe. The claim does not recite testing for the PG ester limitation; it just describes a composition that would have less than 0.43% PG esters if one were to test for them after storing the composition for three months at 25°C. Therefore, Defendants infringe and induce infringement of each of the asserted claims.

Rituximab – USA


On Apr. 27, 2020, Federal Circuit dismissed Pfizer’s appeal for lack of standing as it failed to establish that it was suffering a cognizable injury at all stages of appeals.

Chugai Pharmaceutical Co., Ltd., owns US 7,332,289 and US 7,927,815 patents. In two inter partes review proceedings, Pfizer Inc. petitioned the Patent Trial and Appeal Board to invalidate most of the claims of the ’289 and ’815 patents. In each IPR, the Board held that Pfizer did not prove that any of the challenged claims were unpatentable.

Pfizer appealed.

During appeal, Federal Circuit said that to establish Article III standing, an appellant must show that it has “(1) suffered an injury in fact, (2) that is fairly traceable to the challenged conduct of the defendant, and (3) that is likely to be redressed by a favorable judicial decision.” “To qualify as a case fit for federal-court adjudication, ‘an actual controversy must be extant at all stages of review . . . .’” [Arizonans for Official English v. Arizona, 520 U.S. 43, 67 (1997)]. Pfizer filed its notice of appeal on January 30, 2019. Evidence of standing that Pfizer provided to the court occurred much later in 2019. Specifically, Pfizer submitted evidence that the FDA approved its rituximab biosimilar in July 2019 and that Pfizer announced at the end of October 2019 that it would begin selling the biosimilar in the USA in January 2020 as result of settlement between Pfizer & Genentech (Roche group). F. Hoffmann-La Roche Ltd is the majority owner of appellee, Chugai. But, Chugai was not a party to that settlement agreement, and Pfizer did not get a license from Chugai for the patents at issue in this appeal. Moreover, Pfizer did not cite any evidence regarding its activities or plans relating to its rituximab biosimilar before July 2019. Pfizer thus failed to supply any evidence that it was suffering from an injury in fact when this appeal began. Nor has Pfizer offered evidence that would allow court to evaluate whether it practices or intends to practice the patented methods in the course of making its biosimilar product.

Court also rejected Pfizer’s “self-evident” theory that there was “a product at issue” when the appeal began. Specifically, Pfizer listed “rituximabIPR@win-ston.com” in its petitions as its service email address for the IPR proceedings. Court said that Pfizer’s service email address and Chugai’s response do not tell the court anything useful about Pfizer’s plans for its biosimilar, Ruxience®, as of the beginning of 2019, when this appeal began. Nor does that evidence establish with sufficient likelihood that the processes used to prepare Pfizer’s product would infringe Chugai’s patents. The court therefore did not find standing based on that evidence and dismissed the appeal.


Sunday, April 26, 2020

Fosaprepitant - USA


IPR decision: Apr. 20, 2020

AIA Review #
Filing Date
Institution Date
Petitioner
Patent
Respondent
Status
IPR2019-01446
08/01/2019
01/31/2020
Nevakar, Inc.
9,913,853
Cipla
Terminated-Dismissed

US 9,913,853 (Cipla Ltd.; Exp: 11/3/2036)

1. A liquid composition comprising fosaprepitant or a salt thereof and at least one liquid excipient, wherein after storage at 2-8.degree. C. for at least 1 month, aprepitant is present in an amount concentration of no more than 10%, wherein the composition is ready-to-use or ready-to-dilute.

17. A liquid pharmaceutical composition comprising: a) fosaprepitant dimeglumine in an amount from 50-250 mg; b) at least one salt of ethylenediaminetetraacetic acid in an amount from 10-100 mg; c) albumin in an amount from 250 mg-100 g; and d) water in an amount from 3-300 ml.

20. A liquid pharmaceutical composition comprising: a) fosaprepitant dimeglumine in an amount from 50-250 mg; and b) at least one solubilizer in an amount from 1-5 ml.

Friday, April 24, 2020

Fingolimod – USA


On Apr. 23, 2020, Federal Circuit dismissed Argentum’s appeal for lack of standing without reaching merit of the case.

Petitioners such as Apotex, Sun pharma, Teva/Actavis & Argentum filed IPRs on US 9,187,405 patent with PTAB. On July 11, 2018, the Board concluded that Apotex, Sun, Teva, Actavis, and Argentum had not demonstrated unpatentability of the claims. Petitioners appealed the Board’s findings. During the appeal process, all Petitioners other than Argentum settled their respective appeal with Novartis. On August 29, 2018, before opening briefs had been filed, Novartis filed a motion to dismiss Argentum’s appeal for lack of standing.

Court said that to prove standing, Argentum bears the burden of showing that it has “(1) suffered an injury in fact, (2) that is fairly traceable to the challenged conduct of the defendant, and (3) that is likely to be redressed by a favorable judicial decision.” Argentum argued that it demonstrated at least three concrete injuries in fact.

First, Argentum argued that without an opportunity to seek this Court’s redress, it faces a real and imminent threat of litigation as it jointly pursues, along with its partner KVK-Tech, Inc., a generic version of Novartis’ Gilenya® product for which they are in the process of filing an ANDA. It  further argued that given that Novartis already sued multiple generic companies to protect Gilenya®, “it is virtually certain that Novartis will sue Argentum and KVK,” which is “far from conjectural” and “constitutes an imminent injury for purposes of standing.” Novartis responded that any ANDA to be filed for a generic version of Gilenya® “will be filed by KVK, Argentum’s manufacturing and marketing partner”, and thus KVK, not Argentum is at risk of being sued. And even if the litigation were personal to Argentum, it would not confer standing because it is merely conjectural. Citing decision in “Altaire Pharmaceuticals, Inc. v. Paragon Bioteck, Inc.”, Argentum responded that “showing a concrete injury-in-fact does not necessitate an already-filed ANDA.” Court said that in Altaire, Altaire was the company which intended to file an ANDA and would be at imminent risk of being sued. Unlike in Altaire, according to Mr. Gardner (Argentum’s CEO), any ANDA to be filed will be filed by KVK, Argentum’s manufacturing and marketing partner & Novartis will inevitably sue KVK for patent infringement.

Second, Argentum argued that it will incur significant economic injury as its investments in developing a generic version of Gilenya® and preparing an ANDA would be at risk with a “looming infringement action by Novartis.” Novartis argued that Argentum’s alleged “economic injury,” which is entirely speculative and not personal to Argentum, does not suffice to establish injury in fact because it is not concrete or particularized. Court sided with Novartis & said that Argentum has not provided sufficient evidence to establish an injury in fact through economic harm. Argentum has failed to provide sufficient evidence that it invested in KVK’s generic Gilenya® product or ANDA. It stated only in generalities that both “KVK and Argentum have been diligent in working toward FDA submission of the ANDA” and that “Argentum has invested significant man-power and resources to the endeavor.”

Third, Argentum argued that absent relief from this court, Argentum would be estopped under 35 U.S.C. § 315(e) from raising the patentability and validity issues in a future infringement action. Novartis argued that Argentum has not shown that it will be harmed by estoppel where it has not established there is risk of an infringement suit. Court sided with Novartis & said that § 315(e) does not constitute an injury in fact when, as here, the appellant is not engaged in any activity that would give rise to a possible infringement suit.

Court held that Argentum failed to prove that it has suffered an injury in fact necessary to establish standing & thus, dismissed the appeal.