Insulin (Lantus Solostar) - USA

IPR decision: May 29, 2020

AIA Review #	Filing Date	Institution   Decision       Date	Petitioner	Patent	Respondent	Status
IPR2018-01675	09/10/2018	04/02/2019	Mylan	8,603,044	Sanofi-Aventis	All Challenged Claims Unpatentable
IPR2018-01676	09/10/2018	04/02/2019	Mylan	8,603,044	Sanofi-Aventis	All Challenged Claims Unpatentable
IPR2018-01678	09/10/2018	04/03/2019	Mylan	8,992,486	Sanofi-Aventis	All Challenged Claims Unpatentable
IPR2018-01679	09/10/2018	04/03/2019	Mylan	8,992,486	Sanofi-Aventis	All Challenged Claims Unpatentable
IPR2019-00122	10/29/2018	04/03/2019	Mylan	8,992,486	Sanofi-Aventis	All Challenged Claims Unpatentable
IPR2018-01680	09/10/2018	04/03/2019	Mylan	9,526,844	Sanofi-Aventis	All Challenged Claims Unpatentable
IPR2018-01682	09/10/2018	04/03/2019	Mylan	9,526,844	Sanofi-Aventis	All Challenged Claims Unpatentable
IPR2018-01684	09/10/2018	04/03/2019	Mylan	9,604,008	Sanofi-Aventis	Claims 1, 7, 8, and 17 are Unpatentable

US  8,603,044 (Sanofi-Aventis Deutschland GmbH.; Exp: 03/02/2024):

1. A housing part for a medication dispensing apparatus, said housing part comprising: a main housing, said main housing extending from a distal end to a proximal end; a dose dial sleeve positioned within said housing, said dose dial sleeve comprising a helical groove configured to engage a threading provided by said main housing, said helical groove provided along an outer surface of said dose dial sleeve; a dose dial grip disposed near a proximal end of said dose dial sleeve; a piston rod provided within said housing, said piston rod is non-rotatable during a dose setting step relative to said main housing; a drive sleeve extending along a portion of said piston rod, said drive sleeve comprising an internal threading near a distal portion of said drive sleeve, said internal threading adapted to engage an external thread of said piston rod; a tubular clutch located adjacent a distal end of said dose dial grip, said tubular clutch operatively coupled to said dose dial grip, wherein said dose dial sleeve extends circumferentially around at least a portion of said tubular clutch; and a cartridge retaining part operatively coupled to said main housing, said cartridge retaining part comprising a fluid container, wherein said fluid container defines a medicament filled reservoir with a movable cartridge piston at a proximal end and an outlet at a distal end, said cartridge piston movable by said piston rod to be advanced toward an outlet of said fluid container when said piston rod is moved distally.

11. A housing part for a medication dispensing apparatus, said housing part comprising: a main housing, said main housing extending from a distal end to a proximal end; a dose dial sleeve positioned within said housing, said dose dial sleeve comprising a helical groove configured to engage a threading provided by said main housing, said helical groove provided along an outer surface of said dose dial sleeve; a dose dial grip disposed near a proximal end of said dose dial sleeve; a piston rod provided within said housing, said piston rod is non-rotatable during a dose setting step relative to said main housing; a drive sleeve extending along a portion of said piston rod, said drive sleeve comprising an internal threading near a distal portion of said drive sleeve, said internal threading adapted to engage an external thread of said piston rod; and, a tubular clutch located adjacent a distal end of said dose dial grip, said tubular clutch operatively coupled to said dose dial grip, wherein said dose dial sleeve extends circumferentially around at least a portion of said tubular clutch, and wherein said helical groove of the dose dial sleeve has a first lead and said internal threading of said drive sleeve has a second lead, and wherein said first lead and said second lead are different.

US  8,992,486 (Sanofi-Aventis Deutschland GmbH; Exp: 06/05/2024):

1. A housing part for a medication dispensing apparatus, said housing part comprising: a main housing, said main housing extending from a distal end to a proximal end; a dose dial sleeve positioned within said housing, said dose dial sleeve comprising a helical groove configured to engage a threading provided by said main housing; a dose knob disposed near a proximal end of said dose dial sleeve; a piston rod provided within said housing, said piston rod is non-rotatable during a dose setting step relative to said main housing; a driver extending along a portion of said piston rod, said driver comprising an internal threading near a distal portion of said driver, said internal threading adapted to engage an external thread of said piston rod; and, a tubular clutch located adjacent a distal end of said dose knob, said tubular clutch operatively coupled to said dose knob, wherein said dose dial sleeve extends circumferentially around at least a portion of said tubular clutch.

43. A pen type drug delivery device, said device comprising: an external housing comprising a threading along a portion of an inner surface of said external housing, said external housing extending from a distal end to a proximal end; a dialing element positioned within said housing, said dialing element comprising an outer surface extending from a distal end to a proximal end of said dialing element, wherein said outer surface comprises a helical threading that defines a groove configured to engage said threading provided on said inner surface of said external housing; an actuator disposed about an outer surface of an end of said dialing element near said proximal end of said main housing; a driver extending along at least a portion of a piston rod, said driver comprising a thread adapted to threadingly engage an external thread of a piston rod; and, a clutch positioned at least partially within an open proximal end of said dialing element and located adjacent a distal end of said actuator and operatively coupled to said actuator, wherein said dialing element extends circumferentially around at least a portion of said clutch; a tubular barrel retainer operatively coupled to said external housing, said tubular barrel retainer comprising a cartridge containing a medicament, said cartridge comprising a reservoir, a piston, a septum, and a cap; said piston movable by said piston rod to be advanced toward an outlet of said cartridge when said piston rod is moved distally.

51. A clutch for use within a pen type drug delivery device, said clutch comprising a tubular body, said tubular body extending from a distal end to a proximal end; and said distal end of said tubular body having a diameter sized such that said distal end of said tubular body may be positioned within a proximal end of a dial member.

US  9,526,844 (Sanofi-Aventis Deutschland GmbH; Exp: 03/02/2024):

1. A drive mechanism for use in a drug delivery device comprising: a housing comprising an inner surface; a dose dial sleeve threadedly engaged with the inner surface of the housing through an outer thread having a first lead; an insert that is rotationally and axially fixed relative to the housing; a piston rod engaged with the insert, where the piston rod is threaded with a second lead and remains axially fixed relative to the housing during dose setting and moves axially relative to the insert during dose delivery; a clutch operatively engaged with the dose dial sleeve to allow rotation of the dose dial sleeve during dose setting and dose delivery; and a drive sleeve that extends about the piston rod and is operatively engaged with the clutch, where the clutch connects the drive sleeve and dose dial sleeve so they rotate together and disconnects the drive sleeve and dose dial sleeve so the dose dial sleeve can rotate relative to the drive sleeve, wherein during dose delivery the drive sleeve and the piston rod are configured to rotate relative to one another and the drive sleeve is configured to traverse axially towards the distal end.

21. A drug delivery device comprising: a housing comprising a dose dispensing end and a first thread; a dose indicator comprising a second thread that engages with the first thread; a driving member comprising a third thread; a sleeve that is (i) disposed between the dose indicator and the driving member and (ii) releasably connected to the dose indicator; a piston rod comprising either an internal or an external fourth thread that is engaged with the third thread; a piston rod holder that is rotatably fixed relative to the housing and configured to (i) prevent the piston rod from rotating during dose setting and (ii) permit the piston rod to traverse axially towards the distal end during dose dispensing; wherein: the housing is disposed at an outermost position of the drug delivery device; the dose indicator is disposed between the housing and the sleeve and is configured to (i) rotate and traverse axially away from the dose dispensing end during dose setting and (ii) rotate and traverse axially towards the dose dispensing end during dose dispensing; the driving member is configured to rotate relative to the piston rod; the sleeve is rotatably fixed relative to the driving member and configured to traverse axially with the dose indicator; and the piston rod and the driving member are configured to rotate relative to one another during dose dispensing; and the piston rod is configured to traverse axially towards the dose dispensing end during dose dispensing.

US  9,604,008 (Sanofi-Aventis Deutschland GmbH; Exp: 03/02/2024):

1. A drive mechanism for use in a drug delivery device comprising: a housing comprising a helical thread; a dose dial sleeve having a threaded surface that is engaged with the helical thread of the housing, an insert provided in the housing, where the insert has a threaded circular opening; a drive sleeve releasably connected to the dose dial sleeve and having an internal helical thread; a piston rod having a first thread and a second thread, wherein the first thread is engaged with the threaded circular opening of the insert and the second thread is engaged with the internal helical thread of the drive sleeve; and a clutch located between the dose dial sleeve and the drive sleeve, wherein the clutch is located (i) radially outward of the drive sleeve and (ii) radially inward of the dose dial sleeve.

Dapsone - USA

IPR decision: May 29, 2020

AIA Review #	Filing Date	Institution Decision Date	Petitioner	Patent	Respondent	Status
IPR2019-00207	11/06/2018	05/10/2019	Amneal	9,517,219	Almirall LLC	All Challenged Claims Unpatentable
IPR2019-01095	06/07/2019	11/27/2019	Mylan	9,517,219	Almirall LLC	All Challenged Claims Unpatentable

US 9,517,219 (Allergan, Inc.; Exp: 11/18/2033)

1. A method for treating a dermatological condition selected from the group consisting of acne vulgaris and rosacea comprising administering to a subject having the dermatological condition selected from the group consisting of acne vulgaris and rosacea a topical pharmaceutical composition comprising: about 7.5% w/w dapsone; about 30% w/w to about 40% w/w diethylene glycol monoethyl ether; about 2% w/w to about 6% w/w of a polymeric viscosity builder comprising acrylamide/sodium acryloyldimethyl taurate copolymer; and water; wherein the topical pharmaceutical composition does not comprise adapalene.

6. A method for treating a dermatological condition selected from the group consisting of acne vulgaris and rosacea comprising administering to a subject having the dermatological condition selected from the group consisting of acne vulgaris and rosacea a topical pharmaceutical composition comprising: about 7.5% w/w dapsone; about 30% w/w diethylene glycol monoethyl ether; about 4% w/w of a polymeric viscosity builder comprising acrylamide/sodium acryloyldimethyl taurate copolymer; and water; wherein the topical pharmaceutical composition does not comprise adapalene.

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.

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."

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.

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.

        [Image source: https://cen.acs.org/articles/90/i35/Carfilzomib-Discovery-Drug.html]

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.