Thursday, December 31, 2020

adieu..

It's time to say goodbye to 2020 & also this blog. As most of the you are aware that "Pharma IP Circle" has moved to new address & this current address would no longer serve. Looking forward to 2021 with new learning & experience.


Here is our new address:

https://www.pharmaipcircle.com/


Wish all the readers very hopeful, healthy & happy new year 2021.

Image source: https://i.ytimg.com/vi/atLLOMcK830/maxresdefault.jpg


Wednesday, December 23, 2020

Pemetrexed - USA

 

On Dec. 21, 2020, Federal Circuit affirmed district court’s summary judgment that found infringement under Doctrine of Equivalents (DoE).

Eli Lilly owns US 7,772,209 patent which relates to “a method of administering an antifolate to a mammal in need thereof, comprising administering an effective amount of said antifolate in combination with a methylmalonic acid lowering agent”. Independent claims covers administration of pemetrexed disodium (antifolate) with folic acid & methylmalonic acid lowering agent (vitamin B12). This patent is listed in Orange Book for the product ALIMTA®.  Eli Lilly markets ALIMTA in USA for the treatment of mesothelioma and certain types of lung cancer.  Apotex filed NDA with USFDA to market different salt i.e. pemetrexed dipotassium.  Eli Lilly then sued Apotex for infringement. United States District Court for the Southern District of Indiana issued summary judgment of infringement in favour of Lilly. It found that Lilly is not estopped from arguing DoE because there was no Prosecution History Estoppel (PHE).  

Apotex argued that the term “ALIMTA” in the original claims would have been understood to mean “pemetrexed,” therefore, Lilly’s amendment to replace “ALIMTA” with “pemetrexed disodium” was a narrowing amendment and Lilly surrendered all other salt forms of pemetrexed. Federal Circuit, however, sided with district court & said that this amendment was not narrowing one. The intrinsic record equates ALIMTA with pemetrexed disodium. The specification refers to “pemetrexed disodium” twice, both times in association with ALIMTA. Moreover, the prosecution history confirms that the inventors used “ALIMTA” in the original claims—and the Examiner understood the term—as Lilly’s trade name for pemetrexed disodium. Examiner rejected claims related to ALIMTA trademark under 35 U.S.C. 112, second paragraph because it is improper to use trademark in the claims according to MPEP. In response to the rejection, Lilly canceled its claims reciting the trade name and pursued claims using the generic name (pemetrexed disodium), which mooted the rejection.Therefore, nothing in the prosecution history suggests that Lilly’s amendment narrowed the claims or or that either Lilly or the Examiner understood “ALIMTA” to mean anything other than pemetrexed disodium.

Thus, the district court properly concluded that prosecution history estoppel does not bar Lilly’s infringement claims under the doctrine of equivalents.

Tuesday, December 22, 2020

Pharma IP Circle has got new address


Dear Readers,

Happy to share that "Pharma IP Circle" blog has moved from blogger to full fledged secure website. Please subscribe to the new blog so that you can get the litigation updates. I would be discontinuing this blog from January 01, 2021 & will share update on only new blog thereafter. You can "subscribe" by putting your name & mail id mentioned on the home page.


Here is the new address:🏠

https://www.pharmaipcircle.com


Thanks for your support. Looking forward to much more in 2021. Happy learning to all!😊


Regards,

Mahendra Gunjal


Saturday, December 19, 2020

Budesonide – USA

 

On Dec. 18, 2020, Federal Circuit affirmed (Rule 36 judgment) Delaware court in Uceris® litigation.

Previously, Plaintiffs Bausch Health Americas, Inc., Salix Pharmaceuticals Ltd., and Cosmo Technologies Limited (collectively, "Plaintiffs") filed complaint asserting that Defendants Actavis Laboratories FL., Inc., Actavis Pharma, Inc., Teva Pharmaceuticals USA, Inc., and Teva Pharmaceutical Industries Ltd. (collectively, "Defendants") infringed and continue to infringe U.S. Patent Nos. 10,052,286, 10,064,878, 10,105,374, 10,143,698, 10,154,964, and 10,172,799 by filing ANDA for budesonide extended release tablets, 9 mg. On Oct 28, 2019, Delaware court issued final order & judgment finding of noninfringement in favor of Defendants.

Thursday, December 17, 2020

Rituximab – USA

 

On Dec. 16, 2020, Federal Circuit affirmed (Rule 36 judgment) PTAB finding method of use patent invalid as obvious.You can find the IPR details reported “"here"” on this blog.

Wednesday, December 9, 2020

Sitagliptin - USA

 

IPR decision: Dec. 08, 2020

AIA Review #

Filing Date

Institution Date

Petitioner

Patent

Respondent

Status

IPR2020-01045

06/10/2020

09/01/2020

Teva

7,326,708

Merck

Terminated-Settled

Note: Mylan already filed IPR on US’708 patent on 10/30/2019 and PTAB instituted IPR on 05/12/2020. DRL & Sun also filed IPRs (IPR2020-01060 & IPR2020-01072) which were instituted on 09/01/2020.


US 7,326,708 (Merck & Co.; Exp: 05/24/2027 with PED):

1. A dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine of structural formula I:##STR## or a hydrate thereof.


Tuesday, December 8, 2020

Melatonin – UK

 

On Dec. 04, 2020, UK High Court found second medical use patent valid & infringed by Mylan.

Neurim holds EP 1,441,702 patent, which is related to use of melatonin in improving the restorative quality of sleep, in a patient suffering from primary insomnia.  Mylan/Generics UK plans to bring generic version of drug in the market. The issues before court concerned the invalidity of patent as Mylan admitted infringement if patent is found valid. Mylan asserted that claims of patent are invalid under lack of novelty, lack of inventive step & insufficiency. Claims 1 and 4 were of relevance here:

1.       Use of a prolonged release formulation comprising melatonin in unit dosage form comprising 2 mg of melatonin, in the manufacture of a medicament for improving the restorative quality of sleep in a patient aged 55 years or older suffering from primary insomnia characterized by non-restorative sleep, wherein the medicament comprises also at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers, adjuvant or carrier.

4.         A medicament for use in improving the restorative quality of sleep in a patient aged 55 year or older suffering from primary insomnia characterized by non-restorative sleep, which comprises a prolonged release formulation comprising melatonin in unit dosage form, comprising 2 mg of melatonin, and at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers, adjuvant or carrier.

Mylan cited various prior arts among which “Haimov 1995 was closest one. It disclosed effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs by administering 2 mg sustained-release melatonin. With respect to novelty, Court held that Haimov in no way anticipates the patent because study was directed to a completely different matter. The focus was on “melatonin-deficient” individuals, because the aim of the study was to see if the curing of such a deficiency would improve sleep. There was certainly no focus on restorative sleep or quality of sleep in the technical sense as claimed in patent. Court thus concluded that Skilled Person would have learned nothing about the effect of melatonin on Primary Insomnia characterized by non-restorative sleep from Haimov. 

With respect to inventive step, Mylan combined this reference with another references such as “MELATONEX label and Zisapel”. MELATONEX is a dietary supplement containing melatonin which is sold in USA without prescription. MELATONEX supplementation can help to restore the melatonin for a restful, natural sleep. Zisapel is a review of the literature in the area of melatonin treatment. It neither reported any original research nor did it give any meta-analysis of the data reviewed. Court said that Zisapel goes nowhere close to exploring any relationship between non-restorative sleep in Primary Insomniacs and melatonin. There is nothing to render the invention in the patent obvious to the Skilled Person.

With respect to insufficiency also, Court did not convince with Mylan’s argument.  Mylan contended that there was no data in the patent which evidenced the claimed effect, namely an improvement in the restorative quality of sleep in a patient suffering from Primary Insomnia characterized by non-restorative sleep.  Court focused on Examples 2 and 3 and considered whether they render the patent plausible. Court said that these examples disclose reasonably large clinical study in patients who were Primary Insomniacs at least some of whose sleep was characterized by its non-restorative quality. These studies were conducted on established lines and resulted in a statistically significant outcome in that it enabled the conclusion that melatonin enhanced the restorative value of sleep. Thus Court rejected the contention that the patent is invalid by reason of insufficiency.

Thursday, December 3, 2020

Methylphenidate – USA

 

On Nov. 30, 2020, Delaware court on remand found Quillivant XR® patents valid & infringed by ANDA filer in a Hatch-Waxman suit.

Plaintiff (Tris Pharma) filed suit against defendant (Actavis) for alleged infringement of U.S. Patent Nos. 8,465,765; 8,563,033; 8,778,390; 8,956,649 and 9,040,083. Actavis challenged the validity based on obviousness and obviousness-type double patenting. After a five-day bench trial, the original judge (now retired) found all the asserted claims to be invalid for obviousness under 3 5 U.S. C. § 103. Tris appealed. The Federal Circuit vacated the judgment because [the judge]'s obviousness decision lacked the requisite fact-finding, and because the [judge] erred in rejecting Tris's evidence of objective indicia of non-obviousness." The Federal Circuit thus remanded the obviousness analysis to the district court for further fact-finding.

All asserted claims basically related to methylphenidate aqueous extended release oral suspension & its pharmacokinetic (PK) & pharmacodynamic (PD) aspects. Federal Circuit specifically ordered further fact-finding to address whether a liquid MPH formulation with a single mean PK profile, 12-hour duration of effect, 45-minute onset of action, Tmax range of 4 to 5.25 hours would have been obvious over the prior art. Prior arts cited were disclosing one or more limitations but not all. Most of the prior arts were related to ER solid formulations of methylphenidate. Only one art cited was related to liquid formulation but that disclosed IR composition. The question on remand was whether Actavis has demonstrated by clear and convincing evidence that an artisan of ordinary skill would have been motivated to achieve the combination in question and would have had a reasonable expectation of success in doing so.

Court said that Actavis bears the burden & their arguments are confusing and conflicting. Actavis first submitted that POSA would have been motivated to make a formulation with a single peak profile. Court said that assuming arguendo that this fact were established, it would not by itself constitute clear and convincing evidence that an artisan of ordinary skill would have been motivated to combine a single peak profile with a liquid MPH formulation that has both a 12-hour duration and 45-minute onset. On the contrary, Actavis next states in the opening line of its second argument that its own expert, Dr. Staller, established at trial "that POSA would not have been concerned about the specific shape of the PK curve-[because] clinical effects [i.e., PD characteristics as opposed to PK characteristics] are what matter." Court thus said that, so POSA would have been indifferent (i.e., would have lacked motivation) to use a formulation that produced a single peak profile. Actavis' last affirmative argument with respect to motivation to combine a single peak profile, 12-hour duration, and 45-minute onset in a liquid MPH formulation too, lacks merits. Actavis argued that POSA "would have been motivated to pursue this [combination] because [the combination had] already appeared in the prior art." Court however said that only two of the extended release prior art references disclosed formulations with a single mean peak plasma profile, and neither of those references achieved an onset within 45 minutes. Court also said that there was no reasonable expectation of success because prior art taught away from combining in a liquid MPH formulation a single mean peak, 12-hour duration, and 45-minute onset. Specifically, prior art taught that multiple peaks, achieved by multiple pulses of medication, were required to achieve both a 12-hour duration and 45-minute onset. Thus, the prior art taught away from use of a single peak to achieve that combination of clinical effects.

With respect to secondary consideration, court found unexpected results and long-felt, unmet need in favor of Tris. Court said that combination of single peak profile with a 12-hour duration and 45-minute onset was unexpected as discussed above. Moreover, Tris's evidence of long-felt unmet need as of July 2010 for a liquid methylphenidate formulation with a 12-hour duration and 45-minute onset is especially compelling. Because, children, the primary focus of ADHD treatment, often have difficulty swallowing pills; and it is much easier for patients generally and children in particular to comply with a therapy regimen that is accomplished with a single daily dose as opposed to multiple doses taken throughout the day. The need was long-felt and unmet because even though methylphenidate had been used to treat ADHD since the mid-1950s, the only two formulations available as of July 2010 that allowed for a single daily dose regimen (i.e., 12-hour duration of effect) and an early onset were Concerta® and Focalin®, and both of those formulations required the swallowing of a pill or capsule. The only liquid formulation available at the time, Methylin® OS, was an immediate release product with a duration of effect that lasted only three to four hours.

Court thus concluded that all asserted claims are not invalid and defendants infringed each of the asserted claims.

Tuesday, December 1, 2020

Ibuprofen & Famotidine – USA

 

On Nov. 30, 2020, Delaware court found composition patent covering combination invalid as obvious & not infringing.

Background of the case:

Plaintiffs (Horizon) owns NDA for DUEXIS® (ibuprofen and famotidine) tablets, 800 mg / 26.6 mg. It is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers in patients who are taking ibuprofen for those indications. Defendant (Alkem) submitted ANDA on March 31, 2018 seeking USFDA approval to market generic version. Horizon sued Alkem in district of Delaware for infringement of OB listed patents, such as U.S. Patent Nos. 8,309,127, 8,318,202, 8,449,910, 8,501,228 & 8,067,033. By trial the parties narrowed the case to US’033 patent only.

The asserted patent is directed to stable pharmaceutical compositions of famotidine and ibuprofen separated by way of barrier layer in a single dosage form.  Independent claim 1 is:       

1. A pharmaceutical composition comprising a first portion that comprises 800 mg ibuprofen and a second portion that comprises 26.6 mg famotidine, wherein the surface area of direct physical contact between ibuprofen and famotidine does not exceed 130 mm2 , wherein no more than about 1% sulfamide is present when the composition is stored at 40° C. and 75% relative humidity for a period of one month, wherein the composition is formulated so that release of both the ibuprofen and the famotidine occurs rapidly at about the same time, wherein none of the composition, the famotidine, and the ibuprofen is enterically coated or formulated for sustained or delayed release, and wherein the composition is for use according to a TID (three times per day) administration schedule for reducing 4 the risk of developing ibuprofen-induced ulcers in a human patient requiring ibuprofen for an ibuprofen-responsive condition.

It was known that Ibuprofen (NSAID) causes ulceration when used in the treatment. Therefore search was carried out to prevent this side effects. Famotidine is a gastroprotectant which helps to reduce this side effect. But both these two active ingredients are not compatible when used together. Therefore, plaintiff come with the dosage form where these two actives are separated, such as tablet in tablet dosage form. By doing this the interaction between these two actives was avoided, thus reducing the impurity formation & providing stable product with no or less side effects.

Obviousness:

Defendant argued that asserted claims are invalid as obvious over certain prior arts. These prior arts disclosed claimed limitations such as combination of actives, their dose, their interaction & formation of impurity etc.  One of them was US 2007/0043096, where dispute arose to determine whether it is a prior art under 102(a). [US’096 discloses unit dosage form comprising ibuprofen & famotidine, in amounts suitable for three times per day administration.]  The priority date of the US’033 patent is Nov. 2007. US’096 application was published in Feb. 2007. Defendant argued that US’096 is “by another” as it mentioned different inventors than the US’033. Plaintiff argued that it is not “by another” because the inventive idea was conceived by same inventors mentioned on both US’033 patent & US’096 application. Court, however disagreed & said that claimed limitation regarding stability was not conceived by these same inventors. It was a work from other inventor & therefore it is a prior art under 102(a). Other prior arts disclosed other claimed limitations such as impurity level, rapid dissolution, reduction of risk of ulcer etc.  Plaintiff argued that there was not motivation & reasonable expectation of success in combining these prior arts. But, district court disagreed & said that POSA would have reasonable expectation of success  in doing so because most of things were known in the art with rational behind that.

Indefiniteness:

Defendant argued that the “no more than about 1% sulfamide” limitation is indefinite because scope of the invention in not clear to POSA. Defendant argued that the ’033 patent does not define “sulfamide,” provides no chemical name, structure or specific method of testing for “sulfamide,” does not refer to the USP or Famotidine Impurity C, and does not provide any method for identifying or quantifying “sulfamide” in a composition. Court, however, disagreed & said that a POSA would understand “sulfamide” in the “no more than about 1% sulfamide” limitation in all the asserted claims to be USP Famotidine Impurity C.  US’033 patent explains that “sulfamide” is “a principal degradant of famotidine formed by the interaction of famotidine and ibuprofen.” Therefore, “a POSA would have understood that ‘sulfamide’ in the ’033 patent does not refer to the small molecule sulfamide, but instead means Famotidine Impurity C in the USP because it is the only known principal degradant that contains a sulfamide functional group and that is formed as a result of the acid-catalyzed hydrolysis of famotidine.”

Infringement:

Plaintiff argued that Alkem’s ANDA Product infringes the asserted claims under DOE. Court’s construed - “a first portion” as reciting “an ibuprofen compartment that is not a core” and “a second portion” as reciting “a famotidine compartment that is not a shell”. Plaintiff applied DOE theory to more than one claim element — “a first portion” and “a second portion” — at the same time. Court said that Plaintiff was specifically instructed at trial to provide legal support for this, which seemingly contradicts applying DOE on an element-by-element basis, not to the invention as a whole. Court found DOE theory inapplicable here but still proceeded with the analysis.

Alkem’s ANDA Product is a tablet-in-tablet dosage form with a barrier-coated ibuprofen (800 mg) core portion and a famotidine (26.6 mg) shell portion; on the other hand, the claimed composition required a famotidine (26.6 mg) core and an ibuprofen (800 mg) shell, with an optional barrier layer. Defendant argued the difference in design is not trivial stating that Alkem’s ANDA Product is substantially different in at least two important ways – stability and dissolution. In terms of stability, Alkem contended that the asserted claims rely on the geometry of the small famotidine core to reduce and/or minimize “the surface area of the core, or of direct physical contact between the incompatible active pharmaceutical ingredients.” Moreover, a barrier layer is optional in claimed invention due to the design of the invention. This is not the case with defendant’s product.  Court said that the inventive aspect of the ’033 patent is a stable pharmaceutical composition of famotidine and ibuprofen in a single unit dosage form comprising a famotidine core, having a reduced or minimal surface area, surrounded by a layer of ibuprofen. The specification repeatedly highlights the increased stability provided by the disclosed geometry. Unlike the pharmaceutical composition of the asserted claims, Defendant’s ANDA Product must use a barrier layer and cannot rely on the geometry of a small famotidine core. Therefore, in regard to stability, Defendant’s ANDA Product is substantially different as geometry contributes nothing to stability.

In terms of dissolution, Defendant argued that its ANDA Product is substantially different from the claims. Defendant argued that when DUEXIS® (commercial embodiment of the ’033 patent) is exposed to the dissolution medium, the ibuprofen begins to dissolve from the shell immediately and the famotidine does not begin to significantly dissolve until the dissolution medium further penetrates into the core (i.e., about five minutes later). When Alkem’s ANDA Product is exposed to the dissolution medium, the famotidine begins to dissolve from the shell immediately and the ibuprofen does not begin to significantly dissolve until the dissolution medium further penetrates into the core (i.e., about fifteen minutes later). Court said that, Defendant’s arguments are not as strong. While there is a discernable difference in the release of the ibuprofen and famotidine in Defendant’s ANDA Product occurring about fifteen minutes later than in DUEXIS®, the later release still meets the claim limitation of “release of both the ibuprofen and the famotidine occurring rapidly at about the same time” when “at about the same time” is defined as the ‘033 patent specification defines it: “release of one API begins before release of the second API is completed.”

Under “Function-Way-Result” test, Court agreed with Defendant & said that the ’033 patent specification teaches the use of geometry, with the option of a barrier layer. Moreover, using the design of the present invention, the barrier layer can be omitted without sacrificing stability. Under this view of the “function-way-result” test, while the function and the result may be substantially the same, the way is not. The way does not use geometry at all. As Alkem’s ANDA Product requires a barrier layer as a consequence of its geometrical design, it does not infringe under the “function-way-result” test.


Thursday, November 26, 2020

Vilanterol / Umeclidinium – USA

 

On Nov. 19, 2020, Federal Circuit affirmed judgment of infringement & damages against Glaxo.

Plaintiff (Vectura Ltd) filed suit in 2016 against defendant (Glaxo) for alleged infringement of US 8,303,991 patent. The ’991 patent concerns the production of “composite active particles” for use in pulmonary administration, such as in dry-powder inhalers. The composite active particles described in the patent consist of additive material (magnesium stearate) that is adhered to particles of active ingredient. The additive particles promote the dispersion and delivery of the active ingredient into the lungs when the inhaler is activated. The specification discloses “milling method” to produce composite active particles.

In the district court, Vectura alleged infringement by GSK’s Ellipta-brand inhalers: the Breo, Anoro, and Incruse devices. Each of the accused inhalers features one or more “blisters,” which are sealed receptacles containing a single active ingredient, an excipient, and, optionally, additive material. The blisters use magnesium stearate as the additive material and lactose as the excipient. GSK uses multi-step mixing process. GSK first mixes the lactose excipient with magnesium stearate in the absence of the active ingredient. After a de-lumping step, GSK then mixes the lactose particles with the active ingredient. In that step, small particles of the active ingredient are deposited onto the larger lactose particles.

The issue here is claim construction of two disputed terms: 1) “composite active particles” and 2) “promotes the dispersion of the composite active particles”.

With respect to first claim construction, GSK’s proposed construction of that term included a process limitation requiring that the composite active particles be “formed by milling . . .But district court rejected that argument & construed the term to mean “[a] single particulate entit[y/ies] made up of a particle of active material to which one or more particles of additive material are fixed such that the active and additive particles do not separate in the airstream.”  During appeal Glaxo challenged the said construction & said that the court should have construed that term to require that the composite particles be produced by the “high energy milling” process referred to in the specification. GKS argued this based on support in the specification & based on prosecution history. During prosecution Vectura said that wet-mixing processes disclosed in prior art were different from the “aggressive milling procedure” recited in the application. For this reason, GSK argued, the applicants clearly disclaimed mixing processes other than high-energy milling, confirming that the term “composite active particles” should be construed to include a process limitation.

Federal Circuit, however, denied the arguments & said that although the ’991 patent contains a few statements suggesting that its high-energy milling is required, those statements are outweighed by the numerous statements indicating that high-energy milling is merely a preferred process. Moreover, the fact that the ’991 patent criticizes other methods is not dispositive. Therefore, the specification of the ’991 patent does not make its milling method an essential part of apparatus claim 1. With respect to prosecution response, Federal Circuit said that the statement did not purport to add a process limitation to the apparatus claim. Instead, that statement merely sought to demonstrate that Prior art’s coated particles were necessarily different from the applicants’ coated particles because it used a process that could not possibly produce “particulate additive matter on the surface of [a] particle of active material,” as required by the applicants’ claim. Applicant distinguished prior art based on the unique structure of the claimed composite particles, not the disclosed milling method.

With respect to second claim construction, Parties agreed that Vectura needed to prove that the use of magnesium stearate in the accused inhalers improves the dispersion of the active ingredient compared to identical products in which only the lactose excipient is coated with magnesium stearate. GSK argued that there was no substantial evidence of infringement as to that limitation because Vectura staked its case on a defective scientific test (referred to as “Study 2). Federal Circuit, however, said that the principal flaw in GSK’s argument is that Vectura did not rely solely on Study 2 to prove that the accused inhalers satisfy the dispersion limitation. Vectura introduced other evidence on dispersion as well. Vectura’s witnesses testified that coating active ingredient particles with magnesium stearate helps overcome the tendency of the particles to stick together and therefore increases the dispersion of the particles in the lungs. Evidence of tests conducted on coated and uncoated active-ingredient particles showed that coating the active particles substantially increased the dispersion of the active-ingredient particles and thus the amount of the active ingredient that could be delivered deep into the lungs. Tests run on GSK’s products showed that the particles of vilanterol and umeclidinium were consistently associated with magnesium stearate.

Federal Circuit thus affirmed the infringement & also damages awarded by the Jury.