Saturday, December 29, 2018

Metformin & Pioglitazone - USA


Decision on IPR: Dec 28, 2018

AIA Review
Filing Date
Institution Date
Petitioner
US Patent
Respondent
FINAL WRITTEN DECISION
IPR2017-01648
06/22/2017
12/29/2017
Aurobindo Pharma USA Inc.
6,866,866
Andrx Labs, LLC
Claims 1–25 are patentable

US 6,866,866 (Andrx Labs, LLC; Exp: 03/17/2021) – listed in OB

1. A controlled release oral dosage form for the reduction of serum glucose levels in human patients with NIDDM, comprising an effective dose of metformin or a pharmaceutically acceptable salt thereof and a controlled-release carrier to control the release of said metformin or pharmaceutically acceptable salt thereof from said dosage form, said dosage form being suitable for providing once-a-day oral administration of the metformin or pharmaceutically acceptable salt thereof, wherein following oral administration of a single dose, the dosage form provides a mean time to maximum plasma concentration (Tmax) of the metformin from 5.5 to 7.5 hours after administration following dinner.


Saturday, December 22, 2018

Dexmedetomidine – USA


On Dec 17, an Illinois federal judge invalidated two patents covering a “ready-to-use” version of Hospira Inc.’s sedation drug Precedex.

Background:

Hospira is the owner of brand Precedex® (100 µg/mL, approved in 1999) & new product, known as Precedex Premix (4 µg/mL, approved in 2013 & 2014 in different strengths).  Precedex Premix, is a ready-to-use, diluted version of a Hospira product that has been on the market since 1999. That product, known as Precedex Concentrate, is formulated at 100 micrograms per milliliter (µg/mL) and must be diluted with saline to a concentration of 4 µg/mL before being administered to patients. Precedex Premix has the same formulation and the same package configuration as Precedex Concentrate but is pre-diluted with saline to a 4 µg/mL concentration (Precedex Premix, is the subject of the patents-in-suit). Fresenius Kabi notified Hospira that it had filed an ANDA with the FDA, seeking approval to market its own proposed dexmedetomidine products prior to the expiry of Hospira’s patents [U.S. Patent Nos. 8,242,158 (07/04/2032), 8,338,470 (07/04/2032), 8,455,527 (07/04/2032), and 8,648,106 (07/04/2032)]. Hospira filed suit a month later, alleging patent infringement. In 2017, Hospira obtained a fifth patent covering the same dexmedetomidine product—U.S. Patent No. 9,616,049 (07/04/2032)—and filed a second complaint of patent infringement. Following the court’s claim construction order in Nov. 2017, the parties jointly agreed to limit the number of patent claims asserted in both actions. Since then, Hospira has dropped all but claim 6 of the ’106 Patent and claim 8 of the ’049 Patent. Fresenius Kabi has stipulated that its proposed product would infringe those claims, but maintains its challenges to their validity. The court held a five-day bench trial on the issue of the validity of these claims on July 16, 2018 through July 20, 2018.

Independent claim 1 and dependent claim 6 of the ’106 Patent read as follows:

1. A ready to use liquid pharmaceutical composition for parenteral administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof disposed within a sealed glass container, wherein the liquid pharmaceutical composition when stored in the glass container for at least five months exhibits no more than about 2% decrease in the concentration of dexmedetomidine.

6. The ready to use liquid pharmaceutical composition of claim 1, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 4 μg/mL.

Independent claim 1 and dependent claim 8 of the ’049 Patent read as follows:

1. A ready to use liquid pharmaceutical composition for parenteral administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 0.005 to about 50 μg/mL disposed within a sealed glass container, wherein the liquid pharmaceutical composition has a pH of about 2 to about 10.

8. The ready to use liquid pharmaceutical composition of claim 1, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 4 μg/mL.

Prior arts include among other things mainly, US 4,910,214 (discloses use of dexmedetomidine as a sedative), Precedex Concentrate label (as discussed above), Dexdomitor-2002 (EU approved ready-to-use, 500 μg/mL product), articles by John Fanikos (RTU drug formulations & preparations in general), James G. Cain (premixed syringes of dexmedetomidine, 10 mL with 4 mcg/mL) & Gregory A. Sacha (Glass Storage Containers). All these references were published or otherwise available before Jan 4, 2012.

Court’s analysis:

Fresenius Kabi argued that claim 6 of the ’106 Patent and claim 8 of the ’049 Patent are invalid as obvious under 35 U.S.C. § 103(a). Fresenius Kabi specifically argued that a POSA would have been motivated to combine the disclosures in Precedex Concentrate, Fanikos, the CSHP Guidelines, Cain, Remington, and Sacha to create a ready-to-use 4 μg/mL dexmedetomidine HCl formulation, stored in a Type I glass vial, sealed with a coated rubber stopper. According to Fresenius Kabi, the prior art expressly disclosed these claim limitations. Fresenius relied on doctrine of inherency argument for claim limitation “no more than about 2%” loss in concentration at five months.”  In its post-trial brief, Hospira did not specifically rebut most of the contentions, but it disputed the “about 2%” limitation of the ’106 Patent. Hospira’s key arguments for non-obviousness are that Fresenius Kabi has failed to prove by clear and convincing evidence (1) the inherency of the “about 2%” limitation and (2) that a POSA would have been motivated to combine the prior art teachings with a reasonable expectation of success.

1. Ready-to-Use, Sealed Glass Container with 4 μg/mL Dexmedetomidine HCl:

Precedex Concentrate has been on the market since 1999. Its label discloses the exact contents of its formulation, including that it contains no preservatives, additives, or chemical stabilizers. A named co-inventor of the ’106 Patent, Dr. Roychowdhury, admitted that the label taught her the formulation and that there is “no difference between the formulations of the further diluted Precedex concentrate versus the Precedex Premix product.” Hospira’s corporate representative, Dr. Tata-Venkata, gave similar testimony. The Precedex Concentrate label also discloses that the formulation must be diluted to 4 μg/mL before being administered to humans and sets forth the steps to perform the dilution. Drs. Roychowdhury and Cedergen testified they knew from the label that their goal was to make a 4 μg/mL formulation. For these reasons, the court concluded that the Precedex Concentrate label disclosed how to make the 4 μg/mL formulation. The court also concluded that Precedex Concentrate disclosed a glass container as a storage material for dexmedetomidine HCl. In addition, the court concluded that Precedex Concentrate disclosed the use of a coated rubber stopper to seal the Type I glass vial.

2. The “About 2%” Limitation:

Because the prior art did not explicitly disclose the “about 2%” limitation of claim 6, Fresenius Kabi relied on the doctrine of inherency to supply it. Hospira contended that Fresenius Kabi has not established inherency because it has failed “to exclude the possibility that the combination could be prepared in a way that would fail the limitation.” Court while disagreeing with Hospira, said that Fresenius Kabi need not to prove that every possible embodiment of claim 6 necessarily meets the “about 2%” limitation, that is not the law. Rather, to prove that a claim covering multiple alternative embodiments is invalid, a defendant need only prove that one of the embodiments is invalid (In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1281 (Fed. Cir. 2015). Having disposed of Hospira’s threshold arguments, the court held that all stability data in the record for the 4 μg/mL preferred embodiment shows that there was “no more than about 2%” loss in the tested samples at five months. The data includes stability test results disclosed in the patent, eighteen batch configurations of Precedex Premix in upright and inverted storage, measurements from three batches of Precedex Premix and three batches of Fresenius Kabi’s ready-to-use product. Significantly, this data shows not only that samples from the 4 μg/mL preferred embodiment necessarily lost no more than about two percent of their concentration at five months, but also that many samples lost less than two percent.

Hospira contended that Fresenius Kabi cannot rely on any of the data for the 4 μg/mL preferred embodiment because it is either Hospira’s own development work for the patents-in-suit or is copied from it. But court disagreed & said that in this case, the limitations alleged to have an inherent property when combined are explicitly disclosed in the prior art, and a POSA would have been motivated to combine them. Analyzing data from this prior art combination in order to confirm that a property is in fact inherent is not an application of hindsight, even if the data comes from the inventors. Hospira next argued that even if Fresenius Kabi can rely on this data, the data does not prove inherency by clear and convincing evidence. In support of this argument, Hospira submits that Fresenius Kabi ignored that Hospira’s development work revealed a 2.3 percent loss in concentration after five months. As Fresenius Kabi points out, this argument is puzzling because that data supports the only example in the patent of the “about 2%” limitation. And as previously discussed, named co-inventor of the ’106 Patent, Dr. Roychowdhury, testified that 2.3 percent is “within” two percent. Hospira’s argument that its own development work precludes a finding of inherency is unpersuasive.

The court said that it is aware that in Amneal, in which Hospira has asserted claim 6 of the ’106 Patent against another defendant, the Delaware court determined that the defendant failed to establish inherency of the “about 2%” limitation. The Amneal court faulted the defendant for “offering no expert testimony regarding the scientific principles underlying its inherency argument, and relying on just two examples of stability data covering the claimed 4 μg/mL dexmedetomidine concentration.” The record before this court is different. As referenced above, Fresenius Kabi has offered far more than two examples of stability data for the 4 μg/mL preferred embodiment, all of which show that the drug lost no more than two percent of its concentration at five months. Additionally, unlike in the defendant in Amneal, Fresenius Kabi has offered expert testimony regarding the chemical properties of dexmedetomidine.

Reasonable expectation of success:

Fresenius Kabi argued that a POSA would have had a reasonable expectation of success for developing a ready-to-use, sealed glass container with 4 μg/mL dexmedetomidine HCl. Setting aside the “about 2%” limitation, the court found that a POSA would have had a reasonable expectation of success from combining a 4 μg/mL dexmedetomidine formulation with a Type I glass vial, sealed with a coated rubber stopper. Whether Fresenius Kabi must also prove that a POSA would have had a reasonable expectation of success concerning the “about 2%” limitation is not entirely clear to the court. Because claimed inherent property “added nothing of patentable consequence” to a formulation expressly disclosed in the prior art, without addressing reasonable expectation of success regarding the inherent property. But to the extent such a burden exists, the court concludes Fresenius Kabi has met it. Therefore, the court concluded that there is clear and convincing evidence that a POSA would have had a reasonable expectation of success in meeting the “about 2%” limitation based on the chemical properties of dexmedetomidine; evidence tending to show that dexmedetomidine’s concentration does not affect its stability; and the disclosures in the Precedex Concentrate and Dexdomitor labels.

Like claim 6 of the ’106 Patent, claim 8 of the ’049 Patent covers a ready-to-use, sealed glass container with 4 μg/mL dexmedetomidine HCl. The court has already concluded for purposes of claim 6 of the ’106 Patent that the prior art discloses each of these limitations; a POSA would have been motivated to combine the disclosures; and a POSA would have had a reasonable expectation of success in doing so. That conclusion applies equally to claim 8 of the ’049 Patent. Thus, court finally concluded that Fresenius Kabi has proven by clear and convincing evidence that claim 6 of the ’106 Patent and claim 8 of the ’049 Patent are invalid as obvious.

Friday, December 21, 2018

Trastuzumab - USA


Decision on IPR: Nov 20, 2018

AIA Review
Filing Date
Institution Date
Petitioner
US Patent
Respondent
Status
IPR2017-02019
08/29/2017
03/12/2018
Pfizer, Inc.
6,339,142
Genentech, Inc.
Terminated
IPR2017-02020
08/29/2017
03/12/2018
Pfizer, Inc.
9,249,218
Genentech, Inc.
Terminated
On US’142 & US’218 patents, Pfizer previously filed IPRs (IPR2018-00330 & IPR2018-00331) on 12/18/2017 which were denied by PTAB.

US 6,339,142 (Genentech, Inc.; Exp: May 03, 2019):

1. A composition comprising a mixture of anti-HER2 antibody and one or more acidic variants thereof, wherein the amount of the acidic variant(s) is less than about 25%.

US 9,249,218 (Genentech, Inc.; Exp: May 03, 2019*TD):

1. A therapeutic composition comprising a mixture of anti-HER2 antibody and one or more acidic variants thereof, wherein the amount of the acidic variant(s) is less than about 25%, and wherein the acidic variant(s) are predominantly deamidated variants wherein one or more asparagine residues of the anti-HER2 antibody have been deamidated, and wherein the anti-HER2 antibody is humMAb4D5-8, and wherein the deamidated variants have Asn30 in CDR1 of either or both V.sub.L regions of humMAb4D5-8 converted to aspartate, and a pharmaceutically acceptable carrier.

Patisiran - USA


Decision on PGR: Nov 20, 2018

AIA Review
Filing Date
Institution Date
Petitioner
US Patent
Respondent
Status
PGR2018-00075
07/09/2018
--
Alnylam Pharmaceuticals, Inc.
9,783,802
Silence Therapeutics GMBH
Terminated-Settled
PGR2018-00088
07/17/2018
--
Alnylam Pharmaceuticals, Inc.
9,790,505
Silence Therapeutics GMBH
Terminated-Settled
PGR2018-00089
07/17/2018
--
Alnylam Pharmaceuticals, Inc.
9,790,501
Silence Therapeutics GMBH
Terminated-Settled

US 9,783,802 (Silence Therapeutics GMBH; Exp: Aug 05, 2023*TD):

1. A double stranded siRNA molecule against a target nucleic acid, wherein the double stranded siRNA molecule comprises a first strand and a second strand, wherein the first strand comprises a first stretch that is complementary to the target nucleic acid, wherein the second strand comprises a second stretch that has the same length as the first stretch and is complementary to the first stretch, wherein the first strand and the second strand form a double-stranded structure comprising the first stretch and the second stretch, wherein the first stretch and the second stretch each has the length of 18-19 nucleotides, wherein the first stretch and the second stretch each comprises unmodified ribonucleotides and 2'-O-methyl ribonucleotides, wherein at least one of the two strands has an overhang of at least one nucleotide, and wherein the overhang comprises at least one deoxyribonucleotide.

US 9,790,505 (Silence Therapeutics GMBH; Exp: Aug 05, 2023*TD):

1. A double stranded siRNA molecule against a target nucleic acid, wherein the double stranded siRNA molecule comprises a first strand and a second strand, wherein the first strand comprises a first stretch that is complementary to the target nucleic acid, wherein the second strand comprises a second stretch that has the same length as the first stretch and is complementary to the first stretch, wherein the first strand and the second strand form a double-stranded structure comprising the first stretch and the second stretch, wherein the first stretch and the second stretch each has the length of 17-21 nucleotides, wherein the first stretch and the second stretch each comprises a plurality of groups of 2'-O-methyl ribonucleotides flanked on one or both sides by a flanking group of unmodified ribonucleotides or modified ribonucleotides different from 2'-O-methyl ribonucleotides, and wherein at least one of the two strands has an overhang of at least one nucleotide at the 3'-end.

US 9,790,501 (Silence Therapeutics GMBH; Exp: Aug 05, 2023*TD):

1. A double-stranded siRNA molecule against a target nucleic acid, wherein the double-stranded siRNA molecule comprises a first strand and a second strand, wherein the first strand comprises a first stretch that is complementary to the target nucleic acid, wherein the second strand comprises a second stretch that is the same length as the first stretch and is complementary to the first stretch, wherein the first strand and the second strand form a double-stranded structure comprising the first stretch and the second stretch, wherein the first stretch and the second stretch each comprises contiguous alternating 2'-O-alkyl ribonucleotides, wherein the 2'-O-alkyl ribonucleotides alternate with unmodified or differently modified ribonucleotides, wherein the 2'-O-alkyl ribonucleotides of the first strand are shifted by one ribonucleotide relative to the 2'-O-alkyl ribonucleotides of the second strand, and wherein each of the first stretch and the second stretch consists of at least 17 and fewer than 30 ribonucleotides.

Both the parties have also settled their dispute in EU & worldwide. See below press release for more information.

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Dec. 10, 2018-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that it has resolved all litigation worldwide with Silence Therapeutics. The settlement allows Alnylam to avoid the costs and distraction associated with continued litigation in multiple countries. Under terms of the global settlement, Silence will receive a low royalty on annual net sales of ONPATTRO in the EU only, with tiered royalties of 0.33 percent to 1.0 percent through 2023.


Thursday, December 20, 2018

Patisiran - USA


Decision on PGR: Nov 19, 2018

AIA Review
Filing Date
Institution Date
Petitioner
US Patent
Respondent
Status
PGR2018-00059
04/02/2018
10/10/2018
Alnylam Pharmaceuticals, Inc.
9,695,423
Silence Therapeutics GMBH
Terminated-Settled
PGR2018-00067
06/11/2018
--
Alnylam Pharmaceuticals, Inc.
9,758,784
Silence Therapeutics GMBH
Terminated-Settled

US 9,695,423 (Silence Therapeutics GMBH; Exp: Aug 05, 2023*TD):

1. A double-stranded siRNA molecule wherein: (i) at least one strand of the double-stranded siRNA molecule comprises one or more groups of modified nucleotides and one or more groups of flanking nucleotides, the flanking nucleotides being on one or both sides of the modified nucleotides, wherein: the one or more groups of modified nucleotides have an amino, fluoro, alkoxy, or alkyl modification at the 2'-position; and the one or more groups of flanking nucleotides have an amino, fluoro, alkoxy, or alkyl modification at the 2'-position, the modification at the 2'-position of the flanking nucleotide being different from the modification at the 2'-position of the modified nucleotide, (ii) the number of nucleotides in the one or more groups of modified nucleotides is 1-10 and the number of nucleotides in the one or more groups of flanking nucleotides is 1-10; (iii) the double-stranded siRNA molecule has a double-stranded region of 17-21 nucleotides in length; and (iv) the double-stranded siRNA molecule is capable of RNA interference.

12. A double-stranded siRNA molecule wherein: (i) each strand of the double-stranded siRNA molecule comprises one or more groups of modified nucleotides and one or more groups of flanking nucleotides, the flanking nucleotides being on one or both sides of the modified nucleotides, wherein the one or more groups of modified nucleotides have an amino, fluoro, alkoxy, or alkyl modification at the 2'-position; and the one or more groups of flanking nucleotides have an amino, fluoro, alkoxy, or alkyl modification at the 2'-position, the modification at the 2'-position of the flanking nucleotide being different from the modification at the 2'-position of the modified nucleotide, (ii) the number of nucleotides in the one or more groups of modified nucleotides is 1-10 and the number of nucleotides in the one or more groups of flanking nucleotides is 1-10; (iii) the double-stranded siRNA molecule has a double-stranded region of 17-21 nucleotides in length; and (iv) the double-stranded siRNA molecule is capable of RNA interference.

US 9,758,784 (Silence Therapeutics GMBH; Exp: Aug 05, 2023*TD):

1. A double-stranded siRNA molecule against a target nucleic acid, wherein the double-stranded siRNA molecule comprises a first strand and a second strand, wherein the first strand comprises a first stretch that is complementary to the target nucleic acid, wherein the second strand comprises a second stretch that is complementary to the first stretch, wherein the first strand and the second strand form a double-stranded structure comprising the first stretch and the second stretch, wherein the double-stranded siRNA molecule is blunt ended on at least one end, and wherein each stretch consists of at least 15 and fewer than 30 ribonucleotides and wherein the first stretch and the second stretch each comprises contiguous alternating modified ribonucleotides, wherein the alternating modified ribonucleotides alternate with unmodified or differently modified ribonucleotides.

Both the parties have also settled their dispute in EU & worldwide. See below press release for more information.

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Dec. 10, 2018-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that it has resolved all litigation worldwide with Silence Therapeutics. The settlement allows Alnylam to avoid the costs and distraction associated with continued litigation in multiple countries. Under terms of the global settlement, Silence will receive a low royalty on annual net sales of ONPATTRO in the EU only, with tiered royalties of 0.33 percent to 1.0 percent through 2023.


Wednesday, December 19, 2018

Insulin product(s) - USA


Decision on IPR: Nov 19, 2018

AIA Review
Filing Date
Institution Date
Petitioner
US Patent
Respondent
Status
IPR2018-01677
09/10/2018
--
Mylan Pharmaceuticals Inc.
8,992,486
Sanofi-Aventis US LLC
Terminated-Dismissed

On US’486 patent, Mylan previously filed IPRs (IPR2018-01678, IPR2018-01679 & IPR2019-00122) which are pending as on date.

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

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.

Tiotropium - Netherlands


On Dec 11, 2018, Court of Appeal affirmed the district court’s judgment that amended claims of patent covering inhalation capsule lack inventive step.

Previously, on Sep 07, 2016, District Court of the Hague revoked Dutch part of a European patent (EP1379220) held by Boehringer due to a lack of inventive step. Boehringer is the holder of European patent EP’220 for ‘Inhalation capsules with certain moisture content’, granted on 29 December 2004. EP’220 broadly claims capsule material that has reduced moisture content as a TEWS or halogen drier moisture content of less than 15%. In dependent claims it further narrow downs to less than 5%.  Teva initiated the proceedings for annulment of certain claims of EP'220. The District Court concluded that in absence of criticality of moisture content values, the technical problem is to provide an alternative capsule material for tiotropium to be administered by means of an inhaler. And this problem would be solved by the skilled person without inventive step in the light of an article titled “HPMC Capsules – An Alternative to Gelatin” (Ogura et al). Thus Teva’s claim for annulment of certain (amended) claims of EP’220 was granted.

Court of appeal while affirming the district court’s decision said that the tiotropium in powder form in a capsule for use in a DPI was already known from clinical trials on the priority date (described in Casaburi, among others). Boehringer has not substantiated why the average person skilled in the art, given the technical problems, would find it necessary to make some change. The difference measure to be taken into account only concerns the use of HPMC instead of gelatin as capsule material, without any specific benefit being attached to it. The conclusion is that the reduced moisture content as TEWS or halogen dryer moisture content of <5% (less than 4%, respectively, less than 2%, respectively) from amended claims 6 to 8, have no technical effect attached to it. It follows that the limit values ​​mentioned in claims 6 to 8 cannot be seen otherwise than as arbitrary choices, in which no inventive work can be based on the state of the art recognized. The court has therefore rightly conceded that the inventiveness cannot lie in those particular characteristics.

In addition, Boehringer's view cannot be accepted as correct, since it was known to the average person skilled in the art that disadvantages were associated with the use of gelatine capsules, in particular that such capsules become brittle if the moisture content of the gelatin drops below 10%. This allows the capsules to break easily during storage or use (especially during perforation) and thus become unsuitable for use. Preventing these problems places demands on production and storage conditions and / or packaging. Furthermore, it was known that gelatin can build up a static charge, as a result of which fine particles can stick to the inside of the capsule and the capsule is therefore not completely emptied. In addition - perhaps less, but not without importance - gelatine is an animal material, against the use of which some people object. In the opinion of the Court of Appeal, these drawbacks associated with the use of gelatin are sufficient motivation for the average person skill in the art to investigate the possibility of alternative capsule material, even though tiotropium itself is not sensitive to moisture.

Ogura states precisely that HPMC capsules are suitable for use with an inhaler and Boehringer has not substantiated why the average person skilled in the art would doubt this. Furthermore, it has not been stated or showed that doing research into perforations and the emptying properties of HPMC capsules would require more for the average person skill in the art than doing routine testing or otherwise producing an 'undue burden'. The fact that the average person refrains from research into the suitability of HPMC as capsule material because these capsules are not yet on the market and that a new market authorization is required for such a product cannot be accepted as well.

Therefore, this leads to the conclusion that the average person skilled in the art, starting from Casaburi and acquainted with Ogura, would find the solution to the problem at hand, without inventive work.

Monday, December 17, 2018

Vilanterol & Umeclidinium - UK


On Dec 13, 2018, UK high court found Vectura’s patents invalid, not infringed by Glaxo & thus granted Arrow declaration.

Background:

Vectura (Defendant) alleged that the  GSK (Claimant) have infringed the patents by the manufacture and sale of dry powder inhalers (“DPIs”) containing the active ingredients vilanterol trifenatate (“vilanterol”) and/or umeclidinium bromide (“umeclidinium”) which are used to treat asthma and chronic obstructive pulmonary disease (“COPD”) and which GSK market under the trade mark Ellipta.

Vectura is the proprietor of European Patents (UK) Nos. 1337240 (“240”), 2283817 (“817”), 2283818 (“818”), 1337241 (“241”) and 1920763 (“763”). The patents all have the same earliest claimed priority date of 30 November 2000. Patents claim “composite active particles” & methods of making same. The composite active particles are very fine particles of active material which have upon their surfaces an amount of the additive material. The additive material is preferably in the form of a coating on the surfaces of the particles of active material. Vectura only rely upon claims which require the Magnesium sterate (additive material) to form a coating on the surface of the active. Certain claims require that “the particles of additive material become fused to the surface of the particles of active material”.  It is common ground that these phrases are all ways of describing the same concept, namely that the structure of the additive particles is altered in the milling process so that they become structurally combined with the surface of the active particles. The additive particles no longer keep their original particulate shape and instead deform over the surface of the active particles (i.e. so as to form a coating, which may be discontinuous). 

On 5 August 2010 Vectura granted GSK a licence in respect of Staniforth and any patents deriving from it (“the Staniforth Patents”). GSK exploited the Staniforth Patents and paid Vectura substantial royalties pursuant to this agreement. The agreement identified an additional class of patent applications (referred to as “the Non-Assert Patents”) in respect of which GSK had the option to take a licence. The Staniforth Patents expired on 31 January 2016. On 8 February 2016 GSK informed Vectura that it did not require a licence under of the Non-Assert Patents. GSK’s position was that it uses an obvious development of the process disclosed in Staniforth and not the processes claimed in the patents. Vectura commenced proceedings against GSK for Non-Assert Patents & in response GSK commenced these proceedings. GSK deny infringement and claim revocation of the patents on the grounds of obviousness over three prior arts and insufficiency. GSK also contended that they have a Gillette defence because their process is objectively obvious in the light of the prior art & seeks Arrow declaration. In a nutshell, GSK say that, although their process uses MgSt, this is disclosed by each of the three items of prior art.

Infringement:

GSK disputed the infringement for five main reasons. First, GSK deny that their process includes a milling step where this is required. Secondly, GSK rely on the fact that, if they mill, they do so in the absence of the lactose. Thirdly, GSK dispute that the MgSt particles become structurally combined with the active particles to form composite active particles. Fourthly, GSK dispute that the MgSt is fused to/smeared over the surfaces of the active particles so as to form a coating. Fifthly, GSK dispute that the MgSt is evenly distributed over the active material as required by claim. Vectura relies upon the results of the SEM and EDX experiments carried out by the parties to establish that these integers of the claims are satisfied by GSK’s process and products. GSK challenge the suitability of these techniques for this purpose.

Court said that GSK do not dispute that the experiments show the presence of magnesium, and hence MgSt, in the samples examined. Nor do GSK dispute that it may be concluded that MgSt was closely associated with particles of the active ingredients. But the crucial question is whether Vectura’s experiments demonstrate the presence of composite active particles with MgSt structurally combined with and fused to/smeared over the surfaces of active particles so as to form a coating. On this question there was little disagreement between the experts. Having considered the evidence as a whole, court held that the limitations of EDX experiment, together with the absence of validation, mean that one can have no confidence that the MgSt is on the surface of the active particles, let alone structurally combined with and fused to/smeared over them. It may be, but equally it may not. Therefore, Vectura has not established that GSK have infringed the patents.

Insufficiency:

GSK contend that the specifications of the patents do not disclose the invention clearly and completely enough for it to be performed by a person skilled in the art. Specifically, GSK contend that the patents are insufficient because they do not enable the skilled person to determine whether a process or product falls within the claims since they do not enable the skilled person to determine whether or not there are composite active particles with additive particles fused to/smeared over active particles so as to form a coating, and certainly do not enable the skilled person to do so without undue burden. GSK accept that the skilled person would consider it plausible that, if the process described in Example 4 is followed, the MgSt would deform and spread over the surfaces of the active particles, but point out that the Example does not demonstrate that the MgSt particles are structurally combined with the active particles or fused to/smeared over them to form a coating. Even assuming that the skilled person took on trust the assertion that Example 4 did produce composite active particles as claimed, GSK contend that the skilled person would not know how to determine whether any other process did so. Court agreed with GSK & held that the limitations of EDX mean that it is not a suitable technique for this purpose, at least in the absence of validation, as is demonstrated by Vectura’s failure to establish infringement. This is not because of any peculiarity in GSK’s process, but due to the nature of the technique and Vectura’s failure to validate its use for this purpose. Accordingly, court concluded that the patents are insufficient because they do not enable the skilled person to determine whether or not a process or product is within the claims. Certainly, the patents do not enable the skilled person to do so across the breadth of the claims without undue effort.

Obviousness:

The prior arts disclose blending of MgSt with lactose so as to coat the lactose with the MgSt, followed by blending the mixture with API. Court in conclusion said that there is no evidence, however, that following the teaching of prior arts using a high-shear blender would produce composite active particles with MgSt fused to/smeared over the active particles to form a coating as claimed in the patents. Therefore, GSK have not established that any of the Patents are obvious over prior arts.

Arrow declaration:

An Arrow declaration is, in effect, a declaration that, as of a particular date, a party as Gillette defence against claims of infringement of later patents. In response to GSK’s application to strike out the claim for Arrow relief, Vectura gave an undertaking that it will not assert in any patent applications from within the Non-Assert Patent families. GSK say that Vectura has shown a propensity over many years to describe what is essentially a single inventive concept in a variety of ways. Vectura has the potential to continue to reformulate the inventive concept using applications which are still on file, even if GSK were successful in revoking each of the patents. Vectura contends that its undertaking gives GSK all the protection they require assuming that Vectura is unsuccessful in its claim for infringement of the patents, and according the declarations sought by GSK will not serve a useful purpose. Court said that the GSK’s process and the products obtained thereby, were obvious over prior arts as at 30 November 2000. That is a necessary foundation along with the other evidences for the relief sought by GSK.

Summary of principal conclusions:

i)  Vectura has not established that GSK’s process or products infringe any of the patents;
ii)  all of the patents are invalid on the ground of insufficiency;
iii)  GSK have not established that any of the patents were obvious over any of the cited prior art;
iv)   GSK’s process, and products obtained directly from it, were obvious over prior arts; and
v)   it is appropriate to grant GSK an Arrow declaration in the form of Declaration B, but not Declaration A.

Saturday, December 15, 2018

Paclitaxel - CJEU


On Dec 13, 2018, Advocate General of Court of Justice of European Union (CJEU) opined on the issue of interpretation of Article 3(d) of SPC regulation concerning the applicability of SPC for new formulation of old product.

Background:

This request was made in the context of a dispute between the company Abraxis Bioscience LLC (‘Abraxis’) and the Comptroller General of Patents, Designs and Trademarks (‘the Comptroller’). Abraxis is seeking from the national court the annulment of the Comptroller’s decision to reject the SPC application made by Abraxis for a combination of substances containing the active ingredient paclitaxel in the form of nanoparticles bound to albumin (‘nab-paclitaxel’). Nab-paclitaxel is protected by European patent (UK) No EP 0961612, which claims composition containing albumin bound paclitaxel having certain particle size. In the present case, the active ingredient in Abraxane, paclitaxel, had already been marketed under other brand names for use in eliminating cancer cells pursuant to earlier marketing authorisations. Nab-paclitaxel is a new formulation of that active ingredient and has the same use.

By decision of 26 August 2016, the Comptroller rejected that application on the grounds that, as that marketing authorisation was not the first marketing authorisation for paclitaxel, the condition set out in Article 3(d) of Regulation No 469/2009 was not fulfilled. Abraxis appealed the decision of Comptroller to High Court of Justice (England & Wales), Chancery Division (Patents Court), United Kingdom. The national court has doubts as to the scope of Neurim and, accordingly, as to the interpretation of Article 3(d) of Regulation No 469/2009. In those circumstances, that court decided to stay the proceedings and referred the following question to the CJEU for a preliminary ruling:

‘Is Article 3(d) of Regulation No 469/2009 to be interpreted as permitting the grant of an SPC where the marketing authorisation referred to in Article 3(b) [of that regulation] is the first authorisation within the scope of the basic patent to place the product on the market as a medicinal product and where the product is a new formulation of an old active ingredient?’

CJEU Analysis:

CJEU said that for the purposes of a coherent interpretation of the provisions of Regulation No 469/2009, the terms used in Article 3(d) of that regulation must be read by reference to the definitions in Article 1 thereof. In particular, the concept of ‘product’ means, in accordance with Article 1(b) of that regulation, ‘the active ingredient or combination of active ingredients of a medicinal product’. According to settled case-law beginning with Massachusetts Institute of Technology, the concept of ‘active ingredient’, within the meaning of that provision, excludes those constituents of a medicinal product which do not have any therapeutic effects of their own on the body, such as excipients. In the light of that definition of ‘product’, as set out in Article 1(b) of Regulation No 469/2009, a literal interpretation of Article 3(d) of that regulation presupposes, as the Court expressly found in Medeva, that the ‘first authorisation to place the product on the market as a medicinal product’, within the meaning of that provision, means the first marketing authorisation for a medicinal product incorporating the active ingredient or combination of active ingredients at issue. According to that reading, an SPC can therefore be obtained only on the basis of the first marketing authorisation covering an active ingredient or a combination of specific active ingredients. In Neurim however, the Court held that an SPC could be granted on the basis of that patent and the marketing authorisation for Circadin since, although it was not the first marketing authorisation relating to melatonin, it was the first marketing authorisation covering that active ingredient for a therapeutic use in human falling within the scope of the protection conferred by the basic patent.

CJEU however, rejected the “scope of protection of the basic patent” test & adopted literal meaning of Article 3(d) of that regulation. CJEU thus held that an SPC application must be rejected where the marketing authorisation at issue is not the first marketing authorisation for the product as a medicinal product, irrespective of whether or not that marketing authorisation is the first to fall within the scope of the protection conferred by the basic patent. Also the approach adopted by the legislature inevitably denies the protection of an SPC to certain inventions, such as the formulation of nab-paclitaxel, which, although they concern a previously authorised product, constitute genuine therapeutic advances and are subject to a considerable erosion of the effective duration of the patent by reason of the procedures to be carried out before commercial exploitation is possible. However, that finding does not justify the creation by judicial decision of a test departing from the wording of Article 3(d) of Regulation No 469/2009 and from the intention of the legislature.

Thus, court gave the following answer to the question referred by the High Court of Justice (England & Wales), Chancery Division (Patents Court), United Kingdom:

Article 3(d) of Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009 concerning the supplementary protection certificate for medicinal products precludes the grant of such a certificate where the marketing authorisation relied upon in support of the application for a supplementary protection certificate under Article 3(b) of that regulation is not the first marketing authorisation for the active ingredient or combination of active ingredients at issue as a medicinal product. This is so even in a situation, such as that at issue in the main proceedings, where the marketing authorisation relied upon is the first to cover the formulation protected by the basic patent relied upon in support of the application for a supplementary protection certificate under Article 3(a) of that regulation.

Thursday, December 13, 2018

Mesalamine – USA


On Dec 12, 2018, Federal Circuit affirmed (Rule 36 judgment) Texas district court’s decision which granted summary judgment of non-infringement to ANDA filers in Delzicol® Hatch-Waxman case.

Previously on Oct 24, 2017, District Judge R. Gilstrap accepted Magistrate Judge Payne’s report & recommendations (Sep 28, 2017) regarding claim construction & summary judgment of non-infringement to Teva & Mylan. Allergan objected to the report and recommendation on a number of grounds. Allergan argued that the Magistrate Judge re-construed the term “gelling agent” to a “substance that gels the film composition, but which cannot be water or heated water” in US 6,649,180 & thus excluded the accused product. However, court found no error in this construction. Court said that Allergan’s infringement theory, its expert’s opinion, and the literature upon which it relies all recognize that water merely plays a passive role in the gelling process. This evidence, as the Magistrate Judge correctly concluded, establishes that a person of ordinary skill in the art would not recognize water as a “gelling agent” in the context of the ’180 patent because water at most permits the hydroxypropyl methyl cellulose (HPMC) to gel on its own when an aqueous solution of HPMC is heated. Similarly, in citing the inventor’s admission that water is not a “gelling agent,” the Magistrate Judge did not improperly rely on the inventor’s subjective intent regarding the meaning of a claim term. More importantly, the Magistrate Judge’s clarified claim construction was one of two alternative grounds for recommending summary judgment. The second basis relied on the original claim construction to conclude that, even when all disputed facts are construed in Allergan’s favor, no evidence could support a finding that water gels the film composition in the accused products. Thus, court granted Teva and Mylan’s motions for summary judgment.