Doxycycline – USA

On Aug 27, 2018, District court of Delaware issued opinion (redacted) & held that Galderma patents are valid & infringed by Amneal pharmaceuticals in Hatch-Waxman litigation.

In March 2016, Plaintiffs Galderma filed suit against Defendants Amneal under the Hatch-Waxman Act, 35 U.S.C. § 271(e). Defendants sought to bring to market a generic version of Plaintiffs’ Oracea® Capsules, a once-daily 40 milligram administration of doxycycline for the treatment of the papules and pustules of acne rosacea. Plaintiffs alleged infringement of U.S. Patent Nos. 8,206,740 (“Chang ’740 patent”); 8,394,405 (“Chang ’405 patent”); 8,470,364 (“Chang ’364 patent”); 7,749,532 (“Chang ’532 patent”) (collectively, the “Chang patents”); 7,211,267 (“Ashley ’267 patent”); 7,232,572 (“Ashley ’572 patent”); 8,603,506 (“Ashley ’506 patent”); and 9,241,946 (“Ashley ’946 patent”) (collectively, the “Ashley patents”). The Chang and Ashley patents are generally directed to low-dose doxycycline formulations for the treatment of the papules and pustules of acne rosacea. Specifically, the Chang patents describe “pharmaceutical composition[s] of doxycycline that contain[] an immediate release (IR) component of the drug and a delayed release (DR) component of the drug, which are combined into one dosage unit for once-daily dosing.” The asserted claims of the Ashley patents generally cover methods of treating acne or rosacea by oral administration of a low daily dose doxycycline. In February 2018, the Court held a five-day bench trial.

Infringement of the Chang Patents

Galderma asserted that Amneal’s ANDA product infringes claim 1 of the Chang ’532 patent, claim 1 of the Chang ’740 patent, claims 1 and 3 of the Chang ’405 patent, and claims 1 and 2 of the Chang ’364 patent (the “asserted claims of the Chang patents”) under the doctrine of equivalents. During trial, Amneal contended that Galderma cannot assert infringement under the doctrine of equivalents because: (1) Galderma’s theory would vitiate the claims, (2) Galderma surrendered equivalents to the 10 mg DR portion during prosecution, and (3) Galderma disclaimed in prosecution formulations that release in the stomach. The Court however, disagreed.

Court after hearing both parties said that nothing in the Court’s construction of “delayed release” limits the way in which that delay is created. Thus, it does not matter whether the delay is caused by an enteric coating or some other barrier, so long as release does not occur until “a time other than immediately following oral administration.” Amneal’s ANDA contain two equivalent excipients as a DR portions in which release is delayed until sometime well after “immediately following oral administration.” Accordingly, the Court concluded that Galderma has proven, by a preponderance of the evidence, that Amneal’s two excipients DR portion are insubstantially different or performs the same function in the same way to achieve the same result from the 10 mg DR portion claimed in Chang. Thus, Amneal infringes claim 1 of the Chang ’740 patent, claims 1 and 3 of the Chang ’405 patent, and claims 1 and 2 of the Chang ’364 patent. With respect to ‘532 patent, Galderma has failed to prove that Amneal’s ANDA product infringes claim 1 of the Chang ’532 patent. Claim 1 has an additional limitation missing from the asserted claims of the other Chang patents: the “the DR portion is in the form of pellets” and is “coated with at least one enteric polymer.” Galderma has not demonstrated that enteric polymers, which prevent release in the stomach, would be considered interchangeable with Amneal’s polymer. Nor has Galderma offered evidence proving that Amneal’s ANDA works in the same way as an enteric polymer to delay release.

Infringement of the Ashley Patents

Galderma contended that Amneal’s ANDA product infringes claim 30 of the Ashley ’267 patent and claims 14, 15, 23, 24, and 26 of the Ashley ’572 patent (the “asserted claims of the Ashley I patents”), as well as claims 3, 4, 5, 15, and 16 of the Ashley ’506 patent and claims 13, 14, 15, and 16 of the Ashley ’946 patent (the “asserted claims of the Ashley II patents”), “at least” under the doctrine of equivalents. Amneal responded that Galderma is collaterally estopped from asserting the Ashley I patents and, anyway, Amneal’s ANDA product does not infringe any of the asserted claims of the Ashley patents, literally or under the doctrine of equivalents. Court agreed with Amneal that Galderma is collaterally estopped from asserting the Ashley I patents. With respect to the Ashley II patents, Court held that Galderma has proven by a preponderance of the evidence that Amneal’s ANDA product infringes the asserted claims under the doctrine of equivalents.

Amneal contended that Galderma is collaterally estopped from asserting the Ashley I patents based on the Court’s finding in Mylan that 40 mg doxycycline administered once-daily does not meet the “sub-antibacterial amount” limitation of the Ashley I patents. In Mylan, the Court decided that a 40 mg once-daily administration of doxycycline does significantly inhibit the growth of microorganisms and, therefore, fails to meet the sub-antibacterial limitation of the Ashley I patents. Collateral estoppel applies even if Galderma here presented new evidence that was not before the Court in Mylan. The Court decided the issue of infringement in Mylan following a trial at which Galderma had a full and fair opportunity to present any evidence of infringement it wished. Any new evidence Galderma offers now in support of its doctrine of equivalents infringement theory was neither controlling nor otherwise essential to the Court’s finding of non-infringement in Mylan. Thus, the Court found that Galderma is collaterally estopped from asserting infringement of the Ashley I patents, literally or under the doctrine of equivalents.

Galderma alleges Amneal’s ANDA product infringes the asserted claims of the Ashley II patents “at least” under the doctrine of equivalents. The only limitation in dispute is “wherein the amount [of doxycycline] results in no reduction of skin microflora during a six-month treatment” (the “skin microflora limitation”). The Court construed this term to mean an amount that “results in no reduction of skin microflora vis-à-vis a placebo control during a six-month treatment, with microbiological sampling at baseline and month six.” While Galderma has not proven Amneal’s ANDA product literally meets this limitation, Galderma has proven, by a preponderance of the evidence, that Amneal’s ANDA product infringes the asserted claims of the Ashley II patents under the doctrine of equivalents. Court also held that Galderma has also proven that Amneal’s efforts to persuade doctors and patients to use Amneal’s ANDA product in a manner consistent with Amneal’s Label make Amneal liable for indirectly infringing the asserted claims of the Ashley II patents, by both inducing and contributing to direct infringement by third parties.

Validity of the Ashley Patent:

Amneal contends that: (1) all of the asserted claims of the Ashley patents are invalid for lack of enablement; (2) all of the asserted claims of the Ashley patents are invalid for lack of written description; (3) claim 30 of the Ashley ’267 patent, claim 15 of the Ashley ’506 patent, and claim 13 of the Ashley ’946 patent are invalid as anticipated by Dr. Feldman’s and/or his patient’s use of Periostat® to treat rosacea; (4) claims 3, 4, 5, and 16 of the Ashley ’506 patent, claims 14, 15, and 16 of the Ashley ’946 patent, and all of the asserted claims of the Ashley ’572 patent are obvious in view of Dr. Feldman and/or his patient’s use of Periostat®; and (5) the asserted claims of the Ashley I patents are indefinite in view of the “sub-antibacterial amount” terms. Court however held that, Amneal has failed to meet its burden to prove by clear and convincing evidence that any of the asserted claims are invalid.

CONCLUSION:

Galderma has proven by a preponderance of the evidence that Amneal infringes claim 1 of the Chang ’740 patent; claims 1 and 3 of the Chang ’405 patent; claims 1 and 2 of the Chang ’364 patent; claims 3, 4, 5, 15, and 16 of the Ashley ’506 patent; and claims 13, 14, 15, and 16 of the Ashley ’946 patent. Galderma has not proven Amneal infringes claim 1 of the Chang ’532 patent; claim 30 of the Ashley ’267 patent; or claims 14, 15, 23, 24, and 26 of the Ashley ’572 patent. Amneal has failed to meet its burden to prove by clear and convincing evidence that any of the asserted claims are invalid.

Hydrocodone bitartrate - USA

On Aug 24, 2018, District court of Delaware found Pernix's patents invalid under obviousness & lack of written description .

This is a Hatch-Waxaman litigation where Pernix sued Alvogen for its filing of ANDA for generic version of Zohydro (Hydrocodone) ER capsules. Specifically, Pernix asserted infringement of certain claims of  US 9,265,760 & US 9,339,499 both of which are entitled "Treating Pain in Patients with Hepatic Impairment". Hydrocodone is an opioid that is widely prescribed to treat pain. For many opioids, including hydrocodone, the bulk of the metabolism of the drug occurs  in the liver.  For that reason, persons of skill in the art have frequently expressed the view that dosages of opioids need to be adjusted for persons suffering from hepatic impairment in order to avoid a dangerous build-up of the opioid in the patient’s bloodstream.

Pernix’s patents claim methods of treating pain in patients with mild or moderate hepatic impairment. The parties refer to asserted claims as falling into two groups: the two-step (or “non adjustment”) claims and the one-step (or “pharmacokinetic-only”) claims.  The two-step non adjustment claims (claims 1–4 and 11 of the ’760 patent) include that “the starting dose [for a patient with mild or moderate hepatic impairment] is not adjusted relative to a patient without hepatic impairment.”  Those claims contain two steps: a physician prescribes a starting dose that is not adjusted, and a patient self-administers that starting dose.  The one-step pharmacokinetic claims (claims 12, 17, and 19 of the ’760 patent and claim 1 of the ’499 patent) do not contain a “non-adjustment” limitation, but instead provide for a release profile of hydrocodone that either results in certain defined pharmacokinetic values in patients with mild or moderate hepatic impairment.

Claim 1 of US'760 patent reads (two-step):
A method of treating pain in a patient having mild or moderate hepatic impairment, the method comprising: 
Administering to the patient having mild or moderate hepatic impairment a starting dose of an oral dosage unit having hydrocodone bitartrate as the only active ingredient, 
wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate, and wherein the starting dose is not adjusted relative to a patient without hepatic impairment. 

Claim 1 of US'499 patent reads (one-step):
A method of treating pain in a patient having mild or moderate haptic impairment, the method comprising: 
administering to the patient having mild or moderate hepatic impairment an oral dosage unit having hydrocodone bitartrate as the only active ingredient, wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate, 
wherein the dosage unit provides a release profile of hydrocodone that: 
does not increase average hydrocodone AUC0-inf in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%; and 
does not increase average hydrocodone AUC0-inf in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 30%. 

At trial, Pernix sought to show that Alvogen induced infringement of the asserted claims. Alvogen disputed various aspects of Pernix’s infringement theory, and raised three defenses and counterclaims at trial

Induced Infringement:

Court based on the evidence at trial found that patients with mild or moderate hepatic impairment taking Alvogen’s product in accordance  with the directions in Alvogen’s proposed label would directly infringe the one-step claims.  Physicians would prescribe a non-adjusted dose of Alvogen’s product for patients with mild or moderate hepatic impairment, and the patients would self-administer the dosages as prescribed and directed by their physicians.  The Court next found that physicians and patients would jointly infringe the two-step claims, because the patients would self-administer the drugs pursuant to the physicians’ direction and control.  Finally, the Court found that Alvogen’s label would induce infringement of both the one-step and two-step claims.

The dispute between the parties concerned the extent to which physicians would condition treatment on the patient’s self-administering Alvogen’s proposed product.  The Court found that Pernix has proved by a preponderance of the evidence that physicians would condition a benefit—that is, the prescription of a starting dose or subsequent prescriptions for Alvogen’s proposed product—upon their patients’ self-administration of the drug in accordance with the physicians’ instructions. Alvogen's  label provides both data and instructions on how to prescribe a starting dose in patients with mild or moderate hepatic impairment.  Based on the evidence at trial, the Court found that the contents of that label would encourage a physician to prescribe to patients with mild or moderate hepatic impairment a starting dose of Alvogen’s proposed product that is not adjusted relative to a starting dose prescribed to a patient without hepatic impairment.

Anticipation:

Alvogen argued that all of the asserted claims are anticipated by the Devane reference. Devane is a published patent application entitled “Multiparticulate Modified Release Composition.”Devane teaches that its “modified release composition” can be used with hydrocodone to provide continuous analgesia for up to 24 hours. It provides an example of a hydrocodone bitartrate modified release composition with six possible immediate-release components and seven possible modified-release components. Devane also describes the results of an in vivo study on patients immediately following bunionectomy surgery, in which one of those hydrocodone bitartrate formulations was used to treat the patients’ post-operative pain.

The Court found that Devane anticipates administering an oral dosage unit of extended-release hydrocodone bitartrate, and that Devane inherently anticipates the pharmacokinetic limitations.  However, the Court found that Alvogen has failed to show by clear and convincing evidence that Devane discloses the limitations that recite treating patients with mild or moderate hepatic impairment or administering a starting dose to such patients that is not adjusted relative to the starting dose prescribed to patients without hepatic impairment.

Obviousness:

At trial, Alvogen contended that the asserted claims would have been obvious over Devane in view of one or more of U.S. Patent Publ. No. 2010/0010030 (“Jain”), the 2011 Vicodin label, and/or the 2011 Lortab label. Jain describes an opioid formulation referred to as Vicodin CR, which was a controlled-release analgesic that contained 15 milligrams of hydrocodone bitartrate and 500 milligrams of acetaminophen. Jain describes a hepatic impairment pharmacokinetic study conducted with Vicodin CR.  Jain summarizes those results, reporting that the pharmacokinetic parameters for hydrocodone in that formulation were “similar” in normal subjects and subjects with mild or moderate hepatic impairment. The 2011 Vicodin and Lortab labels describe the safety and dosing instructions for those drugs, both of which contain hydrocodone and acetaminophen in an immediate-release formulation.  Although both labels state that the product should be “used with caution” in patients with severe hepatic impairment, the labels are silent about dosing levels for patients with mild or moderate hepatic impairment. From that silence, Alvogen argued that a person of ordinary skill would assume that no dose adjustment is required in prescribing Vicodin, Lortab, or other hydrocodone-containing products, to patients with mild or moderate hepatic impairment & hence claims are obvious.

Court said that although Pernix’s expert and Alvogen’s experts disagreed about what a person of ordinary skill would understand the silence of those references to teach about the proper starting dose for patients with mild or moderate hepatic impairment, no expert testified that those labels would teach that the product should not be administered to patients with mild or moderate hepatic impairment.  Moreover, Jain’s pharmacokinetic study describes the pharmacokinetic profiles of hydrocodone in normal subjects and in patients with mild or moderate hepatic impairment as “similar.” That characterization indicates that a hydrocodone-containing extended-release product could be safely administered to a patient with mild or moderate hepatic impairment.  Pernix argued that there is no motivation to combine Devane, an opioid-only formulation, with Lortab, Vicodin, and Jain’s Vicodin CR because each of the latter three formulations is a combination product that contains acetaminophen.Court, however disagreed & said that person skilled in the art would have combined these references with reasonable expectation of success because importantly acetaminophen is different drug which metabolizes differently than hydrocodone & it would not have had significant impact on metabolism of hydrocodone. With respect to limitation of 'no dose adjustment', court said that person skilled in the art when considering whether a dose adjustment of Devane’s formulation would be necessary for patients with mild or moderate hepatic impairment, would have been motivated to look to Jain and to the Vicodin and Lortab labels for a guidance as to the appropriate dosing levels of Devane’s formulation for patients with mild or moderate hepatic impairment. The Court found that a person of ordinary skill would have understood that Jain’s qualitative statement that the pharmacokinetic parameters for hydrocodone were “similar” means that a dose adjustment would not be not required for patients with mild or moderate hepatic impairment.

Pernix argued that the silence of the Vicodin and Lortab labels as to the proper dosing for patients with mild or moderate hepatic impairment does not justify the inference that a dose adjustment is not required for those patients.  Dr. Gudin testified that “it was common knowledge that clinicians were required to adjust the dose and adjust the starting dose of opioids when administering these agents to patients with liver issues.”Therefore, he testified, a person of ordinary skill would not read the silence of those labels regarding mild or moderate hepatic impairment as suggesting that no dose adjustment would be required for such patients. But court discredited the testimony & held that person of ordinary skill would have had a reasonable expectation of success that Devane’s extended-release hydrocodone bitartrate could be administered to patients with mild or moderate hepatic impairment without adjusting the starting dose.

Written Description:

Alvogen argued mainly on one point that all that the inventors contributed to the art was “to recognize that, based on the [pharmacokinetic] results of a routine [hepatic impairment] study, the HC-ER prior art formulation did not require a dose adjustment for patients with mild or moderate [hepatic impairment].  Rather than claim only that narrow invention, however, the inventors sought, and obtained, much broader claims & thus are invalid for failure to satisfy the written description requirement. Alvogen argued that the asserted claims are broadly cast in generic form.The asserted claims of the two Pernix patents do not recite methods of treatment involving the use of a particular identified formulation, or even a group of identified formulations.  Instead, the formulation limitations recited in the claims read on all oral dosage units comprising extended-release hydrocodone in which hydrocodone is the only active ingredient.  That genus of formulations incorporates an essentially limitless number of formulation species. The other limitations in the asserted claims are all functional in nature.  The functional limitations include the limitation that the starting dose of the formulation is not adjusted for persons with mild or moderate hepatic impairment relative to patients without hepatic impairment, as well as the limitations related to pharmacokinetic parameters.

The common specification discloses only one formulation that was found to satisfy all the 
limitations of any of the claims, including the functional limitations.  That formulation, set forth
in Example 8 of the specification, was the formulation used in both Devane’s bunionectomy
study and the Zohydro ER hepatic impairment study, and it is the only formulation that is shown
by the common specification to satisfy the functional limitations of the claims. Alvogen argued that the single embodiment set forth in the specification does not supply adequate written description support for the asserted claims. According to Alvogen, the record reflects that clinical testing would be required in order to determine which if any of those formulations—or any other of the virtually infinite number of potential formulations covered by the claims—would produce the functional results recited in the asserted claims. Pernix responds that the common specification describes more than just the single embodiment set forth in Example 8. Pernix contends that the specification contains several different sets of ingredients for the immediate-release component hydrocodone solutions and the modified-release coating solutions in Tables 1 and 2, and that the specification describes nine different dosage levels of the hydrocodone formulation, between 10 and 80 milligrams.

Court held that neither the specification nor any evidence offered at trial points to any structural features that would assist a person of ordinary skill in the art in identifying species falling within the asserted generic claims.  The pharmacokinetic data and dissolution profile for the Devane formulation provide no guidance as to whether other formulations would satisfy the functional limitations of the claims, and the sample components for the immediate release hydrocodone and modified release coating solutions in Table 1 and Table 2 would contain candidate components for the formulation,but no assurance that any particular formulation using those components would work. Moreover, the inventors admitted at trial that they did not know why the Devane formulation functioned in the way it did, to produce pharmacokinetic results for patients with mild or moderate hepatic impairment  similar to those for patients with normal hepatic function. Dr. Koleng (Plaintiff's expert) admitted at trial that he did not “consider how specific attributes of Example 8 or the HC-ER formulation related to the PK results that that formulation generated.” Dr. Koleng admitted, the only way to determine which formulations would satisfy the limitations of the claims would be to conduct hepatic impairment studies.  Thus, Dr. Koleng’s statements to the effect that a person of skill in the art, “with the patents in hand could readily envision and make formulations to hit target PK profiles provided in the patent,” were subject to the considerable qualification that the task of determining which formulations would work for that purpose would require clinical hepatic impairment testing of each formulation. 

Court said that Pernix repeatedly emphasizes that the specification of its patents shows a specific method that works.  What Pernix fails to acknowledge, however, is that it has claimed not just the formulation disclosed in the common specification, but any formulation that will work to produce the results recited in the claims, i.e., pharmacokinetic profiles for subjects with mild or moderate hepatic impairment that are close to those for normal patients. Therein lies the written description problem: the claims are far broader than the disclosure.  As the Federal Circuit put the matter in Ariad, the claims are defective because they “cover any [formulation] later actually invented and determined to fall within the claim’s functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”  598 F.3d at 1353.

Thus, Based on the findings set forth above, the Court concluded that the asserted claims of the ’760 and ’499 patents are not supported by an adequate written description, as required by section 112(a) & that the asserted claims are therefore invalid.

Treprostinil - USA

IPR decision (Aug 27, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-01621	06/21/2017	01/11/2018	Watson Laboratories, Inc.	9,358,240	Terminated-Settled
IPR2017-01622	06/21/2017	01/11/2018		9,339,507

US 9,358,240 (United Therapeutics Corp; Exp: 05/05/2028) –OB listed

1. A method of treating pulmonary hypertension comprising: administering by inhalation to a human suffering from pulmonary hypertension a therapeutically effective single event dose of a formulation comprising from 200 to 1000 .mu.g/ml of treprostinil or a pharmaceutically acceptable salt thereof with a pulsed ultrasonic nebulizer that aerosolizes a fixed amount of treprostinil or a pharmaceutically acceptable salt thereof per pulse, said pulsed ultrasonic nebulizer comprising an opto-acoustical trigger which allows said human to synchronize each breath to each pulse, said therapeutically effective single event dose comprising from 15 .mu.g to 90 .mu.g of treprostinil or a pharmaceutically acceptable salt thereof delivered in 1 to 18 breaths.

US 9,339,507 (United Therapeutics Corp; Exp: 03/10/2028) –OB listed

1. A kit for treating pulmonary hypertension comprising: (i) a formulation comprising 200 to 1000 .mu.g/ml treprostinil or a pharmaceutically acceptable salt thereof; (ii) a pulsed ultrasonic nebulizer comprising an opto-acoustical trigger, configured to (a) aerosolize a fixed amount of treprostinil per pulse, and (b) deliver by inhalation a therapeutically effective single event dose of said formulation, said single event dose comprising 15 .mu.g to 90 .mu.g treprostinil or a pharmaceutically acceptable salt thereof delivered in 1 to 18 breaths; and (iii) instructions for using the pulsed ultrasonic nebulizer with the formulation to treat a patient with pulmonary hypertension by delivering 15 .mu.g to 90 .mu.g treprostinil or a pharmaceutically acceptable salt thereof in 1 to 18 breaths to the patient in the single event dose.

Tocilizumab – UK/USA

On Aug 24, 2018, England and Wales High Court (Patents Court) found Chugai’s product not infringing UCB’s patent & denied royalty.

This case is about United States patent 7,566,771 (expires in 2026); entitled “Humanized Antibodies”. The patent is licensed to the Chugai under a patent licence agreement between Chugai and UCB. This worldwide licence was entered into on 10^th December 2007. Royalties are due on sales of a relevant product in a territory if that product falls within the scope of one of the claims of a patent which is in force in that territory, unless and until that patent expires or is finally held invalid.

Chugai has a pharmaceutical product called tocilizumab. Tocilizumab is an immunosuppressive drug mainly used in the treatment of rheumatoid arthritis. It is a humanised antibody to the interleukin-6 (IL-6) receptor. The brand name for Chugai’s tocilizumab in the USA is Actemra. Chugai has been paying royalties under the licence in relation to sales of tocilizumab. In this particular action, Chugai contends that tocilizumab does not “infringe a Valid Claim of the 771 patent and therefore does not attract royalties to the extent the product is manufactured after 13^th January 2016 (when other remaining patents expire). Accordingly Chugai contends that once the 771 patent is the only remaining patent in force, no royalties are due under the licence for such products. Chugai seeks an appropriate declaration to that effect from the English court.

By the trial the issues had narrowed down to the single question of whether tocilizumab falls within the scope of claim 2 of the 771 patent. Claim 2 is provided herein below:

2. A humanised antibody molecule having affinity for a predetermined antigen and comprising a composite heavy chain and a complementary light chain, said composite heavy chain having a variable domain including complementarity determining regions (CDRs) and framework regions, wherein, according to the Kabat numbering system, in said composite heavy chain: said CDRs are non-human donor at residues 31 to 35, 50 to 58, and 95 to 102; and said framework regions are non-human donor at:

a) residue 6;

b) one or more of residues 23 and 24;

c) one or more of residues 48 and 49;

d) one or more of residues 71 and 73;

e) one or more of residues 75, 76, and 78; and

f) one or more of residues 88 and 91;

provided that said heavy chain is not a chimeric antibody heavy chain having a donor variable domain and a human constant region.

Chugai contends that on UCB’s construction of the claim, the claim would be invalid because it would cover a prior art antibody called anti-Tac described in a reference called Queen. UCB admits that on its case on claim construction the antibody in Queen would indeed fall within the relevant claim and also admits, for the purposes of these proceedings only, that that would make the claim invalid. However, UCB’s submission is that subject to one point, this consequence is irrelevant to the issues the English court has to decide. UCB maintains its case on construction and argues that Chugai’s true remedy is and has always been to bring proceedings in the US court to invalidate the relevant claims. If those proceedings were to be commenced, one of the things UCB has made clear is that it would defend such an invalidity attack on the basis that it can “swear behind” Queen. 

Court after hearing both the parties said that the claims alone could be read either way. The specification, which is the single best guide and primary basis for construing the claims, is hard to interpret and contains some material which positively supports one side and some material which positively supports the other side. The prosecution file is similar, containing statements which support each side’s case. The extrinsic evidence, albeit the least powerful source of evidence, is different. It firmly supports Chugai construction of “donor” residue. Court said that claim 2 can be seen that for an antibody to fall within the claim requires that certain specified residues in the framework region “are non-human donor”. UCB’s case is that “donor” includes conserved residues. Chugai’s case is that the term “donor” is used to describe source and so, since the source of the acceptor framework region is human, only framework residues which have been changed into a different mouse residue count as donor. An unchanged framework residue is an acceptor residue. Thus for the numbered framework residues set out in the claims, any framework residues which are conserved as between the murine and human sequences are not “donor”. Court held that on UCB’s case the claim would cover an antibody for which no changes were made at all but, despite the breadth of the description, and the suggestion that one way to go is to go for high homology, the idea of no changes at all is not suggested anywhere and in court’s judgment the person of ordinary skill in the art would not understand the specification to go that far.

Thus, Court held that Chugai’s tocilizumab product does not infringe a valid claim of US patent 7,566,771. No royalties are due for tocilizumab under the patent licence between Chugai and UCB for product manufactured after 13^th January 2016.

Bupropion - Canada

On Aug 20, 2018, Federal Circuit of Canada found Ranbaxy’s generic product non-infringing & dismissed the application by Valeant to prohibit the Minister of Health from issuing a Notice of Compliance.

The Applicant, Valeant applied to the Court on December 22, 2016, under the prior Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 [NOC Regulations] for an order prohibiting the Minister of Health [the Minister] from issuing a Notice of Compliance [NOC] to the Respondent, Ranbaxy Pharmaceuticals. This prohibition order would prevent Ranbaxy from marketing Ran-Bupropion XL Tablets (150 mg and 300 mg), an extended relief medication that Valeant says infringes Patent No. CA 2,524,300 [the 300 Patent]. The 300 Patent expires on August 8, 2023. The 300 Patent is titled "Modified-Release Tablet of Bupropion Hydrochloride". The 300 Patent discloses ' and claims a daily anti-depression medicine that improves patient compliance with extended drug release, which Valeant markets as "Wellbutrin XL''.

The only issue was whether Ranbaxy’s product infringes the 300 Patent. Ranbaxy's argument was that its product falls outside of claim 1 of the 300 Patent -namely, its tablets are not comprised of a permeation enhancer in the amount of “about 20% to about 40%" of the moisture barrier dry weight.

Claim 1 is reproduced herein below:

A modified-release tablet comprising:

(i) a core comprising an effective amount of pharmaceutically acceptable salt of bupropion, a binder, a lubricant and optionally other conventional excipients;

(ii) a first control-releasing coat surrounding said core wherein said first control-releasing coat comprises a water-insoluble water-permeable film-forming polymer, a plasticizer and a water-soluble polymer, wherein the ratio of the water-insoluble water-permeable film-forming polymer to the water-soluble polymer is from about 3:4 to about 5:3; and

(iii) a moisture barrier surrounding said first control releasing coat, wherein said moisture barrier comprises an enteric polymer and a permeation enhancer and optionally comprises a plasticizer and wherein the permeation enhancer is present in an amount of from about 20% to about 40% of the moisture barrier dry weight;

wherein the modified release tablet is bioequivalent to Wellbutrin® or Zyban®/Wellbutrin® SR tablets over a 24 hour period when administration of said modified-release tablet is as a once-a-day bupropion treatment regimen to a patient in need of such administration and wherein more than 10% of the pharmaceutically acceptable salt of bupropion is released in one hour in 0.1N HCL or less than 75% of the pharmaceutically acceptable salt of bupropion is released in 45 minutes in pH 6.8 buffer.

Silicon dioxide is the preferred permeation enhancer in the 300 Patent, in the amount of "about 20% to about 40%" of the moisture barrier dry weight. Ranbaxy argued that the word "about" in the 300 Patent means plus or minus 10%, which works out to a range of 18% to 44%. And while Ranbaxy's formulation also uses silicon dioxide as the permeation enhancer, it argued it is present in an amount below the range claimed in the 300 Patent.  But Valeant argued that two other chemicals in Ranbaxy's product-polyethylene glycol [PEG] and triethyl citrate [TEC] (used as plasticizer) should be treated as permeation enhancers and therefore are included in the weight calculation.

Court however, denied Valeant’s proposed construction & held that specification of 300 patent mentions PEG & TEC as plasticizer & to some extent as glidant, but not as permeation enhancers. Court accepted Ranbaxy’s expert (Dr. Laskar) testimony & said that PEG would not fall under the definition of permeation enhancers given in specification as PEG while allowing water to come inside would disrupt the membrane. Although there are certain literatures available which discloses PEG as permeation enhancers but purposive construction requires reference to specification & not to functional characteristics of excipients. Therefore, only Silicon dioxide present in Ranbaxy’s product act as permeation enhancers.

Next, turning to the term “about”, Court held that it should be construed as plus or minus 10%. Court relied on Dr. Laskar's opinion that a POSITA would understand that "about" means a 10% deviation of the percentage range in the 300 Patent's formulation based on certain authorities such as USP monographs which use the range 90.0-110.0% of label claim as the quality standard. Therefore, amount of permeation enhancer works out to a range of 18% to 44% as argued by Ranbaxy. And since Ranbaxy’s product contains silicon dioxide below this range, it would not infringe the 300 patent. Thus, Valeant failed to satisfy its onus to show on a balance of probabilities that Ranbaxy's allegation of non-infringement is unjustified.

Bortezomib - Canada

On July 18, 2018, Federal court of Canada found Velcade® patents invalid & not infringed by Teva’s generic version.

This action began as a claim by plaintiff, Teva Canada Limited (Teva), against Janssen Inc. (Janssen) and Millennium Pharmaceuticals, Inc. (Millennium) for compensation under s. 8 of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 [the Regulations] for losses suffered during the time that Teva was kept off the market for its version of a drug for treating cancer that is marketed in Canada by Janssen under the name Velcade. Teva’s product is called Teva-bortezomib. Janssen had rights in Canada to Canadian Patent Nos. 2,203,936 (Compound Patent) and 2,435,146 (Composition Patent) as well as Canadian Patent No. 2,738,706 (Process Patent).

In 2012, it commenced two applications under the Regulations against Teva seeking orders prohibiting the issuance of a notice of compliance (NOC) to Teva until expiration of the 936 and 146 Patents, respectively. Both applications were dismissed by decisions of Justice Robert L. Barnes concluding that the claims in issue of each of the 936 and 146 Patents were invalid for obviousness. These decisions are cited as Janssen Inc v Teva Canada Limited, 2015 FC 247 and Janssen Inc v Teva Canada Limited, 2015 FC 184, respectively. Teva subsequently obtained its NOC and commenced the present action.

The parties have managed to reach agreement on a number of issues, including the quantum of any compensation or damages that may be payable. The parties have indicated that only the following issues remain in dispute:

Ø  With regard to the 936 Patent (whether claims 37 and 69 are obvious);

Ø  With regard to the 146 Patent (whether the asserted claims are obvious); and

Ø  With regard to the 706 Patent (whether Teva‑bortezomib infringes)

Conclusions of Court:

Ø  Claims 37 and 69 of the 936 patent are invalid for obviousness.

Ø  Solution provided by the 146 patent lyophilisation of bortezomib and mannitol, would have been obvious to try.

Ø  Teva-bortezomib does not infringe claim 1 & dependent claims of the 706 patent.

Oxycodone - USA

IPR decision (Aug 21, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2018-00625	02/27/2018	--	Kashiv Pharma LLC	9,492,392	Terminated-Settled
IPR2018-00717	02/28/2018	--		9,492,393	Terminated-Settled

US 9,492,392 (Purdue Pharma; Exp: 08/24/2027) – OB listed

1. A cured shaped pharmaceutical tablet comprising: (1) at least a first compression shaped and then air cured matrix, wherein said curing is without compression, by heated air having a temperature of at least about 62.degree. C. for a duration of at least about 5 minutes, said matrix comprising oxycodone or a pharmaceutically acceptable salt thereof in combination with at least one high molecular weight polyethylene oxide having, based on rheological measurements, an approximate molecular weight selected from the group consisting of 4,000,000, 7,000,000, and a combination thereof, and optionally further comprising at least one low molecular weight polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000; (2) optionally a second air cured matrix comprising oxycodone or a pharmaceutically acceptable salt thereof in combination with at least one low molecular weight polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000; and (3) optionally a coating, wherein, in said tablet: (i) said oxycodone or pharmaceutically acceptable salt thereof is provided in a dose selected from the group consisting of 10 mg, 15 mg, 20 mg, and 30 mg; the total combined weight of said low molecular weight polyethylene oxide, if present, and said high molecular weight polyethylene oxide is at least 79% by weight of the total weight of said tablet, excluding the weight of any coatings; and said low molecular weight polyethylene oxide, if present, is at least 10% by weight of the total weight of said tablet, excluding the weight of any coatings; or (ii) said oxycodone or pharmaceutically acceptable salt thereof is provided in a dose selected from the group consisting of 40 mg, 60 mg, and 80 mg; the total combined weight of said low molecular weight polyethylene oxide, if present, and said high molecular weight polyethylene oxide is at least 65% by weight of the total weight of said tablet, excluding the weight of any coatings; and said low molecular weight polyethylene oxide, if present, is at least 10% by weight of the total weight of said tablet, excluding the weight of any coatings; and said tablet provides a dosage form for twice-daily extended release administration of oxycodone or pharmaceutically acceptable salt thereof.

US 9,492,393 (Purdue Pharma; Exp: 08/24/2027) – OB listed

1. A method of treating pain comprising administering to a patient in need thereof a pharmaceutical tablet comprising: (1) at least a first compression shaped and then air cured matrix, wherein said curing is without compression by heated air having a temperature of at least about 62.degree. C. for a duration of at least about 5 minutes, said matrix comprising oxycodone or a pharmaceutically acceptable salt thereof in combination with at least one high molecular weight polyethylene oxide having, based on rheological measurements, an approximate molecular weight selected from the group consisting of 4,000,000, 7,000,000, and a combination thereof, and optionally further comprising at least one low molecular weight polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000; (2) optionally a second air cured matrix comprising oxycodone or a pharmaceutically acceptable salt thereof in combination with at least one low molecular weight polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000; and (3) optionally a coating, wherein in said tablet: (i) said oxycodone or pharmaceutically acceptable salt thereof is provided in a dose selected from the group consisting of 10 mg, 15, mg, 20 mg, and 30 mg; the total combined weight of said low molecular weight polyethylene oxide, if present, and said high molecular weight polyethylene oxide is at least 79% by weight of the total weight of said tablet, excluding the weight of any coatings; and said low molecular weight polyethylene oxide, if present, is at least 10% by weight of the total weight of said uncoated tablet, excluding the weight of any coatings; or (ii) said oxycodone or pharmaceutically acceptable salt thereof is provided in a dose selected from the group consisting of 40 mg, 60 mg, and 80 mg; the total combined weight of said low molecular weight polyethylene oxide, if present, and said high molecular weight polyethylene oxide is at least 65% by weight of the total weight of said tablet, excluding the weight of any coatings; and said low molecular weight polyethylene oxide, if present, is at least 10% by weight of the total weight of said tablet, excluding the weight of any coatings; and said tablet provides a dosage form for twice-daily extended release administration of oxycodone or pharmaceutically acceptable salt thereof.

Difluprednate - USA

On Aug 08, 2018, The Federal Circuit in one-liner decision affirmed the Patent Trial and Appeal Board’s decision (IPR2015-01205) to invalidate several claims in a patent covering Alcon Laboratories' Durezol eye drops.

PTAB on Nov 22, 2016 issued final written decision that the challenged claims are unpatentable. Akorn, Inc. (“Petitioner”) challenged claims 1–4, 6–10, 12–14, and 18 of U.S. Patent No. 6,114,319 under 35 U.S.C. § 103 as being obvious over the combination of the teachings of U.S. Patent 5,556,848 and WO 95/31211 (Ding). The ’319 patent is directed to compositions of difluprednate, a steroid drug that was known to have superior anti-inflammatory action for skin disorders. The inventors of the ’319 patent explain that difluprednate has extremely low solubility in water, making it difficult to prepare a stable eye, nose, or ear drop and resulting in aqueous suspensions that are uncomfortable and delivered unevenly. The inventors solved this problem by preparing a composition of difluprednate as an emulsion with oil, water, and an emulsifier. However, PTAB was persuaded by the evidence presented by Petitioner. Specifically that the ’848 patent shows that difluprednate was a known drug, useful for treating various eye ailments & Ding, that disclosed emulsions as recited in the challenged claims were known for solving the formulation problems of similar steroids in ocular treatments.

Deferiprone - USA

IPR decision (Aug 07, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-01446	05/16/2017	11/28/2017	Taro Pharma	7,049,328	Terminated-Settled

Litigation status: In May 2016, Apopharma sued Taro in Eastern District Court of Texas for infringement of US’328 patent. Bench trial is scheduled on 10/22/18.

US 7,049,328 (Apotex Inc; Exp: 06/28/2021) – listed in OB

1. A method of treating iron induced cardiac disease in a blood transfusion dependent patient experiencing an iron overload condition of the heart, said method comprising administering to the patient a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof sufficient to stabilize/reduce iron accumulation in the heart resulting from being transfusion dependent.

2. A method of treating iron loading in the heart of a blood transfusion dependent patient experiencing an iron overload condition of the heart, said method comprising administering to the transfusion dependent patient a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof sufficient to reduce further iron overload in the heart normally associated with iron induced cardiac disease.

3. A method of treating iron loading in the heart of a blood transfusion dependent patient risking iron overload of the heart, comprising the administration of a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof to the patient.

4. A method of stabilizing iron induced heart disease in blood transfusion dependent patients having iron overload, comprising the administration of a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof sufficient to treat the iron burden in the heart normally associated with iron induced cardiac disease.

5. A method of reducing the iron burden in the heart associated with iron induced heart disease in blood transfusion dependent patients having iron overload, comprising the administration of a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof sufficient to reduce the iron burden of the heart normally associated with iron induced cardiac disease.

6. A method of treating iron induced heart disease in a blood transfusion dependent patient having an iron overload condition of the heart comprising administering to the patient a therapeutically effective amount of deferiprone, or a physiologically acceptable salt thereof in order to reduce the iron stores in the heart in preference to general iron stores in the body, such as found in the liver.

7. A method of treating iron loading in the heart of blood transfusion dependent patient having an iron overload condition of the heart comprising administering to the patient a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof to chelate the iron stores in the heart in preference to general iron stores in the body, such as found in the liver.

8. A method of treating iron loading in the heart of blood transfusion dependent patient having an iron overload condition of the heart comprising administering to the patient a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof to reduce the iron stores in the heart in preference to general iron stores organs/tissue in the body, such as found in the liver.

9. A method of treatment of iron induced heart disease in a blood transfusion dependent patient having an iron overload condition of the heart comprising administering to the patient a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof for the direct reduction/removal of intracellular iron stores in the heart.

10. A method to reduce the occurrence of iron-induced cardiac disease in a blood transfusion dependent patient with an iron overload condition, comprising administering to said patient a therapeutically effective amount of deferiprone or a physiologically acceptable salt thereof, wherein deferiprone's efficacy is cardio preferential when compared with its ability to lower total iron stores in the body.

Infliximab - USA

On Jul 30, 2018, US District Court of Massachusetts ruled that Celltrion’s biosimilar Inflectra (infliximab-dyyb) didn’t infringe Janssen’s patent.

The ruling involved J&J's U.S. Patent No. 7,598,083, which claims cell culture media compositions used to produce infliximab. Janssen does not allege literal infringement of the '083 patent. Rather, Janssen argues only that Celltrion's accused media infringe claim 1 under the doctrine of equivalents. It is undisputed that the accused media contain all 52 ingredients required by claim 1, as well as additional ingredients. However, several of the claimed ingredients are present in the accused media in amounts that fall outside the literal concentration ranges recited the claim. Janssen argues that the amounts of those ingredients used by Celltrion are not substantially different from the amounts claimed in claim 1 and, therefore, the accused media infringe the patent under doctrine of equivalents. The defendants deny the allegations and have moved for summary judgment of non-infringement on the grounds that Janssen's asserted scope of equivalents would ensnare the prior art.

District Court Judge Mark Wolf in his 104-page ruling held that the “defendants are entitled to summary judgment of non-infringement of the '083 patent because Janssen has not produced sufficient evidence to prove that the scope of equivalents would not ensnare the prior art.” In essence, the court finds that no reasonable factfinder could conclude that the hypothetical claims that Janssen relies upon to avoid ensnarement would have been patentable because they were obvious rather than inventive. Undisputed and strong evidence compels the conclusion that a person of ordinary skill in the art (a "POSA") would have had the ability and motivation to combine familiar ingredients from prior art cell culture media compositions in predictable concentrations to create what Janssen claims as its hypothetical invention. Moreover, the POSA would have predicted the combination's successful results. Therefore, ensnarement bars Janssen from prevailing under the doctrine of equivalents.

Janssen previously focused on its allegation that the defendants infringed its U.S. Patent No. 6,284,471 covering the infliximab antibody. In 2016, this court invalidated the '471 patent for obviousness-type double patenting.

FDA approved Inflectra in April 2016 and Pfizer, who has U.S. rights to the drug from Celltrion, launched the drug in Nov 2016. Then Pfizer in Sep 2017 filed a complaint in a US District Court in Pennsylvania alleging that J&J is using "improper exclusionary tactics" to maintain dominance in the US market for its blockbuster Remicade (infliximab) despite recently introduced biosimilar competition.