Thursday, August 30, 2018

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.

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