UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`PAR PHARMACEUTICAL, INC.
`Petitioner
`
`v.
`
`SUMITOMO DAINIPPON PHARMA CO., LTD.
`Patent Owner
`_______________________
`U.S. Patent No. 9,555,027
`
`Title: Pharmaceutical Composition
`_______________________
`
`Inter Partes Review Case No. Unassigned
`_______________________
`
`DECLARATION OF DR. ADAM KAPLIN
`17 April, 2017
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 001
`
`
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`PAR PHARMACEUTICAL, INC.
`Petitioner
`
`v.
`
`SUMITOMO DAINIPPON PHARMA CO., LTD.
`Patent Owner
`_______________________
`U.S. Patent No. 9,555,027
`
`Title: Pharmaceutical Composition
`_______________________
`
`Inter Partes Review Case No. Unassigned
`_______________________
`
`DECLARATION OF DR. ADAM KAPLIN
`17 April, 2017
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 001
`
`
`
`
`
`
`
`
`
`CONTENTS
`
`
`
`Page
`
`INTRODUCTION .......................................................................................... 1
`
`BACKGROUND AND QUALIFICATIONS ................................................ 2
`
` LEVEL OF ORDINARY SKILL IN THE ART ............................................ 4
`
` SUMMARY OF OPINIONS .......................................................................... 5
`
` OPTIMAL LURASIDONE DOSAGE RANGE ............................................ 6
`
` OPTIMAL DELIVERY OF LURASIDONE USING A SINGLE
`TABLET ......................................................................................................... 8
`
`
`
`IMMEDIATE RELEASE PREPARATIONS .............................................. 10
`
` CONCLUSION ............................................................................................ 12
`
`
`
`i
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 002
`
`
`
`
`
`I, Dr. Adam Kaplin, hereby declare as follows.
`
`
`
`INTRODUCTION
`1.
`
`I am over the age of eighteen and otherwise competent to make this
`
`declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Par
`
`Pharmaceutical, Inc. (“Par”) for the above-captioned Inter Partes Review (“IPR”).
`
`I am being compensated for my time in connection with this IPR at my standard
`
`consulting rate, which is $400 per hour for my work on this matter. I also am
`
`reimbursed for travel and other direct expenses. I have no personal or financial
`
`interest in the outcome of this proceeding.
`
`3.
`
`I understand that this declaration is being submitted in support of a
`
`petition for IPR of U.S. Patent No. 9,555,027 (Ex. 1001, “the ’027 Patent”), which
`
`issued from U.S. Application No. 14/512,189 on January 31, 2017. The ’027
`
`Patent names Kazuyuki Fujihara as inventor. I further understand that, according
`
`to USPTO records, the ’027 Patent is currently assigned to Sumitomo Dainippon
`
`Pharma Co., Ltd.
`
`4.
`
`In preparing this declaration, I have reviewed the ’027 Patent, as
`
`well as each of the documents cited herein, in light of the general knowledge in the
`
`field as of May 26, 2005. In forming my opinions, I have relied upon my
`
`experience, education, and knowledge in the relevant art.
`
`1
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 003
`
`
`
`
`
` BACKGROUND AND QUALIFICATIONS
`5.
`I am the Chief Neuropsychiatric Consultant at the Johns Hopkins
`
`Multiple Sclerosis and Transverse Myelitis Centers, where my research focuses on
`
`the biological bases of the effects of the immune system on mood regulation and
`
`cognition, the biological bases of depression and dementia, and discovering new
`
`ways to diagnose and treat such diseases. I also provide a weekly
`
`Neuropsychiatric Consultation Clinic for patients around the world to receive
`
`ongoing care for such conditions.
`
`6.
`
`I received my B.S. in Biology from Yale University in 1988 and my
`
`M.D. and Ph.D. from Johns Hopkins School of Medicine in 1996. While
`
`completing my undergraduate research thesis, I trained in the laboratory of Nobel
`
`Laureate Sidney Altman, Ph.D. As an assistant researcher at the Yale School of
`
`Medicine, I also trained in the laboratory of Nobel Laureate George Palade, M.D.
`
`I then completed my Ph.D. and postdoctoral training in the laboratory of Solomon
`
`Snyder, M.D., a recipient of the National Medal of Science.
`
`7.
`
`More recently, I have helped develop and apply technological
`
`innovations to improve patient care and clinical research, including inventing and
`
`developing an automated mood-tracking technology that functions as a
`
`personalized, electronic health diary for clinical patients.
`
`2
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 004
`
`
`
`
`
`8.
`
`I am on the board of medical advisors to the Montel Williams MS
`
`Foundation, Cody Unser First Step Foundation, Nancy Davis MS Foundation and
`
`Center Without Walls, and Johns Hopkins Multiple Sclerosis and Transverse
`
`Myelitis Center’s Project RESTORE. I am also a medical advisor to Remedy
`
`Health Media, Anthrotonix Inc., and My Counterpane.
`
`9.
`
`At Johns Hopkins School of Medicine, I have taught post-doctoral
`
`courses on bioethics and psychiatry courses for medical students. I continue to
`
`teach seminars on ethics in psychiatry.
`
`10.
`
`I have published over 40 peer-reviewed research articles in the areas
`
`of spinal cord disorders, depression, and other neurologic disorders. I have also
`
`authored books and book chapters on diseases of the nervous system and other
`
`neurological and psychiatric disorders, including contributions to the Oxford
`
`Textbook of Psychiatry. In addition, I am a named inventor on 10 patents and
`
`patent applications, including several for the treatments of neurological
`
`autoimmune diseases.
`
`11.
`
`In more recent years, I have received Baltimore Magazine’s Top
`
`Psychiatrist award for 2012, the inaugural Elsevier Clinical Keys Innovator Award
`
`in 2013, and the inaugural PM360 award as ELITE Tech Know Geek for
`
`excellence and innovation in Health Information Technology in 2015.
`
`3
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 005
`
`
`
`
`
`12.
`
`A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is separately submitted as Exhibit 1007.
`
` LEVEL OF ORDINARY SKILL IN THE ART
`13.
`
`I understand that a person of ordinary skill in the art is a hypothetical
`
`person who is presumed to be aware of all pertinent art at the time of the invention,
`
`and also is a person of ordinary creativity.
`
`14.
`
`I understand for the purposes of this declaration that the relevant
`
`timeframe is May 26, 2005, the earliest effective filing date of the application that
`
`led to the ’027 Patent.
`
`15.
`
`I have been informed that a person of ordinary skill in the art as of
`
`May 26, 2005, would be a formulator with a Ph.D. in pharmaceutics or in a drug
`
`delivery-relevant field of a related discipline such as physical chemistry, or could
`
`have a bachelor’s degree in pharmaceutics or in a related field, plus two to five
`
`years of relevant experience in developing solid oral drug formulations. This
`
`description is approximate, and a higher level of education or skill might make up
`
`for less experience, and vice versa. This person of ordinary skill may also consult
`
`with others from an interdisciplinary team, such as a clinician with experience in
`
`treating and/or dosing schizophrenic patients.
`
`
`
`4
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 006
`
`
`
`
`
` SUMMARY OF OPINIONS
`16.
`I evaluated a certified English translation of WO 2004/017973 (Ex.
`
`1019, Japanese WO 2004/017973; Ex. 1012, English translation of WO
`
`2004/017973, “Nakamura”), which was published on March 4, 2004, and lists
`
`Mitsutaka Nakamura et al. as inventors. Nakamura describes a novel method of
`
`treating integration dysfunction syndrome using from 5 mg to 120 mg per day of
`
`the active compound (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-
`
`piperazinylmethyl]-1 cyclohexylmethyl]-2,3-bicyclo[2.2.1] heptanedicarboximide
`
`(hereafter referred to as lurasidone, the current nomenclature, rather than SM-
`
`13496 used in Nakamura). Ex. 1012 at Abs.
`
`17.
`
`In this declaration I present three main opinions based on my review
`
`of Nakamura.
`
`18.
`
`First, the clinical responses in Nakamura’s clinical trials provide a
`
`motivation to administer lurasidone at doses higher than 40 mg to achieve more
`
`efficacious results.
`
`19.
`
`Second, there was a motivation to administer the higher doses of
`
`lurasidone referenced in Nakamura as a single tablet, rather than as a divided dose
`
`spread across several tablets, based on the knowledge that this would improve
`
`patient adherence, particularly in schizophrenic populations.
`
`5
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 007
`
`
`
`
`
`20.
`
`Third, Nakamura provides a motivation to pursue immediate-release
`
`lurasidone formulations.
`
` OPTIMAL LURASIDONE DOSAGE RANGE
`21.
`Nakamura describes the use of a placebo-controlled double blind
`
`experiment involving 149 patients with acute exacerbations of schizophrenia,
`
`involving lurasidone treatments at an oral dose of 40 mg or 120 mg, or a placebo
`
`that was orally administered once a day for 6 weeks. Ex. 1012 at 5-6. The
`
`researchers measured the efficacy of the trial using PANSS, Extracted-BPRS, and
`
`CGI-S/I scales, whereas safety was assessed using the EPS Rating scale of
`
`Simpson-Angus, Barnes (AIMS), a 10-item scale used to evaluate drug-related
`
`extrapyramidal symptoms. Ex. 1012 at 7-11. The PANSS (Positive And Negative
`
`Syndrome Scale), used for measuring symptom severity of schizophrenic patients,
`
`is comprised of 30-items each scored on a 7-point (1–7) rating scale; the Extracted-
`
`BPRS (Brief Psychiatric Rating Scale) is a shorter and older scale based on 18
`
`items and is also used to measure psychiatric symptoms found in patients with
`
`schizophrenia; and the CGI-S/I (Clinical Global Impression) is a rating scale which
`
`rates the overall severity of psychiatric disease based on a clinician’s judgment.
`
`Further, the PANSS, which was derived and extended from the BPRS in an attempt
`
`to provide a more complete and comprehensive assessment of patients with
`
`schizophrenia, is considered to be “consistently better” than the BPRS. Ex. 1016,
`
`6
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 008
`
`
`
`
`
`Morris Bell et al., The Positive and Negative Syndrome Scale and the Brief
`
`Psychiatric Rating Scale: Reliability, Comparability, and Predictive Validity, 180
`
`J. NERVOUS & MENTAL DISEASE 723 (1992).
`
`22.
`
`Regarding efficacy, the results in Table 2 of Nakamura show that
`
`beneficial responses to both the 40 mg and the 120 mg doses of lurasidone were
`
`statistically significant when calculated as the change in BPRS total scores
`
`measured prior to dosing compared to those at the end of the trial (i.e. after 6
`
`weeks of lurasidone treatment). However, only the response to the 120 mg dose
`
`had sufficient efficacy to reach statistical significance during the trial when
`
`measured with PANSS. Under the PANSS, those patients given the 40 mg dose of
`
`lurasidone daily did not have a statistically significant improvement in the
`
`psychiatric symptoms of their schizophrenia from the beginning to the end of the
`
`study. The response on the PANSS was in fact 23% greater in those subjects
`
`receiving the 120 mg dose as compared to those receiving the smaller 40 mg dose.
`
`Ex. 1012 at 7. One of ordinary skill would consider the lack of significant findings
`
`after treatment with the 40 mg dose of lurasidone as compared to the 120 mg dose
`
`on the PANSS to have greater clinical relevance than the BPRS findings.
`
`23.
`
`Regarding safety and the risk of side effects or adverse events,
`
`Table 5 of Nakamura shows that using the higher 120 mg lurasidone dose did not
`
`result in any greater rate of adverse events than using the 40 mg dose (80% vs
`
`7
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 009
`
`
`
`
`
`78%, respectively), and likewise resulted in an equivalent rate of serious adverse
`
`events (6% vs 6%). Ex. 1012 at 8. In addition, as shown in Table 8, there was no
`
`greater burden of extrapyramidal symptoms, one of the principal dose-related side
`
`effects of all antipsychotics, for those patients given the 120 mg as compared to
`
`those given the 40 mg dose. Ex. 1012 at 11.
`
`24.
`
`In light of the foregoing, since the 120 mg dose was both more
`
`effective and equivalently safe to the 40 mg dose, Nakamura provides a motivation
`
`to use higher doses than 40 mg to provide an efficacious use of lurasidone.
`
` OPTIMAL DELIVERY OF LURASIDONE USING A SINGLE
`TABLET
`25.
`
`There was a motivation to administer the higher doses of lurasidone
`
`referenced in Nakamura as a single tablet. While the once-a-day 120 mg dosage of
`
`lurasidone could be achieved with, for example, three 40 mg tablets, there is
`
`extensive literature suggesting this approach is not the preferred dosing regimen.
`
`26. Medication non-adherence is a major source of poor treatment
`
`outcomes and increased patient care costs, with an estimated 50% to 70% of
`
`patients failing to comply with prescribed medications during their first year of
`
`treatment. Ex. 1026, Martin B. Keller, Improving the Course of Illness and
`
`Promoting Continuation of Treatment of Bipolar Disorder, 65 J. CLINICAL
`
`PSYCHIATRY 10 (2004) (“Keller”). Patient adherence effects as a function of the
`
`dosing regimen were also well-known before May 26, 2005. Ex. 1057, Barry
`
`8
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 010
`
`
`
`
`
`Blackwell, Treatment Adherence, 129 BRITISH J. PSYCHIATRY 513 (1976). A large
`
`number of trials involving the treatment of chronic illnesses, ranging from the use
`
`of antihypertensives to antidiabetic medications, have further demonstrated that the
`
`more complex the regimen (sometimes called the “pill burden”), the greater the
`
`patient medication nonadherence. Ex. 1034, Daniel R. Vanderpoel et al.,
`
`Adherence to a Fixed-Dose Combination of Rosiglitazone Maleate/Metformin
`
`Hydrochloride in Subjects with Type 2 Diabetes Mellitus: A Retrospective
`
`Database Analysis, 26 CLINICAL THERAPEUTICS 2066 (2004); Ex. 1050, Richard H.
`
`Chapman et al., Predictors of Adherence with Antihypertensive and Lipid-
`
`Lowering Therapy, 165 ARCHIVE INTERNAL MED. 1147 (MAY 2005). This has
`
`resulted in the combining of multiple individual component medications into a
`
`single pill to improve patient adherence. But nowhere is the effect of pill burden
`
`or medication regimen complexity more important than with psychotic patients
`
`such as schizophrenics. Ex. 1048, Peter M. Haddad et al., Nonadherence with
`
`Antipsychotic Medication in Schizophrenia: Challenges and Management
`
`Strategy, 5 PATIENT RELATED OUTCOME MEASURES 43 (2014). In my opinion, one
`
`of skill would have been equally motivated to pursue a single-tablet dose in 2005
`
`as they would today.
`
`27.
`
`Further, studies of patients with psychotic disorders (i.e.
`
`schizophrenia and bipolar disorder) have shown that the fewer pills a patient must
`
`9
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 011
`
`
`
`take daily, the greater their adherence to treatment. Ex. 1026, Keller. For
`
`schizophrenic patients in particular, one would be motivated to decrease the pill
`
`burden because: (1) more complicated regimens in general are associated with
`
`decreased adherence; (2) schizophrenic patients often have cognitive impairment
`
`as part of their disease, thereby making more complicated regimens more difficult
`
`for them to manage; and 3) schizophrenic patients are frequently burdened by
`
`delusions (often of a paranoid nature) such that the simpler the regimen, the less
`
`likely the patient will require convincing that his regimen is safe. These particular
`
`dosing regimen considerations for schizophrenic patients and those with other
`
`psychotic disorders would also apply before May 26, 2005. Again, in my opinion,
`
`there was ample motivation to pursue a single-tablet dose in schizophrenic patient
`
`populations in 2005 as there is today.
`
`28.
`
`Thus, one skilled in the art of treating patients with schizophrenia
`
`would know that a regimen involving a single 120 mg tablet of lurasidone would
`
`be more likely to result in improved patient adherence and efficacious therapeutic
`
`outcomes than a regimen involving multiple lower-dose tablets.
`
`IMMEDIATE RELEASE PREPARATIONS
`
`29.
`
`Nakamura provides a motivation to pursue immediate-release
`
`lurasidone formulations. The lurasidone preparations of Nakamura are orally
`
`administered in a prescribed dose once a day. Ex. 1012 at 4-5. As shown in Table
`
`10
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 012
`
`
`
`6, the exacerbation of schizophrenia in the treated group was substantially less than
`
`that of the placebo group (2% vs 8% respectively). Ex. 1012 at 9. If the treatment
`
`drug had a short half-life, one would expect that, during the portion of the day
`
`when the level of medication drops below therapeutic levels, the patients would not
`
`be adequately covered and therefore show periodic exacerbations of their
`
`symptoms. This was not seen in the Nakamura study. Thus, one could reasonably
`
`conclude from Nakamura’s data that the half-life of lurasidone in the body was
`
`long enough to last the day such that an extended release formulation was
`
`unnecessary.
`
`30.
`
`Further, as noted above in Section V, the higher dose of 120 mg
`
`lurasidone did not result in any more significant side effect burden than did the
`
`lower 40 mg dose, which also demonstrates that lurasidone has a long half-life.
`
`And yet this medication is known to have Dopamine Receptor Type 2 (D2)
`
`antagonism that often can result in some extrapyramidal symptoms, much like the
`
`vast majority of related medications in the class of atypical antipsychotics.
`
`Medications that have a short half-life also have a more rapid onset and higher
`
`peak dose levels as a result of the principles of pharmacokinetics. The fact that
`
`lurasidone did not elicit a dramatic increase in the prevalence of extrapyramidal
`
`symptoms when given at a 3-fold higher dose (i.e. 120 mg compared to 40 mg)
`
`11
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 013
`
`
`
`
`
`suggests that its half-life is sufficiently long such that its peak blood levels did not
`
`dramatically increase with the higher dosing.
`
`31.
`
`Indeed, it is now known in the field that a dose of 120 mg of
`
`lurasidone has a half-life of 31 hours. Ex. 1052, William M. Greenberg & Leslie
`
`Citrome, Pharmacokinetics and Pharmacodynamics of Lurasidone Hydrochloride,
`
`a Second-Generation Antipsychotic: A Systematic Review of the Published
`
`Literature, 56 CLINICAL PHARMACOKINETICS 493 (2017). Although the specific
`
`half-life of lurasidone was not published at the time of the Nakamura study,
`
`determining the half-life of a drug is a routine part of drug development involving
`
`well-known procedures. Ex. 1018, U.S. Food & Drug Admin., Guidance for
`
`Industry: Bioavailability and Bioequivalence Studies for Orally Administered
`
`Drug Products — General Considerations (Mar. 2003) at 19. Further, the findings
`
`discussed above from Nakamura already demonstrate that before May 26, 2005,
`
`there was no need to sustain the release of lurasidone to achieve once-a-day
`
`dosing.
`
`32.
`
`In sum, one could reasonably conclude from Nakamura that
`
`lurasidone had a sufficiently long half-life such that an immediate release
`
`formulation would be preferred for a once-a-day dose.
`
` CONCLUSION
`
`12
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 014
`
`
`
`33,
`
`All statements made herein of my own knowledgeare true, and all
`
`statements made on information and belief are believed to be true, and further
`
`these statements were made with the knowledge that willful false statements and
`
`the like so madeare punishable by fine or imprisonment or both under 18 U.S.C.
`
`§ 1001.
`
`Dated: April17_, 2017
`
`AA
`
`Dr. Adam Kaplin
`
`13
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 015
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 015
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
