Paper No. 10
`Entered: October 13, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`--------------------------
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`--------------------------
`
`ROXANE LABORATORIES, INC.,
`Petitioner,
`
`v.
`
`VANDA PHARMACEUTICALS INC.,
`Patent Owner.
`
`--------------------------
`
`Case IPR2016-00690
`Patent No. 9,138,432
`
`--------------------------
`
`
`
`PATENT OWNER VANDA PHARMACEUTICAL’S RESPONSE TO
`ROXANE’S REQUEST FOR REHEARING OF THE DECISION
`DENYING INSTITUTION
`
`
`Entered: October 13, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`--------------------------
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`--------------------------
`
`ROXANE LABORATORIES, INC.,
`Petitioner,
`
`v.
`
`VANDA PHARMACEUTICALS INC.,
`Patent Owner.
`
`--------------------------
`
`Case IPR2016-00690
`Patent No. 9,138,432
`
`--------------------------
`
`
`
`PATENT OWNER VANDA PHARMACEUTICAL’S RESPONSE TO
`ROXANE’S REQUEST FOR REHEARING OF THE DECISION
`DENYING INSTITUTION
`
`
`
`Paper No. 10
`Case IPR2016-00690
`Patent No. 9,138,432
`
`Table of Contents
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`1. The Board Did Not Overlook Roxane’s Arguments And
`Evidence........................................................................................................... 1
`2. Roxane’s Attempt To Reargue Its Position Should Also Be
`Rejected For The Reasons The Board Already Identified .............................. 7
`3. Conclusion ..................................................................................................... 10
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`Page
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`Case IPR2016-00690
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`Because the Decision Denying Institution of Inter Partes Review (Paper 8)
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`shows that the Board understood and considered the arguments and evidence that
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`Roxane now argues it overlooked, Roxane’s Request for Rehearing (Paper 9)
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`should be denied.
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`1. The Board Did Not Overlook Roxane’s Arguments And Evidence
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`Roxane’s Petition argued that “[i]n order to arrive at the claimed dosages, a
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`POSA need only have followed FDA Guidance 1999’s comprehensive guidelines
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`for the performance of drug interaction and dose regimen studies,” using only
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`“routine experimentation” and with “predictable results.” Pet. at 54–55 (Ground
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`I), 58 (Ground II). Roxane now asserts that the Board overlooked these arguments
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`and supporting evidence. Rehearing Req. at 4–5. But the Decision shows that the
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`Board considered and rejected them.
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`First, the Decision provides an extensive summary of FDA Guidance 1999,
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`including its recommendations and guidance regarding in vivo metabolic drug-drug
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`interaction studies, the general concepts underlying its recommendations, its goal
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`of determining the clinical significance of any increase or decrease in exposure to a
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`substrate in the presence of an interacting drug, and examples of drug-drug
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`interactions involving the P450 enzymes CYP3A4 and CYP2D6. Decision at 10–
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`1
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`12. This shows that the Board considered the disclosures of FDA Guidance 1999,
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`Paper No. 10
`Case IPR2016-00690
`Patent No. 9,138,432
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`and did so in detail.
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`Second, the Decision provides an extensive summary of Roxane’s
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`arguments regarding FDA Guidance 1999, including those that Roxane now
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`contends the Board overlooked:
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`• “In particular, Petitioner argues that, as reflected in FDA
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`Guidance 1999, ‘in order to safely administer a drug like
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`iloperidone to a patient, a POSA needed to first review the
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`drug’s metabolic pathways, identify all of the patient’s
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`concurrent medications, and determine what dose
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`adjustments might be necessary based on potential drug
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`interactions.’” Decision at 16 (quoting Pet. at 40–41).
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`• “Petitioner further argues that ‘analysis of a drug’s
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`metabolic interactions and dosing adjustments was a routine
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`part of drug development explicitly recommended by the
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`FDA’ and, therefore, ‘POSAs involved in the development
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`of a drug like iloperidone were motivated to combine the
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`teachings of FDA Guidance 1999, Mutlib, Brosen, and
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`Mealy in order to secure FDA approval.’” Decision at 17
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`(quoting Pet. at 42–43) (emphasis added).
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`• “With respect to Ground II . . . Petitioner takes a similar
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`position with respect to motivation to combine, in particular,
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`that ‘FDA Guidance 1999 comprehensively motivates
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`review of these references, instructing on the study of drug
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`interactions both as part of standard clinical practice and in
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`order to secure a drug’s FDA-approval.’” Decision at 17–18
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`(quoting Pet. at 45) (emphasis added).
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`These excerpts show that the Board was aware of and gave detailed consideration
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`to the arguments Roxane now asserts it overlooked.
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`Third, the Decision shows that, having considered Roxane’s arguments that
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`the claimed dosages were the result of routine experimentation, the Board denied
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`institution, not because the Board misunderstood Roxane’s arguments, but because
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`it found Vanda’s arguments more persuasive. As the Board explained:
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`In response, Patent Owner argues that FDA Guidance 1999,
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`Petitioner’s primary reference, provides only an “invitation to
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`experiment” without any indication of whether the interaction of
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`fluoxetine with iloperidone would be clinically meaningful “or what
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`conclusions would be reached by drug companies following its
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`recommendations.” Prelim. Resp. 24–25, 38–47. We find this
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`argument persuasive. As set forth in section II(D)(i), above, the
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`Guidance states that drug-drug interactions “should be explored as
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`part of an adequate assessment of [a new drug’s] safety and
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`effectiveness,” and provides recommendations regarding the conduct,
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`design, analysis of those studies.
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`Decision at 19 (emphasis in original). The Board went on to note that FDA
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`Guidance 1999 “also emphasizes that one of ordinary skill in the art must
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`determine whether any observed drug-drug interaction is clinically meaningful,”
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`including “‘whether the interaction is sufficiently large to necessitate a dosage
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`adjustment.’” Decision at 19 (quoting Ex. 1005 (FDA Guidance 1999) at 3, 12).
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`Thus, as these excerpts show, the Board did not “stop” its analysis at the
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`point of recognizing that Roxane’s references provided only an “invitation to
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`experiment,” as Roxane contends. Rehearing Req. at 1. Nor are these the only
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`portions of the Board’s Decision that are inconsistent with Roxane’s rehearing
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`request, which fails to recognize that in rejecting Roxane’s Petition, the Board also
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`found persuasive Vanda’s evidence regarding prior art overlooked by Roxane.
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`Decision at 19–23. Among other things, the Board cited Vanda’s “persuasive
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`4
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`evidence that even where two drugs share the same metabolic pathway, the clinical
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`significance of any drug-drug interaction ‘is unpredictable and needs to be
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`empirically determined,’” id. at 19 (citing Prelim. Resp. at 6 and supporting
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`evidence); found that in “the absence of evidence regarding the relative
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`contribution of the parent drug, iloperidone, and its metabolites to the QTP side
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`effect, one of skill in the art could not have known whether impaired CYP2D6
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`metabolism would have affected the risk of QT prolongation, either positively or
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`negatively,” Decision at 19–20; provided multiple prior art examples supporting
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`this finding, id. at 20–22; and concluded “the art as a whole taught a careful
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`evaluation of such drugs for evidence of clinically-relevant drug-drug interactions,
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`which may, or may not be addressed with dose reductions. Such invitations to
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`experiment do not, in light of the current record, predict the dosage reduction of
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`the subject claim,” id. at 22.
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`Fourth, Roxane ignores the caselaw the Board provided in support of its
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`finding that the invitations to experiment in the prior art did not render Vanda’s
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`invention obvious. The Board quoted the following from In re Cyclobenzaprine
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`Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063, 1073
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`(Fed. Cir. 2012): “[W]here the prior art, at best gives only general guidance as to
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`the particular form of the claimed invention or how to achieve it, relying on an
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`5
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`obvious-to-try theory to support an obviousness finding is impermissible.” This
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`defeats another of Roxane’s arguments on rehearing: Roxane now states that it
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`“does not ask the Board to revisit” its conclusion that “the amount of the needed
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`dose reduction (if any) is unpredictable, and would need to be determined
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`empirically,” but argues that an empirical study would require only “routine
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`experimentation” and therefore would have been obvious. Rehearing Req. at 6–7.
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`Roxane offers no evidence to support this proposition, and instead cites only the
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`pre-KSR decision in Merck & Co. v. Biocraft Laboratories, Inc., 874 F.2d 804, 809
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`(Fed. Cir. 1989). Merck involved co-administration of two diuretic compounds
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`whose combined effect “was to be expected from the known natriuretic properties
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`of the two diuretics” and thus truly was predictable. See id. In the present case, in
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`which the drug-drug interactions are wholly unpredictable, Cyclobenzaprine is on
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`point and Merck is not.
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`The Federal Circuit held in Cyclobenzaprine: “While it may have been
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`obvious to experiment with the use of the same PK profile when contemplating an
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`extended-release formulation, there is nothing to indicate that a skilled artisan
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`would have had a reasonable expectation that such an experiment would succeed in
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`being therapeutically effective.” 676 F.3d at 1070. Likewise, and as the Board
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`found:
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`6
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`Thus, we agree with Patent Owner that “[w]ithout knowing in
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`advance whether it was iloperidone, one of its metabolites, or some
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`combination thereof that was causing the observed QT prolongation, it
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`could not be predicted whether a change in iloperidone metabolism
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`would have increased, decreased, or had no effect on the risk of QT
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`prolongation.”
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`Decision at 23 (quoting Prelim. Resp. at 15–16). It was this reasoning, not failure
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`to consider any part of Roxane’s submissions, that led the Board to deny
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`institution.
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`2. Roxane’s Attempt To Reargue Its Position Should Also Be Rejected
`For The Reasons The Board Already Identified
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`The last five pages of the rehearing request merely seek to reargue Roxane’s
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`position without identifying any argument or evidence that the Board allegedly
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`overlooked. Rehearing Req. at 7–11. Roxane cites KSR, Merck, and other cases
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`for the proposition that an invention is obvious if it only requires following routine
`
`procedures. Once again, this ignores the Board’s citation of Cyclobenzaprine and
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`it ignores the Board’s findings showing that the work to achieve Vanda’s invention
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`was not routine.
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`The Board specifically found, for example, that “one of ordinary skill could
`
`not have known whether impaired CYP2D6 metabolism would have affected the
`
`7
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`risk of QT prolongation, either positively or negatively,” Decision at 20; that “the
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`Case IPR2016-00690
`Patent No. 9,138,432
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`art as a whole taught” that drug-drug interactions “may or may not be addressed
`
`with dose reductions,” id. at 22; and that “it could not be predicted whether a
`
`change in iloperidone metabolism would have increased, decreased, or had no
`
`effect on the risk of QT prolongation,” id. at 23. Roxane also ignores the evidence
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`Vanda provided regarding Novartis’s failed efforts to bring iloperidone to market.
`
`As Vanda explained in its Preliminary Response:
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`During its development of the drug, Novartis conducted the very type
`
`of study that Roxane contends FDA Guidance 1999 would have
`
`motivated a skilled artisan to conduct. Guengerich Decl. [Ex. 2001]
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`¶ 81. Novartis was certainly part of the target audience for that
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`publication, i.e., a large pharmaceutical company conducting clinical
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`trials of a drug. Guengerich Decl. ¶ 89. . . . Novartis found that
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`CYP2D6 normal metabolizers had twice as many side effects as those
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`with impaired CYP2D6 function. Novartis 0104 Study Report (Ex.
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`2030) at 50; Guengerich Decl. ¶ 86. Similarly, Novartis found that
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`individuals not co-administered a CYP2D6 substrate had twice as
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`many side effects as those co-administered a CYP2D6 substrate.
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`Novartis 0104 Study Report (Ex. 2030) at 50; Guengerich Decl. ¶ 86.
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`8
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`A highly motivated company with vast resources at its disposal
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`conducted exactly the kind of study that Roxane says would have
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`been obvious and reached exactly the wrong conclusion. Guengerich
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`Decl. ¶¶ 88–89.
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`Prelim. Resp. at 46–47 (emphasis in original). This squarely rebuts Roxane’s
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`arguments about purported “routine experimentation” and “reasonable expectation
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`of success.”
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`Roxane concludes by asserting that its arguments and evidence are
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`“undisputed” and citing the rule that “genuine issues of material fact” are “viewed
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`in the light most favorable to the petitioner” at the institution stage. Rehearing
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`Req. at 10–11 (quoting 37 C.F.R. § 42.108(c)); see also id. at 2–3, 5–6. It should
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`be apparent that Vanda disputes Roxane’s arguments for all of the reasons above
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`and in its Preliminary Response. As to the evidence, Roxane once again is missing
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`the point. Roxane filed its Petition based on a narrow set of prior art that does not
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`show what one of ordinary skill would have understood from the art as a whole.
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`Roxane failed to address anything outside this narrow set of facts, including the
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`complete lack of knowledge in the prior art as to how iloperidone and its
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`metabolites affected QT prolongation and the resulting fact that, as the Board
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`stated, “one of skill in the art could not have known whether impaired CYP2D6
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`9
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`metabolism would have affected the risk of QT prolongation, either positively or
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`negatively.” Decision at 19–20. There was no evidentiary dispute to be resolved
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`here since Roxane provided no evidence on this point. Roxane concedes that there
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`was no evidentiary dispute to be resolved. Rehearing Req. at 5–6, 10.
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`In the same vein, the Board properly considered the art as a whole in making
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`its obviousness determination. See id. at 19–23. Notably, Roxane does not
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`identify any error the Board made in considering, for example, the Bertilsson, Shah
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`and Desai references discussed on pages 19–22 of the Decision. The Board’s
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`Decision was well-founded on consideration of all of the arguments and evidence
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`before it; there is no basis for rehearing; and the Decision should not be disturbed.
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`3. Conclusion
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`Roxane’s request for rehearing should be denied.
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`10
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`Dated: October 13, 2016
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`Paper No. 10
`Case IPR2016-00690
`Patent No. 9,138,432
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`Respectfully submitted,
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`
`
`
`By: /s/ David J. Ball, Jr.
`David J. Ball, Jr. (Reg. No. 36,083)
`Josephine Young (Reg. No. 48,308)
`PAUL, WEISS, RIFKIND, WHARTON &
`GARRISON LLP
`1285 Avenue of the Americas
`New York, NY 10019
`Tel: (212) 373-3716
`Fax: (212) 492-0716
`
`Counsel for Patent Owner
`Vanda Pharmaceuticals Inc.
`
`11
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`Case IPR2016-00690
`Patent No. 9,138,432
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`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. § 42.6(e), I certify that on October 13, 2016, a true
`
`and correct copy of the foregoing PATENT OWNER VANDA
`
`PHARMACEUTICAL’S RESPONSE TO ROXANE’S REQUEST FOR
`
`REHEARING OF THE DECISION DENYING INSTITUTION was served by
`
`email on the following counsel of record for Roxane Laboratories, Inc.:
`
`Daniel G. Brown (Reg. No. 54,005)
`daniel.brown@lw.com
`Latham & Watkins LLP
`885 Third Avenue
`New York, NY 10022-4834
`T: 212.906.1200
`F: 212.751.4864
`Robert Steinberg (Reg. No. 33,144)
`bob.steinberg@lw.com
`Latham & Watkins LLP
`355 South Grand Avenue
`Los Angeles, CA 90071-1560
`T: 213.485.1234
`F: 213.891.8763
`
`
`
`Emily C. Melvin (Reg. No. 66,586)
`Timothy J. O’Brien (Reg. No. 68,264)
`emily.melvin@lw.com
`timothy.obrien@lw.com
`Latham & Watkins LLP
`330 North Wabash Avenue, Suite 2800
`Chicago, IL 60611
`T: 312.876.7700
`F: 312.993.9767
`
`
`
`
`By,
`
`
`/s/ David J. Ball, Jr.
`
`David J. Ball, Jr. (Reg. No. 36,083)
`PAUL, WEISS, RIFKIND, WHARTON &
`GARRISON LLP
`1285 Avenue of the Americas
`New York, NY 10019
`Tel: (212) 373-3716
`Fax: (212) 492-0716
`
`Counsel for Patent Owner
`Vanda Pharmaceuticals Inc.
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