UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`MYLAN PHARMACEUTICALS INC. and AMNEAL
`PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO. LTD.,
`Patent Owner
`____________
`
`
`Case No. IPR2015-00644
`Patent 8,399,413
`____________
`
`
`PATENT OWNER’S REQUEST FOR REHEARING
`
`
`
`
`
`
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`MYLAN PHARMACEUTICALS INC. and AMNEAL
`PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO. LTD.,
`Patent Owner
`____________
`
`
`Case No. IPR2015-00644
`Patent 8,399,413
`____________
`
`
`PATENT OWNER’S REQUEST FOR REHEARING
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I. SUMMARY OF ISSUES FOR REHEARING ................................................... 1
`II. LEGAL STANDARD ...................................................................................... 4
`III. ARGUMENT .................................................................................................... 5
`A. The Board Overlooked and Misapprehended Evidence Regarding the
`Tolerability of Less Frequent Dosing of GA. ......................................................... 6
`B. The Board Overlooked Evidence of Decreased Tolerability of 40 mg GA. .. 10
`C. Analysis of the Prior Art As a Whole Necessitates a Finding that the Claims
`of the ’250 Patent Are Not Obvious. .................................................................... 12
`D. The Board Overlooked Evidence Regarding the Expected Decrease in
`Tolerability in its Discussion of Secondary Considerations. ................................ 14
`IV. CONCLUSION .............................................................................................. 15
`
`
`
`
`
`
`
`
`
`I.
`
`SUMMARY OF ISSUES FOR REHEARING
`
`Patent Owner Yeda Research and Development Co. Ltd. (“Yeda” or “Patent
`
`Owner”) requests rehearing under 37 C.F.R. § 42.71(d) of the Board’s Final
`
`Written Decision (“FWD”) holding that claims 1-20 of U.S. Patent No. 8,399,413
`
`(“the ’413 patent”) are unpatentable. Rehearing is appropriate in this case because
`
`the Board misapprehended or overlooked evidence in the prior art teaching that
`
`less frequent dosing of 40 mg of glatiramer acetate (“GA”) would lead to more
`
`injection related adverse events. Thus, the Board’s rulings on patentability should
`
`be revisited.
`
`In its decision, the Board found that the treatment regimens claimed in the
`
`’413 patent are obvious over the prior art. The claims of the ’413 patent are
`
`directed to: (a) methods of reducing the frequency of relapses in a patient with
`
`multiple sclerosis with a regimen comprising three subcutaneous injections of a 40
`
`mg dose of glatiramer acetate (“GA”) over a period of seven days with at least one
`
`day between every subcutaneous injection (see, e.g. Claim 1); and (b) methods of
`
`reducing the frequency of relapses in a patient with multiple sclerosis with the
`
`above regimen, wherein the frequency of an immediate post injection reaction or
`
`the frequency of an injection site reaction is reduced relative to these reactions
`
`caused by 20 mg daily treatment of GA (see Claim 7). In rendering its decision,
`
`the Board found that a person of ordinary skill in the art would have been
`
`
`
`1
`
`
`
`motivated to develop a regimen of GA treatment to reduce side effects and thereby
`
`increase tolerability over the prior art GA regimens. (FWD at 12, 13, 15.) The
`
`Board also found that a person of skill at the time of the invention would have
`
`expected a 40 mg, three times per week dosing regimen to improve the tolerability
`
`of GA treatment through a reduction in the number of injection related adverse
`
`events such as injection site reactions and immediate post injection reactions.
`
`(FWD at 24.) The teaching of the prior art as a whole, however, does not support
`
`either of these findings.
`
`Contrary to the Board’s findings and Petitioner’s “common sense”
`
`arguments that reducing frequency of injections would increase tolerability of
`
`treatment, the prior art as a whole taught that a less frequent dosing schedule with
`
`40 mg of GA would decrease the tolerability of GA treatment. For example, the
`
`Board explicitly erred in its analysis of the Flechter prior art reference and the
`
`adverse event data therein. Data in the Flechter reference reflects that more
`
`frequent adverse events were observed in patients being administered a 20 mg
`
`every other day regimen compared to daily treatment. The Board rejected Patent
`
`Owner’s evidence on this issue by pointing to the wrong data in Flechter, citing
`
`efficacy data on relapse rate rather than the data cited by Patent Owner’s experts
`
`concerning the incidence of injection related adverse events. (FWD at 26.) The
`
`Board thus conflated the data regarding tolerability and efficacy. Analyzing this
`
`
`
`2
`
`
`
`data correctly makes clear that the teaching of the prior art as a whole did not
`
`identify a tolerability advantage with less frequent dosing of GA.
`
`Moreover, the Board overlooked other important data in the prior art that
`
`suggested a 40 mg, three times per week regimen would result in worse tolerability
`
`than the 20 mg daily regimen. For instance, the Board’s decision did not address
`
`tolerability data from the prior art Cohen reference, which reported that “features
`
`of injection site reactions and immediate postinjection reactions were more
`
`common and severe with the higher [40 mg] dose [of GA].” (emphasis added)
`
`(Ex. 1006 at Abstract.) Nor did the Board’s decision address the finding from the
`
`FORTE study – the only statistically significant finding from that large Phase III
`
`study reported in the prior art – that a 40 mg dose of GA resulted in nearly double
`
`the rate of early treatment discontinuation due primarily to injection site reactions.
`
`(Ex. 2028 at 5.)
`
`This data and the adverse event data from Flechter, when properly analyzed,
`
`make clear that the prior art as a whole would not have motivated a person of skill
`
`to pursue a 40 mg, three times per week regimen. Nor would the prior art have
`
`supported a reasonable expectation that such a regimen would result in improved
`
`tolerability. The Board’s errors and omissions are particularly acute with respect
`
`to claim 7 that includes a limitation explicitly requiring an increase in tolerability
`
`as compared with the older GA regimen of daily subcutaneous injections of 20 mg.
`
`
`
`3
`
`
`
`In order to make out even a prima facie obviousness case on claim 7, Petitioners
`
`must demonstrate that a person of ordinary skill in the art would have expected the
`
`claimed regimen to result in improved tolerability when compared to the 20 mg a
`
`day regimen. For the reasons set forth above, the prior art as a whole did not
`
`provide a basis for such an expectation, nor a motivation to develop a 40 mg three
`
`times per week regimen.
`
`The Board’s decision rested on a finding that the prior art disclosed various
`
`regimens of treating multiple sclerosis with GA, each of which were, according to
`
`the Board, efficacious and did not decrease, and instead increased, tolerability
`
`compared to the 20 mg daily regimen. The Board’s misunderstanding and
`
`incomplete review of Patent Owner’s evidence regarding the tolerability reported
`
`in these same prior art references therefore necessitates a rehearing in this case.
`
`For these reasons, Patent Owner respectfully requests that the Board reconsider its
`
`decision and find that claims 1-20 are not obvious over the prior art based on the
`
`evidence of record.
`
`II. LEGAL STANDARD
`A request for rehearing “must specifically identify all matters the party
`
`believes the Board misapprehended or overlooked, and the place where each
`
`matter was previously addressed in a motion, an opposition, or a reply.” 37 C.F.R.
`
`§ 42.71(d). Here, the Board misapprehended and overlooked the prior art
`
`
`
`4
`
`
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`teachings that (1) less-frequent-than-daily administration, and (2) a 40 mg dose of
`
`glatiramer acetate would have been expected to decrease tolerability.1 The Board’s
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`obviousness findings regarding motivation, reasonable expectation and unexpected
`
`results were therefore erroneous.
`
`III. ARGUMENT
`A conclusion that claims are obvious over the prior art requires factual
`
`findings that a person of ordinary skill in the art would have been motivated to
`
`combine the prior art to arrive at the claimed invention, and that the person of
`
`ordinary skill in the art would have had a reasonable expectation of success that the
`
`combination would work for its intended purpose. Insite Vision Inc. v. Sandoz,
`
`Inc., 783 F.3d 853, 859 (Fed. Cir. 2015). Further, a finding of obviousness must
`
`consider the prior art as a whole. See, e.g., Panduit Corp. v. Dennison Mfg. Co.,
`
`810 F.2d 1561, 1577-78 (Fed. Cir. 1987) (“The district court did not follow
`
`established legal standards (Part I) in finding the content of the prior art. It treated
`
`no claim, nor the entire prior art, nor any prior patent ‘as a whole,’ but selected bits
`
`and pieces from prior patents”).
`
`
`1 Patent Owner seeks rehearing on the Board’s errors that are discussed in this
`
`Request. Correction of these errors is sufficient to result in reversal of the Board’s
`
`finding that the claims are obvious. Patent Owner specifically reserves the right to
`
`raise additional errors in the Board’s Final Written Decision on appeal.
`
`
`
`5
`
`
`
`In this case, the Board found that daily injections of GA, which cause some
`
`significant injection related adverse events and therefore have tolerability
`
`problems, are difficult for some patients to maintain over a life-time of treatment,
`
`and thus, a person of ordinary skill in the art would have been motivated to
`
`develop a regimen which would increase the tolerability of GA treatment. (FWD
`
`at 13-15.) The Board further found that a person of ordinary skill in the art would
`
`therefore have been motivated to develop the claimed regimen, which has a
`
`decreased frequency of injection compared to the prior art, due to the “benefits of
`
`less frequent injections.” (Id. at 17.) The Board also found that a person of skill
`
`would have possessed a reasonable expectation of improved tolerability from the
`
`claimed 40 mg, three times per week regimen. (Id. at 24.)
`
`Patent Owner submits these findings were based on a misapprehension of
`
`the record and failed to take into account the teaching of the prior art as a whole,
`
`both as to the impact of reducing the frequency of dosing and increasing the dose
`
`of GA compared to the prior art treatment regimens.
`
`A. The Board Overlooked and Misapprehended Evidence Regarding
`the Tolerability of Less Frequent Dosing of GA.
`
` First, the Board explicitly misinterpreted the data from the Flechter
`
`reference as to tolerability. Flechter reports on the efficacy and tolerability of
`
`alternate day dosing of 20 mg of GA. (POR, at 29-30; Zeimssen Decl., Ex. 2135 at
`
`¶¶ 86-91; Ex. 1008.) Flechter compares the efficacy and tolerability data to a
`
`
`
`6
`
`
`
`different study, “Meiner,” which reports on the efficacy and tolerability of daily
`
`dosing of 20 mg of GA. (POR at 29-30, Zeimssen Decl., 2135 at ¶¶ 86-91; Ex.
`
`1008; Ex. 1009)
`
`The Board misconstrued data in Flechter illustrating that alternate day
`
`dosing was as effective as daily dosing and found instead that the data taught that
`
`less-frequent-than-daily administration would have been more tolerable than daily
`
`administration2: “Patent Owner next argues that “[i]t was … surprising and
`
`unexpected that the 40 mg three injections weekly regimen was shown to be
`
`associated with fewer and less severe injection site reactions than 20 mg daily.”
`
`[POR] at 55-56…When viewed correctly, we agree that Flechter teaches a slightly
`
`lower relapse rate in patients treated with 20 mg every other day than patients
`
`treated with 20 mg every day.” (FWD at 25-26.) But, Flechter’s teaching
`
`regarding relapse rate concerns only the efficacy of the treatment. The relapse rate
`
`is irrelevant to the tolerability of the treatment, which measures adverse events,
`
`such as injection site reactions and post-injection reactions.
`
`Compounding the error of this incorrect factual finding, the Board
`
`overlooked the entire body of evidence presented by Patent Owner teaching that
`
`2 Patent Owner has contested the interpretation of this data and continues to
`
`disagree that the data teaches that alternate day dosing would have been as
`
`effective as daily dosing.
`
`
`
`7
`
`
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`less-frequent-than-daily administration would have been expected to result in
`
`decreased tolerability. The Patent Owner Response makes it clear that the data in
`
`Flechter teaches less tolerability with alternate day administration than with daily
`
`administration:
`
`In addition, in Flechter, 17% of all patients participating in the
`alternate day dosing trial did not report any adverse events. This
`compares poorly to Meiner’s daily dosage trial, in which 30% of
`patients did not report any adverse events. Further, while 16.6% of
`patients in Flechter reported IPIRs, only 13.6% of the patients in
`Meiner reported IPIRs. All in all, Flechter’s alternate day dosage
`patients reported 50% injection site reactions, which is significantly
`higher than Meiner’s report of only 44% of patients on the daily
`dosage schedule. Flechter thus indicates that the less frequent
`injection regimen of GA was less tolerable than daily injections.
`
`POR at 35-36 (citations omitted; emphasis in original); see also Zeimssen Decl. at
`
`¶ 89; Flechter, Ex. 1008 at Table 4 (reporting on adverse events with alternate day
`
`dosing); Meiner, Ex. 1009 at Table 25.3 (reporting on adverse events with daily
`
`dosing).
`
`The following table compares the tolerability data in Flechter and Meiner
`
`side-by-side, and clearly illustrates that the prior art data provided no support for
`
`any expectation that decreased frequency of injection would increase tolerability of
`
`a GA treatment regimen:
`
`8
`
`
`
`
`
`
`
`
`
`
`
`% Total Patients
`Withdrawing due to
`adverse events
`% Total Withdrawals due
`to adverse events
`% Total Patients
`Reporting an adverse
`event
`%Total Patients
`Reporting at Least One
`injection site reaction
`% Total Patients
`Reporting at Least One
`IPIR6
`% Total Patients
`Reporting at Least One
`IPIR (Using Flechter’s
`“one or more” EU
`definition in both studies)
`
`
`
`Flechter Study (Ex. 1008)
`Alternative Day Dosing of 20
`mg GA
`
`8/68=11.8%
`
`8/27=29.6%
`
`Meiner 1997 (Ex.
`1009)
`Daily Dosing of 20
`mg GA
`
`24/271=8.9%3
`
`24/99=24.2%4
`
`56/68=82.4%
`
`169/271=62.4%5
`
`34/68=50%
`
`119/271=44.0%
`
`16/68=23.5%
`
`37/271=13.7%7
`
`16/68=23.5%
`
`56/271=20.7%
`
`
`3 Reported as 8.8% in Meiner (Ex. 1009).
`
`4 This number is misreported as “34.2%” in Flechter (Ex. 1008), Table 5.
`
`5 Meiner at p. 215 reports 102 of 271 subjects as free of adverse events.
`
`6 Using the definitions set forth in each study.
`
`7 Reported as “13.6%” in Meiner.
`
`
`
`9
`
`
`
`
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`B.
`
`The Board Overlooked Evidence of Decreased Tolerability of 40
`mg GA.
`
`The Board also overlooked the entire body of evidence presented by Patent
`
`Owner which taught that a 40 mg dose of GA would have been expected to result
`
`in decreased tolerability when compared with a 20 mg dose.
`
`For example, Cohen reports on a Phase II study concerning the tolerability
`
`and efficacy of 40 mg GA administered daily and compares those data with the
`
`tolerability and efficacy of 20 mg GA administered daily. (See POR at 7, n. 1;
`
`Cohen, Ex. 1006.) The single statement in the abstract section in Cohen that
`
`discusses tolerability states that “features of injection site reactions and immediate
`
`postinjection reactions were more common and severe with the higher [40 mg]
`
`dose.” (emphasis added) (Cohen, Ex. 1006 at Abstract; POR at 7, n. 1.) Cohen
`
`also compares thirteen categories of adverse events between the two regimens. In
`
`all but one category, more patients experienced adverse events on the 40 mg
`
`regimen than on the 20 mg regimen, as shown in Table 3, reproduced below:
`
`
`
`10
`
`
`
`
`
`Cohen also reports that immediate post-injections reactions were of greater
`
`severity in the 40 mg group, being categorized most often as “moderate severity,”
`
`than in the 20 mg group, where they were categorized as “mild.” (POR at 20; see
`
`also Cohen, Ex. 1006 at 6; Fox Decl., Ex. 2129 at ¶ 51.) The Board did not discuss
`
`Cohen in the Final Written Decision.
`
`The FORTE study also taught that the tolerability of 40 mg in a single dose
`
`was decreased as compared with the tolerability of 20 mg in a single dose. (POR
`
`at 18.) Data reported following completion of the FORTE study showed that the
`
`
`
`11
`
`
`
`40 mg dose was associated with a statistically significant increase in treatment
`
`discontinuation due to injection site reactions compared with the 20 mg dose. (Id.;
`
`see also Ex. 2028 at 5; Zeimssen Decl., Ex. 2135 at ¶ 100.) This finding was the
`
`only statistically significant finding from the study reported in the prior art. The
`
`Board did not discuss these results from FORTE in its Final Written Decision.
`
`(See FWD at 14, discussing only a single sentence in the FORTE press release, Ex.
`
`2001, and overlooking the tolerability data presented to persons of ordinary skill in
`
`the art, Ex. 2028.)
`
`Other prior art presented to the Board also taught that increasing doses of
`
`GA were expected to increase the severity of side effects, including skin reactions.
`
`(See POR at 21; Fox Decl., Ex. 2129 at ¶¶ 54-56; Levi-Schaffer, Ex. 2054.) The
`
`Board also did not discuss this data in the Final Written Decision.
`
`C. Analysis of the Prior Art As a Whole Necessitates a Finding that
`the Claims of the ’250 Patent Are Not Obvious.
`
`In addition to its error involving the proper interpretation of the data in
`
`Flechter Table 5, the Board also erred in not considering the prior art as a whole.
`
`“[T]he obviousness inquiry [asks] whether the claimed inventions are rendered
`
`obvious by the teachings of the prior art as a whole.” Allied Erecting And
`
`Dismantling Co. v. Genesis Attachments, LLC, 825 F.3d 1373, 1380 (Fed. Cir.
`
`2013). When the data is properly considered as a whole, the prior art taught that
`
`both decreased frequency of injection and increased dosage amount per injection
`
`
`
`12
`
`
`
`were expected to decrease the tolerability of GA treatment. A person of ordinary
`
`skill in the art thus would not have been motivated to develop the claimed
`
`treatment regimen in an effort to increase tolerability of GA treatment.
`
`Moreover, for dependent claim 7, which requires that the claimed regimen
`
`decrease the frequency of immediate post injection reactions and injection site
`
`reactions as compared to the prior art 20 mg daily regimen, a person of ordinary
`
`skill in the art would also not have had a reasonable expectation of success.
`
`For these reasons, Petitioners and the Board have failed to demonstrate that
`
`the claims of the ’413 patent are prima facie obvious over the prior art. Other than
`
`the erroneous interpretation of the Flechter data, the only prior art teaching relied
`
`upon by the Petitioners and the Board to suggest an improvement in tolerability
`
`were observations reported in the Khan 2008 and Caon 2008 abstracts. (FWD at
`
`16.) But neither of those references contained any data whatsoever nor did they
`
`involve experimentation with a 40 mg dose. The reported data found in the prior
`
`art as a whole clearly suggested that decreased tolerability would result from a 40
`
`mg, three times per week regimen and the Board’s decision erred in finding
`
`13
`
`otherwise.
`
`
`
`
`
`
`
`D. The Board Overlooked Evidence Regarding the Expected
`Decrease in Tolerability in its Discussion of Secondary
`Considerations.
`
`The Board propagated its error regarding motivation and reasonable
`
`expectation into the secondary considerations portion of its decision. In that
`
`section, the Board found that it was not unexpected that the claimed regimen was
`
`effective and more tolerable than the 20 mg daily regimen. (FWD at 25.) Again,
`
`the Board failed to address the data in Flechter suggesting decreased tolerability
`
`with less frequent dosing. (FWD at 26.) And, again, the Board failed to address
`
`prior art like Cohen, FORTE, and Levi-Schaffer, which collectively taught that
`
`tolerability would be worsened with a 40 mg dose of GA. This prior art would
`
`have created an expectation of decreased tolerability which renders the actual
`
`results of the claimed regimen unexpected. (POR at 53-55; Wolinsky, Ex. 2029 at
`
`3; McKeague, Ex. 2025 at 5.)
`
`The Board’s finding that Patent Owner failed to provide any evidence of
`
`improved tolerability over the Pinchasi reference (FWD at 26-27) is also incorrect.
`
`As Patent Owner made clear in its submissions, the Pinchasi application was based
`
`upon the same data reported in the Cohen study, a fact a person of skill would have
`
`recognized. (POR at 7; Ex. 2135 at ¶ 101.) As set forth above, the improved
`
`tolerability of the claimed regimen would have been unexpected in view of the
`
`reported data from Cohen as well as Pinchasi – both of which reported an increase
`
`
`
`14
`
`
`
`in adverse events such as immediate post injection reactions. (POR at 7, n. 1; Ex.
`
`1006 at 6.)
`
`The unexpected results of the increased tolerability with the claimed GA
`
`treatment regimen further supports the non-obviousness of the claimed regimen.
`
`IV. CONCLUSION
`For the reasons set forth above, Patent Owner respectfully requests that the
`
`Board institute a rehearing and find that claims 1-20 of the ’413 patent are not
`
`obvious and are patentable over the prior art.
`
`Dated: September 23, 2016
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`Respectfully submitted,
`/Elizabeth J. Holland/
`Elizabeth J. Holland
`Registration No. 47,657
`GOODWIN PROCTER LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10019-1405
`Tel: 212-813-8800
`Fax: 212-355-3333
`
`
`
`15
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`
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`CERTIFICATE OF SERVICE
`
`The undersigned hereby certifies that the foregoing PATENT OWNER’S
`
`REQUEST FOR REHEARING was served electronically via e-mail on September
`
`23, 2016 on the following:
`
`Jeffrey W. Guise
`
`jguise@wsgr.com
`
`Brandon M. White
`
`BMWhite@perkinscoie.com
`
`Shannon Bloodworth
`
`Sbloodworth@perkinscoie.com
`
`David Anstaett
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`DAnstaett@perkinscoie.com
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`Richard Torczon
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`rtorczon@wsgr.com
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`
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`Dated: September 23, 2016
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`/Elizabeth Holland/
`Counsel for Patent Owner
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