Filed: March 9, 2016
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`————————————————
`
`MYLAN PHARMACEUTICALS INC.
`
`Petitioner,
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO. LTD.
`
`Patent Owner.
`
`————————————————
`
`Case IPR2015-00644
`
`Patent No. 8,399,413
`
`————————————————
`
`MYLAN’S REPLY TO YEDA’S PATENT OWNER RESPONSE
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`————————————————
`
`MYLAN PHARMACEUTICALS INC.
`
`Petitioner,
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO. LTD.
`
`Patent Owner.
`
`————————————————
`
`Case IPR2015-00644
`
`Patent No. 8,399,413
`
`————————————————
`
`MYLAN’S REPLY TO YEDA’S PATENT OWNER RESPONSE
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`The Prior Art Motivated Development of a Less Frequent Dosing
`Regimen ........................................................................................................... 3
`
`A.
`
`B.
`
`POSAs Knew Less Frequent Dosing Would Improve
`Convenience .......................................................................................... 3
`
`POSAs Knew Less Frequent Dosing Would Increase
`Tolerability by Reducing ISRs .............................................................. 4
`
`II. A POSA Would Have Reasonably Expected a 40 mg TIW Regimen to
`Be Efficacious .................................................................................................. 8
`
`A.
`
`B.
`
`C.
`
`The Prior Art Suggested Less Frequent GA Administration Was
`Efficacious and Expressly Encouraged Pursuit of Such a
`Regimen ................................................................................................. 8
`
`The Claimed Regimen Falls Squarely Within a Known Range
`of Therapeutically Efficacious Doses ................................................... 9
`
`The SBOA Pharmacokinetic Data Provide a Reasonable
`Expectation of Success ........................................................................ 14
`
`D. Dr. Ziemssen’s Mechanism of Action Theory Does Not Teach
`Away From Less Frequent Than Daily Dosing .................................. 16
`
`III. All Dependent Claims Are Obvious .............................................................. 18
`
`IV. Patent Owner’s Secondary Considerations Cannot Save The Patent ............ 19
`
`A.
`
`B.
`
`Patent Owner Has Not Established Any Unexpected Results ............ 19
`The Established Copaxone® Brand and Steep Price Discounts
`Drove Copaxone® 40mg Sales, Not The Claimed Subject
`Matter .................................................................................................. 20
`
`C.
`
`The Patent Satisfied No Long-Felt But Unmet Need ......................... 21
`
`
`
`
`
`i
`
`
`
`
`
`TABLE OF AUTHORITIES
`
`CASES
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................ 9, 13, 21, 22
`
`Hoffman-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ................................................................ 3, 10, 13
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .............................................................................................. 3
`
`Merck & Co., Inc. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 10
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 11
`
`Teva Pharms. USA, Inc. v. Sandoz, Inc.,
`789 F.3d 1335 (Fed. Cir. 2015) .......................................................................... 21
`
`
`
`
`
`ii
`
`
`
`
`
`TABLE OF ABBREVIATIONS
`
`
`
`ABBREVIATION
`
`CNS
`FDA
`Fletcher 2002A
`
`GA
`IPIRs
`ISRs
`MS
`Pinchasi
`
`POSA
`RRMS
`SBOA
`
`Teva
`
`TIW
`Yeda
`
`
`
`DESCRIPTION
`Central nervous system
`U.S. Food and Drug Administration
`Shlomo Flechter et al., Copolymer 1
`(Glatiramer Acetate) in Relapsing Forms
`of Multiple Sclerosis: Open Multicenter
`Study of Alternate-Day Administration.
`25:1 CLINICAL NEUROPHARAMCOLOGY,
`11-15 (2002) (Ex. 1008)
`Glatiramer acetate
`Immediate post injection reactions
`Injection site reactions
`Multiple Sclerosis
`Irit Pinchasi: International Publication No.
`WO 2007/081975 (published July 19,
`2007) (Ex. 1005)
`Person of ordinary skill in the art
`Relapsing remitting multiple sclerosis
`Ex. 1007, Summary Basis of Approval for
`the New Drug Application for 20 mg daily
`Copaxone® (NDA #20-622).
`Teva Pharmaceuticals Industries Ltd. is the
`exclusive licensee of the ’250, ’302,
`and ’413 patents. Teva Pharmaceuticals
`USA, Inc. is the holder of the New Drug
`Application for Copaxone®, a drug for
`which the ’250, ’302, and ’413 patents are
`listed in the FDA publication “Approved
`Drug Products with Therapeutic
`Equivalence Evaluations,” commonly
`referred to as “the Orange Book.” Teva
`Neuroscience, Inc. markets and sells
`Copaxone® in the United States.
`Three injections per week
`Yeda Research & Development Co. Ltd.
`
`iii
`
`
`
`
`
`All claims of the ’413 patent are obvious based on Pinchasi in view of either
`
`(1) Flechter 2002A, or (2) the SBOA. Pinchasi disclosed administration of 40 mg
`
`of GA every other day, a regimen nearly identical to the claimed 40 mg TIW
`
`regimen. As Pinchasi is practically anticipatory, its combination with either
`
`Flechter 2002A or the SBOA easily shows obviousness. Patent Owner stakes its
`
`case on the untenable position that, despite its own disclosure of 40 mg every other
`
`day dosing in Pinchasi, the prior art teaches away from less frequent than daily
`
`dosing.
`
`Patent Owner’s position contradicts basic knowledge in the art and
`
`overwhelming clinical data. POSAs have long known that patients dislike
`
`Copaxone’s daily
`
`injections, which cause
`
`ISRs, needle
`
`fatigue, and
`
`noncompliance. At least since an FDA reviewer in 1996 suggested less frequent
`
`GA administration as a possible solution (Ex. 1007), artisans have investigated
`
`lower frequency dosing, achieving promising results. Only Patent Owner’s
`
`blocking patents on GA (and its manufacturing process) impeded earlier
`
`commercialization of the claimed regimen. As shown in the table below, by 2009,
`
`clinicians had amassed data that showed (1) every other day GA administration is
`
`as effective as daily administration (Ex. 1008, 1010, 1011), (2) 40 mg is a safe,
`
`efficacious, and well-tolerated dose (Ex. 1005, Ex. 1006), and (3) GA is
`
`efficacious in total weekly doses between 70 mg and 280 mg.
`
`1
`
`
`
`Day
`
`Bornstein
`1984
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`5 mg
`
`5 mg
`
`5 mg
`
`5 mg
`
`5 mg
`
`
`
`
`5 mg
`
`5 mg
`
`
`
`Flechter
`2002A/B;
`Khan
`20 mg
`
`
`
`Patent Pinchasi Copaxone® Cohen; ’413 Pinchasi
`40 mg
`40 mg
`20 mg
`40 mg
`
`
`
`
`20 mg
`
`
`40 mg
`
`
`40 mg
`
`
`20 mg
`
`
`40 mg
`
`
`40 mg
`
`
`40 mg
`
`
`
`
`
`
`20 mg
`
`
`
`20 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`10
`
`11
`
`12
`
`13
`
`14
`
`5 mg
`
`5 mg
`
`5 mg
`
`
`
`
`
`
`
`20 mg
`
`
`
`20 mg
`
`
`
`Total / 2 wks
`
`50 mg
`
`140 mg
`
`
`40 mg
`
`
`40 mg
`
`
`40 mg
`
`
`40 mg
`
`
`40 mg
`
`
`40 mg
`
`
`
`240 mg 280 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`20 mg
`
`40 mg
`
`280 mg
`
`560 mg
`
`Avg. / wk
`
`25 mg
`
`70 mg
`
`120 mg 140 mg
`
`140 mg
`
`280 mg
`
`Injections/ wk
`
`
`5
`
`3, 4
`
`3
`
`3, 4
`
`7
`
`7
`
`2
`
`
`
`
`
`In sum, the published prior art as of August 2009 provided all of the data a
`
`POSA would need to try—with a reasonable expectation of success—a reduced-
`
`injection dosing regimen within the scope of the ’413 patent claims. See Ex. 1003
`
`¶ 76, Tables. It was thus obvious to administer 40 mg of GA TIW, for a total
`
`weekly dose of 120 mg.
`
`I.
`
`THE PRIOR ART MOTIVATED DEVELOPMENT OF A LESS
`FREQUENT DOSING REGIMEN
`
`“One of the ways in which a patent’s subject matter can be proved obvious
`
`is by noting that there existed at the time of invention a known problem for which
`
`there was an obvious solution . . . .” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
`
`419–20 (2007). In pharmaceutical cases, “[c]onclusive proof of efficacy is not
`
`necessary to show obviousness. All that is required is a reasonable expectation of
`
`success.” Hoffman-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir.
`
`2014) (citations omitted). By 2009, less frequent GA administration was an
`
`obvious solution to improve patient tolerability, convenience and compliance and
`
`reduce ISRs.
`
`POSAs Knew Less Frequent Dosing Would Improve Convenience
`
`A.
`All parties’ experts agree that patients disliked Copaxone’s daily injections,
`
`which led to compliance issues, and that less frequent administration solved this
`
`problem. See Hoffman-La Roche, 748 F.3d at 1332 (“At the very least, the 150 mg
`
`dose was obvious to try: There was a need to solve the problem of patient
`
`3
`
`
`
`
`
`compliance by looking to less-frequent dosing regimens.”). Patients prefer fewer
`
`injections. See Ex. 1085 ¶¶ 23–25; Ex. 2129 ¶¶ 37, 39. Daily injections caused
`
`some patients to develop injection phobia or needle fatigue. See Ex. 1085 ¶ 24. In
`
`addition, as the experts agree, there were known lifestyle benefits specific to a TIW
`
`regimen. See Ex. 2129 ¶¶ 37, 39; Ex. 1085 ¶ 25. Patients can “take the weekend
`
`off” from injections and more easily pack for an overnight trip. Ex. 1085 ¶ 25; Ex.
`
`2129 ¶ 37. These benefits were not newly discovered with the introduction of
`
`Copaxone® 40 mg—it was long-known in the art that less frequent injections
`
`would be more convenient for patients. Ex. 1085 ¶ 25; Ex. 1138 at 48:20–49:7
`
`(challenges Teva faced when it first started selling Copaxone in 1996 included “the
`
`fact that [Copaxone was] a daily injectable versus less frequently administered
`
`medications”). This fact alone motivated artisans to explore less frequent GA
`
`administration in prior art studies like Flechter 2002A, Flechter 2002B, Pinchasi,
`
`Khan 2008, and Caon. See Ex. 1005, 1008, 1010, 1011, 1012; see also Ex. 1085
`
`¶¶ 23–25.
`
`B.
`
`POSAs Knew Less Frequent Dosing Would Increase Tolerability
`by Reducing ISRs
`POSAs also knew that fewer GA injections would result in fewer ISRs. See
`
`Ex. 1085 ¶ 26. As Dr. Green opines, “[t]his knowledge is common sense—fewer
`
`injections means fewer chances to have an ISR.” Id. The prior art concurs.
`
`Flechter 2002B concludes that “[t]he fact that Copaxone injected on alternate days
`
`4
`
`
`
`
`
`seems to be equally effective as the Copaxone injected daily is important to
`
`patients with injection-related adverse events,” implying that ISRs decline with
`
`less frequent injections. Ex. 1012 at 5. Similarly, Khan 2008 and Caon reported
`
`that, after two years, all subjects in the 20 mg daily arm chose to switch to 20 mg
`
`every other day dosing. Ex. 1010, 1011. Caon also reports that “[i]njection related
`
`lipoatrophy was significantly less in the [every other day] group.” Ex. 1011. This
`
`indicates that patients find less frequent injections more tolerable. Ex. 1085 ¶ 27.
`
`A POSA would have seen reducing injection frequency as an obvious solution to
`
`the ISR problem. Ex. 1087 (“Patients who receive daily injections of glatiramer
`
`acetate often develop lipotrophy [sic] and injection-site reactions . . . . There was
`
`interest, therefore, in testing the effects of another treatment regimen, apart from
`
`20 mg daily, with the goal of minimising adverse events . . . .”).
`
`In response, Patent Owner claims that based on the FORTE clinical trial,
`
`administration of 40 mg would have been expected to cause more ISRs than 20
`
`mg. This argument is flawed. Patent Owner mischaracterizes FORTE in
`
`contending that the daily 40 mg dose led to “a statistically significant increase” in
`
`ISRs. Ex. 2129 at ¶ 52. As Patent Owner’s expert Dr. Fox admitted, the available
`
`data showed no statistically significant difference in ISRs and IPIRs in FORTE’s
`
`two arms. Ex. 2146 141:4–144:2; see also Ex. 2028 at 9 (slide 25) (40 mg daily
`
`dose had a “[s]afety profile similar to that observed in previous studies of GA
`
`5
`
`
`
`
`
`20mg” and “both doses were well-tolerated”); Ex. 1085 ¶ 78; Ex. 2147 at 125:6–
`
`14, 126:18–22 (ISRs “comparable” in Pinchasi and FORTE). Cohen, the Phase II
`
`precursor to FORTE, also concluded that “the overall incidence of injection site
`
`reactions was similar.” Ex. 1006 at 6. And FORTE compared 40 mg daily to 20
`
`mg daily. FORTE does not contradict overwhelming authority that ISRs decrease
`
`with less frequent dosing.
`
`Patent Owner also asserts that POSAs would have expected less frequent
`
`GA administration to cause more frequent ISRs because a POSA would have
`
`thought ISRs were caused by local histamine release. See Paper 27 at 21–22; Ex.
`
`2129 ¶ 53–58. The prior art disproves this theory. Patent Owner omits the fact
`
`that Teva, the patent’s exclusive licensee and the inventor’s former employer,
`
`commissioned studies assessing whether antihistamine use prior to GA injection
`
`reduced ISRs, as would be expected if ISRs were caused by histamine release. In
`
`Teva’s clinical trials, antihistamines had no meaningful effect on ISRs. Ex. 1069
`
`(Pardo and Zwibel). For example, Pardo reports on a Phase IV trial in which
`
`patients were given an antihistamine or placebo before daily GA injection. Id.
`
`(Pardo). Pardo found that “the comparison between arms was not statistically
`
`significant (primary endpoint)” and concluded that “[a]ntihistamine use as a
`
`strategy to reduce [local ISRs] in patients on GA therapy, cannot be recommended
`
`at this time.” Id. Zwibel performed a similar study, finding—like Pardo—that
`
`6
`
`
`
`
`
`“[c]ompared to using placebo, patients who took an oral antihistamine prior to each
`
`self-injection of GA for 14 days did not record a statistically significant difference
`
`on the primary endpoints . . . .” Id. (Zwibel); Ex. 1085 ¶¶ 34–40.
`
`The references relied on by Patent Owner—Shalit 1996 and Katz 2003—
`
`pre-date Pardo and Zwibel and are unpersuasive. Shalit 1996 studied intradermal
`
`(not subcutaneous) injection of GA and reported that use of an antihistamine
`
`reduced skin reactions, a finding discredited by Teva’s later studies. Ex. 2054 at 3;
`
`Ex. 1069. Further, while Shalit 1996 reports that GA induced histamine release in
`
`rat peritoneal mast cells, it also reports that “human basophils of MS patients and
`
`of healthy subjects were relatively resistant to [GA].” Ex. 2054 at 3 (emphases
`
`added). Katz 2003, a study of only one ISR in two patients, fares no better. Ex.
`
`1085 ¶ 36. A POSA in 2009 would instead credit Pardo and Zwibel’s more recent
`
`and rigorous clinical trial results. Id. ¶¶ 37–40. Indeed, if Dr. Fox’s histamine
`
`theory were correct, the art would have investigated more frequent GA
`
`administration and doctors would have prescribed antihistamines with GA. But
`
`Dr. Ziemssen admits there were no such studies, Ex. 2147 at 238:20–24, and Dr.
`
`Green explains that POSAs did not routinely prescribe antihistamines, Ex. 1085
`
`¶ 39. Importantly, Dr. Fox’s theory conflicts with actual clinical data reporting
`
`improved ISRs with less frequent GA injections. Ex. 1010, 1011. A POSA would
`
`not have credited Dr. Fox’s theory. Ex. 1085 ¶¶ 34–40.
`
`7
`
`
`
`
`
`II. A POSA WOULD HAVE REASONABLY EXPECTED A 40 MG TIW
`REGIMEN TO BE EFFICACIOUS
`A. The Prior Art Suggested Less Frequent GA Administration Was
`Efficacious and Expressly Encouraged Pursuit of Such a Regimen
`
`Based on clinical data showing that less frequent dosing regimens were
`
`efficacious, the prior art repeatedly and expressly encouraged a POSA to
`
`investigate less frequent GA dosing. Beginning in 1996, the SBOA asks “[a]re
`
`daily s.c. injections really necessary?” and “recommend[s] that the Sponsor
`
`evaluate the necessity of daily s.c. injections as opposed to more infrequent
`
`intermittent administration of the drug.” Ex. 1007 at 252. Upon finding that every
`
`other day administration of GA 20 mg “is safe, well tolerated, and probably as
`
`effective as daily Copolymer 1,” Flechter 2002A recommended that those in the art
`
`“examine[] [its results] in larger studies . . . .” Ex. 1008 at 5. While Patent Owner
`
`now claims Flechter 2002A is unreliable, Flechter’s contemporaries considered
`
`Flechter 2002A sufficiently rigorous to “provide the clinician with some guidance
`
`for alternatives for patients on GA therapy whose skin reactions to injections might
`
`otherwise compromise compliance.” Ex. 1088 at 12.
`
`Clinical interest in less frequent dosing therapies continued unabated after
`
`Flechter 2002A. In 2007, Pinchasi disclosed every other day administration of 40
`
`mg of GA. Ex. 1005 at 22. The next year, Khan 2008 and Caon performed
`
`another pilot study corroborating Flechter 2002A’s results. Ex. 1010, 1011.
`
`8
`
`
`
`
`
`Following in Flechter 2002A’s footsteps, Khan 2008 and Caon both encouraged
`
`further investigation of less frequent dosing. Khan 2008 counsels that its results
`
`“may have implications for the long-term use of GA,” and both references suggest
`
`that others conduct “large multi-center studies . . . to identify the optimal dose of
`
`GA in RRMS.” Ex. 1010, 1011. As of 2009, the prior art expressly taught that
`
`less frequent administration of GA was efficacious, and further development was
`
`warranted. Ex. 1085 ¶¶ 29–33.
`
`B.
`
`The Claimed Regimen Falls Squarely Within a Known Range of
`Therapeutically Efficacious Doses
`
`40 mg TIW administration of GA fell precisely in the middle of a range of
`
`doses known in the prior art to be efficacious. Ex. 1085 ¶¶ 15–21; see Galderma
`
`Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013) (“[W]here there is a
`
`[dosing] range disclosed in the prior art, and the claimed invention falls within that
`
`range, the burden of production falls upon the patentee to come forward with
`
`evidence that (1) the prior art taught away from the claimed invention; (2) there
`
`were new and unexpected results relative to the prior art; or (3) there are other
`
`pertinent secondary considerations.”) (citation omitted). By 2009, a POSA knew
`
`that total average weekly doses between 70 mg and 280 mg were likely
`
`efficacious. Ex. 1003 ¶ 76, Tables; Ex. 1085 ¶¶ 16, 21. And the prior art also
`
`includes two versions of a 140 mg total average weekly dose: (i) the FDA-
`
`approved 20 mg daily regimen and (ii) 40 mg administered every other day as
`
`9
`
`
`
`
`
`disclosed in Pinchasi. See Ex. 1005.
`
`Patent Owner complains that Pinchasi cites no data for its 40 mg every other
`
`day regimen. Data is not required. After all, the challenged patents themselves
`
`contain no efficacy data for the claimed 40 mg TIW regimen—they disclose only a
`
`prophetic proposed clinical trial. See Merck & Co., Inc. v. Teva Pharms. USA,
`
`Inc., 395 F.3d 1364, 1374 (Fed. Cir. 2005) (where both the asserted patent and
`
`prior art articles contained “no human clinical or laboratory data showing the
`
`safety and tolerability of the treatment methods claimed by the patent[,]” the
`
`“claimed invention adds nothing beyond the teachings of [the prior art] articles”
`
`and “the district court clearly erred in finding any difference between the claimed
`
`invention and the articles on this point”).
`
`GA was also well known to be forgiving, meaning occasional missed doses
`
`do not impact efficacy. Ex. 1085 ¶¶ 19–20. Therefore, for a POSA looking to
`
`develop a less frequently administered GA dosing regimen, 40 mg TIW was an
`
`obvious choice. See id. ¶¶ 15–21. It provided a convenient dosing schedule, and
`
`its total weekly dose (120 mg) falls in the known range of likely efficacious doses
`
`(70 mg to 280 mg) and is similar to the 20 mg daily dose (140 mg). See id. ¶¶ 16,
`
`21. At a bare minimum, 40 mg TIW was obvious to try. Hoffman La-Roche, 748
`
`F.3d at 1332 (“The prior art provided substantial guidance as to the total dose,
`
`within a given time period, that would produce effective results. . . . At the very
`
`10
`
`
`
`
`
`least, the 150 mg dose was obvious to try . . . .”).
`
`Patent Owner incorrectly claims that the prior art provides no motivation
`
`because it did not “alter the standard of care.” Paper 27 at 59–60. First, according
`
`to Wolinsky, Flechter 2002A alone was sufficient to encourage physicians to try
`
`every other day use of Copaxone. See Ex. 1088 at 12. Second, the law does not
`
`require the prior art to “alter the standard of care.”1 “[O]nly a reasonable
`
`expectation of success, not a guarantee, is needed.” Pfizer, Inc. v. Apotex, Inc., 480
`
`F.3d 1348, 1364 (Fed. Cir. 2007) (citations omitted). Third, the prior art provides
`
`ample motivation. For example, Khan 2008 invited POSAs to conduct a larger
`
`trial. Ex. 1010. That is exactly what happened—following Khan 2008’s success,
`
`Teva hired Dr. Khan to run the GALA trial that led to approval of the 40 mg TIW
`
`regimen. Ex. 1034.
`
`Patent Owner also claims that Flechter 2002A shows that patients on 20 mg
`
`every other day experienced a relapse rate double that of patients on 20 mg daily.
`
`
`1 Dr Ziemssen sets an equally high bar for the POSA. See Ex. 2147 at 157:20–
`
`158:7 (“Q. [L]ooking at the available data in August of 2009, understanding that
`
`you still have an injection cite [sic] reaction problem with the 20-milligram daily
`
`dosing, what does a person of ordinary skill in the art need to conceive of a
`
`solution to that problem. . . . A. A POSA would need a randomized, high-level
`
`clinical Phase III trial.”).
`
`11
`
`
`
`
`
`Patent Owner misinterprets the data—Flechter 2002A reports a non-annualized
`
`(i.e. two year) relapse rate, whereas Meiner reports an annualized (i.e. one year)
`
`relapse rate. Ex. 1085 ¶ 79. When properly compared, patients on 20 mg every
`
`other day actually had a slightly lower relapse rate than patients on 20 mg daily.
`
`Ex. 1008 at 4 (Table 5), 5; Ex. 1085 ¶ 79. Patent Owner’s skewed interpretation of
`
`Flechter 2002A is entirely at odds with its authors’ conclusion that the “results of
`
`the present alternate-day treatment were slightly better than those of the previous
`
`study with daily treatment; results were not significantly different except for a
`
`lower dropout rate in the present study.” Ex. 1008 at 4 (emphasis added); see also
`
`id. at 3 (relapse rate reduction for 20 mg EOD dose was “highly statistically
`
`significant.”).
`
`Patent Owner also asserts that FORTE, which showed that 40 mg daily was
`
`not superior to 20 mg daily, teaches away from using a 40 mg dose. In this regard,
`
`Patent Owner relies on a press release announcing top-line results from the FORTE
`
`trial, which says that 20 mg “remains the optimal treatment dose.” Ex. 2001 at 1.2
`
`2 Notably, Patent Owner took a decidedly different view of FORTE when
`
`prosecuting the Pinchasi application, telling the PTO that the FORTE “Press
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`Release contains only highly abbreviated information,” whereas Pinchasi contains
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`“[m]ore detailed data, such as that presented in the specification, show[ing] the
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`advantages” of the 40 mg dose. Ex. 1035 at 27.
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`12
`
`
`
`
`
`Patent Owner is wrong as a matter of law. “‘A reference does not teach away . . .
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`if it merely expresses a general preference for an alternative invention but does not
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`criticize, discredit, or otherwise discourage investigation into the invention
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`claimed.’” Galderma Labs., 737 F.3d at 738 (quoting DePuy Spine, Inc. v.
`
`Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)). In
`
`Galderma, the Federal Circuit found that prior art statements “that 0.1% was the
`
`optimal concentration of adapalene for the treatment of acne” did not teach away
`
`from a 0.3% concentration because a “teaching that a composition may be optimal
`
`or standard does not criticize, discredit, or otherwise discourage investigation into
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`other compositions.” Id. at 739.
`
`Moreover, the ’413 patent claims efficacy, not superior efficacy, to 20 mg.
`
`Ex. 1001. FORTE found “[n]o significant difference in efficacy measures between
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`GA 20mg and GA 40mg” and that “[b]oth doses demonstrated remarkable
`
`reduction compared to baseline in clinical and MRI activity.” Ex. 2028 at 9 (slide
`
`26); Ex. 1085 ¶¶ 74–77; see Hoffman-La Roche, 748 F.3d at 1332 (“Even though
`
`the 5 mg dose did not demonstrate greater efficacy than the 2.5 mg dose, it was
`
`still deemed an equivalently effective dose so that someone scaling it to a single
`
`monthly dose of 150 mg . . . would have anticipated equivalent success . . . .”).
`
`And for the greatest expectation of success, a POSA would choose a total weekly
`
`dose (120 mg) comparable to the known 20 mg daily regimen (140 mg). See Ex.
`
`13
`
`
`
`
`
`1085 ¶¶ 15–33, 73–81. For administration TIW, use of the known 40 mg dose is
`
`obvious.
`
`C. The SBOA Pharmacokinetic Data Provide a Reasonable
`Expectation of Success
`
`In the face of this overwhelming evidence, Patent Owner adopts a myopic
`
`view of the pre-clinical data in the SBOA to argue that it would not suggest less
`
`frequent dosing. The SBOA’s pharmacokinetic data shows that, as reported by
`
`Teva to the FDA, GA has a half-life of about 80 hours. Ex. 1007 at 197. This
`
`half-life is consistent with the clinical data, which suggests that less frequent
`
`dosing may be efficacious. Ex. 1085 ¶¶ 15–21, 29–33.
`
`Patent Owner argues that the pharmacokinetic data is irrelevant because
`
`“GA acts locally, in the periphery, affecting the immune system, which in turn
`
`decreases the pathology in the brain.” Paper 27 at 39. This argument is based on
`
`evidence that GA is extensively hydrolyzed at the injection site. Ex. 1085 ¶ 47.
`
`Although this was suggested in the art, it is undisputed that GA’s active species is
`
`not known. See id. ¶¶ 44–46. As Patent Owner concedes, “it is unknown whether
`
`it is the smaller peptide degradation products or the polypeptides found in the GA
`
`drug product itself (or both) that are responsible for the clinical effect of the drug.”
`
`Paper 27 at 15. GA’s therapeutically relevant site of action is also unknown. See
`
`Ex. 1085 ¶¶ 47–48. Indeed, Copaxone’s label states that “[s]ome fraction of the
`
`injected material, either intact or partially hydrolyzed . . . may enter the systemic
`
`14
`
`
`
`
`
`circulation intact.” Ex. 1047 at 1. As Dr. Green explains, it is thus possible that
`
`GA acts in or after passing through the systemic circulation, so “a POSA would not
`
`discard data regarding GA’s plasma half-life when evaluating the viability of
`
`changes in dosing frequency.” Ex. 1085 ¶¶ 48.
`
`Patent Owner’s repeated representations that no pharmacokinetic data exists
`
`for Copaxone are also misleading. The animal pharmacokinetic data provided to
`
`FDA by Teva in the SBOA and published in Lobel (Ex. 1022) continued to be
`
`cited in peer-reviewed publications, including those relied upon by Patent Owner’s
`
`experts. See Ex. 1085 ¶ 48 n.2.
`
`Dr. Gristwood asserts that the pharmacokinetic data is irrelevant. He is not
`
`qualified to opine on the subject—he has no experience with MS or GA, Ex. 2145
`
`at 31:4–7, 25:4–6, was retained less than three weeks before he signed his
`
`declaration, and learned about GA’s mechanism of action by “conduct[ing] a
`
`Wikipedia search on both MS and [GA]” and “a PubMed search . . . just to get a
`
`flavor of the kind of references that were out there.” Id. at 31:12–17, 51:3–16.3
`
`And Dr. Gristwood’s criticisms of the pharmacokinetic data rest on a graph that
`
`even he admits is based on “insufficient data.” Id. at 102:17–22; 104:17–24. Dr.
`
`Gristwood conjures two trend lines based on only two data points each, and then
`
`3 It is difficult to square Patent Owner’s repeated and unjustified attacks on
`
`Mylan’s experts’ qualifications with its own expert’s Wikipedia knowledge of GA.
`
`15
`
`
`
`
`
`draws conclusions based on the extrapolated trends. Ex. 2134 ¶¶ 47–49. A POSA
`
`would certainly consider the SBOA PK data that Teva reported to the FDA more
`
`rigorous than Dr. Gristwood’s methods. The pharmacokinetic data thus also
`
`provides a POSA a reasonable expectation of success.
`
`D. Dr. Ziemssen’s Mechanism of Action Theory Does Not Teach
`Away From Less Frequent Than Daily Dosing
`
`Patent Owner further argues that, despite the wealth of clinical data
`
`supporting the efficacy of less frequent dosing regimens, a POSA would not have
`
`pursued less frequent dosing because it was known that GA’s mechanism of action
`
`requires daily dosing. Paper 27 at 15–16, 24–26, 54. However, as Patent Owner
`
`stated in its preliminary response “[n]ot only is the active molecule(s) of GA
`
`unknown, but the mechanism by which the drug works is also not fully understood,
`
`despite extensive research.” Paper 12 at 13; see also Ex. 2135 ¶ 37. Although
`
`Patent Owner now takes a different position, all agree that GA’s specific
`
`mechanism of action was, and remains, unknown. Ex. 1085 ¶¶ 41–46; Ex. 2147 at
`
`171:22–25. In 2009, the art included at least seven unique, non-mutually exclusive
`
`theories of GA’s mechanism of action. Ex. 1085 ¶¶ 45–46. Because of this
`
`uncertainty, a POSA would not have relied on any single theory as teaching away
`
`from pursuing less frequent dosing—particularly in the face of promising clinical
`
`data. Id. ¶¶ 43–44, 49, 71. When patient-derived clinical data (such as Flechter
`
`2002A, Khan 2008, and Caon) conflicts with claims about a drug’s purported
`
`16
`
`
`
`
`
`mechanism of action, a POSA would discount the mechanism of action theory, not
`
`the real-world data. Id.
`
`Even if a POSA would have considered Dr. Ziemssen’s theory, the prior art
`
`teaches that daily dosing is not required. See Ex. 1085 ¶¶ 43–44, 49-72. Patent
`
`Owner argues that GA must constantly activate anti-inflammatory Th2 cells so
`
`they cross the blood-brain barrier (“BBB”) into the central nervous system
`
`(“CNS”), and that daily GA dosing is required to achieve this effect. Paper 27 at
`
`15–16, 24–26, 54. Dr. Ziemssen cites a handful of papers4 suggesting that Th2
`
`cells can cross the BBB “because they are activated by daily immunization.” Ex.
`
`2047 at 4; see also Ex. 2135 at ¶¶ 63–64. Of course, when these papers were
`
`written the only approved regimen was daily 20 mg GA injections. Importantly,
`
`none of the papers that Dr. Ziemssen relies on in support for his opinion that daily
`
`dosing is required explore the impact of less frequent dosing on this purported
`
`mechanism of action. Ex. 1085 ¶¶ 50, 63–69; Ex. 2147 at 214:3–8.
`
`More importantly, Patent Owner omits that the prior art, including the
`
`references Dr. Ziemssen cites, discloses that GA-specific Th2 cells accumulate in
`
`
`4 Applying a double standard, Dr. Ziemssen discounts the human clinical data
`
`available to a POSA because it does not meet the high bar he sets for it, see, e.g., n.
`
`1, supra, but relies on mechanism of action studies performed in animal models to
`
`argue that the prior art teaches away from pursuing a less frequent dosing regimen.
`
`17
`
`
`
`
`
`the CNS and remain functional for at least several days, and perhaps even over a
`
`week. See, e.g., Ex. 1085 ¶¶ 50–62, 70; Ex. 2075 at 5 (“However, if the cells . . .
`
`were specific for an antigen in the CNS, such as MBP, their concentration
`
`remained
`
`elevated
`
`above
`
`baseline
`
`for
`
`days.”); Ex.
`
`1091
`
`at
`
`4
`
`(“T-lymphocytes able to recognize their specific antigen in the CNS of the host
`
`persisted in or cyclically reentered the [CNS] at numbers significantly above
`
`baseline levels beyond 72 hr.”); Ex. 2044 at 4 (“The Cop 1-specific cells were
`
`found in most (78–88%) of the brain sections after 3 and 7 days and, in a
`
`substantial number (12–58%) of slides, even 10 days after their injection.”); Ex.
`
`1084 at 3–5. And as Dr. Ziemssen wrote in his own review article, Aharoni 2000
`
`demonstrates “that activated TH2 cells are able to cross the blood-brain barrier
`
`(BBB), accumulate in the CNS and express in situ antiinflammatory cytokines
`
`. . . .” Ex. 2009 at 4; Ex. 2147 at 210:13–211:7.
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`Therefore, even had a POSA subscribed to Dr. Ziemssen’s theory, she would
`
`have expected less frequent dosing would be efficacious because the prior art
`
`shows that GA-specific Th2 cells continue to exert their therapeutic effect days
`
`after a GA injection enables them to cross the BBB into the CNS.
`
`III. ALL DEPENDENT CLAIMS ARE OBVIOUS
`Patent Owner’s experts do not dispute that the prior art discloses all
`
`limitations in the ’413 patent’s dependent claims. All dependent claim elements
`
`18
`
`
`
`
`
`are both taught by Pinchasi and well within a POSA’s knowledge. Ex. 1005; Paper
`
`2 at 26–34, 50–51; Ex. 1085 ¶ 82. As set forth in the Petition and accompanying
`
`declarations, the ’413 patent’s dependent claims fall within its inde
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