Paper No. ______
`
`Filed on behalf of Apotex Inc.
`By: Kenneth J. Burchfiel
`
`Grant S. Shackelford
`
`Sughrue Mion, PLLC
`
`2100 Pennsylvania Ave., NW
`
`Washington, DC 20037
`
`Telephone: 202-293-7060
`
`Facsimile: 202-293-7860
`
`email:
`kburchfiel@sughrue.com
`gshackelford@sughrue.com
`
`
`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`APOTEX INC.
`Petitioner
`
`v.
`
`MERCK & CO., INC.
`Patent Owner
`__________________
`
`Case IPR2015-00419
`Patent No. 5,691,336
`__________________
`
`
`
`APOTEX REQUEST FOR RECONSIDERATION
`UNDER 37 C.F.R § 42.71(d)
`
`
`
`

`
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES ...................................................................................... III
`
`EXHIBITS CITED ...................................................................................................... IV
`
`I.
`
`INTRODUCTION .............................................................................................. 1
`
`II.
`
`STANDARD OF REVIEW ................................................................................ 2
`
`III. THE STANDARD OF LAW APPLIED BY THE PANEL
`CONFLICTS WITH OTHER BOARD DECISIONS ...................................... 2
`
`A.
`
`B.
`
`C.
`
`“Activity data” is not required for a compound to be a
`lead compound and render obvious a structurally similar
`compound .............................................................................................. 2
`
`A compound named in a reference may not be dismissed
`as a lead compound because the reference also discloses
`other compounds ................................................................................... 4
`
`Structural similarity alone is sufficient to make a prior art
`compound a lead compound for obviousness ....................................... 5
`
`IV. USING THE CORRECT STANDARD OF OBVIOUSNESS,
`INSTITUTION SHOULD BE GRANTED ....................................................... 6
`
`A.
`
`B.
`
`C.
`
`The Board erred in failing to consider the structural
`similarity between aprepitant and its prodrug
`fosaprepitant .......................................................................................... 6
`
`The Board erred in requiring the disclosure of “activity
`data” for aprepitant in Dorn ʼ699 .......................................................... 9
`
`The Board erred in concluding that aprepitant is not a
`lead compound because Dorn ʼ699 also discloses other
`compounds ........................................................................................... 10
`
`D. Denial of review was based on an erroneous factual
`finding.................................................................................................. 12
`
`E.
`
`The inventors’ admissions confirm that the development
`of fosaprepitant would have been obvious .......................................... 13
`
`i
`
`
`
`

`
`V.
`V.
`
`CONCLUSION ................................................................................................. 15
`CONCLUSION ............................................................................................... .. 15
`
`
`
`
`
`
`
`ii
`
`

`
`TABLE OF AUTHORITIES
`
`CASES
`
`Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999 (Fed. Cir. 2009) .................. 4, 8
`
`Atl. Research Mktg. Sys. v. Troy, 659 F.3d 1345, 1359 (Fed. Cir. 2011) ................................. 2
`
`Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293 (Fed. Cir. 2007) ............. 6
`
`Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 769 F.3d 1339 (Fed.Cir.
`2014) (per curiam) ................................................................................................................ 8
`
`Daiichi Sankyo Co., Ltd. v. Matrix Labs., Ltd., 619 F.3d 1346 (Fed. Cir. 2010) ................. 3, 4
`
`Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353 (Fed. Cir. 2008) ...................... 6, 7, 8
`
`Ex parte Cao, Appeal No. 2010-004081 (B.P.A.I. Sept. 19, 2011) ..................................... 2, 5
`
`Ex parte Dong, Appeal No. 2011-010047 (P.T.A.B. Jan. 28, 2013) ............................... passim
`
`In re Dillon, 919 F.2d 688 (Fed. Cir. 1990) (en banc) .................................................... passim
`
`Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804 (Fed. Cir. 1989) ............... 4, 10
`
`Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280 (Fed. Cir. 2012) ................... 3, 10, 11
`
`Renda Marine, Inc. v. U.S., 509 F.3d 1372 (Fed. Cir. 2007).................................................... 2
`
`REGULATIONS
`
`37 C.F.R § 41.3 ......................................................................................................................... 2
`
`37 C.F.R. § 42.71(c) ................................................................................................................. 2
`
`
`
`
`
`
`
`iii
`
`

`
`EXHIBITS CITED
`
`Ex. 1001 U.S. Patent No. 5,691,336 to Dorn et al.
`
`Ex. 1002 Declaration of Longqin Hu, Ph.D. (“Hu Decl.”)
`
`Ex. 1003 U.S. Patent No. 5,637,699 to Dorn et al.Ex. 1026 Ex parte Dong,
`Appeal. No. 2011-010047 (P.T.A.B. Jan. 28, 2013)
`
`Ex. 1026
`
`Ex parte Dong, Appeal No. 2011-010047 (P.T.A.B. Jan 28, 2013)
`
`Ex. 1027 Ex parte Cao, Appeal No. 2010-004081 (B.P.A.I. Sept. 19, 2011)
`
`Ex. 1028 Hale, J.J. et al., Structural Optimization Affording 2-(R)-(l-(R)-3,5-
`Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-
`l,2,4-triazol-5-yl)methylmorpholine, a Potent, Orally Active, Long-
`Acting Morpholine Acetal Human NK-1 Receptor Antagonist, J. MED.
`CHEM., 41, 4607-4614 (1998)
`
`Ex. 1029 Hale, J.J., et. al., Phosphorylated Morpholine Acetal Human
`Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs, J.
`MED. CHEM., 43, 1234-1241 (2000)
`
`
`
`
`
`
`
`
`
`iv
`
`

`
`
`
`I.
`
`INTRODUCTION
`
`Apotex Inc. (“Petitioner”) requested inter partes review of Claims 1, 3-8,
`
`and 10-25 of U.S. Patent No. 5,691,336 (Ex. 1001). On June 25, 2015, the Board
`
`denied the Petition, on the basis that aprepitant, which is the parent compound of
`
`the claimed prodrug fosaprepitant, is not suggested as a “lead compound” by the
`
`primary reference U.S. Patent No. 5,637,699 (Dorn ʼ699, Ex. 1003). Dec., Paper
`
`14, at 6-13. The Board’s Decision is based on three incorrect legal conclusions:
`
`1)
`
`The prior art compound (aprepitant) having the closest chemical
`
`structure to the claimed prodrug (fosaprepitant) is not a “lead compound” for an
`
`obviousness analysis. Dec., at 9, 12.
`
`2)
`
`Aprepitant is not a “lead compound” because Dorn ’699 does not
`
`disclose “activity data” for aprepitant. Dec., at 9, ll. 7-8, 19-21.
`
`3)
`
`Because Dorn ʼ699 discloses over 600 specific compounds, the closest
`
`structurally related compound cannot be a “lead compound” in the obviousness
`
`analysis. Dec., at 11.
`
`The Board’s lead compound analysis also conflicts with earlier Board
`
`decisions. Rehearing is required to ensure that the Board applies a correct and
`
`uniform standard of obviousness for chemical compounds. A Petition Suggesting
`
`Reconsideration By An Expanded Panel pursuant to 37 C.F.R § 41.3 is filed
`
`concurrently herewith.
`
`
`
`1
`
`

`
`
`
`II.
`
`STANDARD OF REVIEW
`
`Under 37 C.F.R. § 42.71(c), “[w]hen rehearing a decision on petition, a
`
`panel will review the decision for an abuse of discretion.” An abuse of discretion
`
`“occurs when a court misunderstands or misapplies the relevant law” or makes
`
`erroneous factual findings. Renda Marine, Inc. v. U.S., 509 F.3d 1372, 1379 (Fed.
`
`Cir. 2007) (citation omitted). “A decision based on an erroneous view of the law
`
`… invariably constitutes an abuse of discretion.” Atl. Research Mktg. Sys. v. Troy,
`
`659 F.3d 1345, 1359 (Fed. Cir. 2011) (internal quotation omitted).
`
`III. THE STANDARD OF LAW APPLIED BY THE PANEL CONFLICTS
`WITH OTHER BOARD DECISIONS
`
`The “lead compound” analysis applied by the Board conflicts with earlier
`
`Board decisions, holding that a “lead compound” analysis has not supplanted the
`
`“structural obviousness” standard for chemical compounds mandated by In re
`
`Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990) (en banc).
`
`A.
`
`“Activity data” is not required for a compound to be a lead
`compound and render obvious a structurally similar compound
`
`The Board concluded that “absent any reported activity data, compound 96
`
`could not have served as a natural choice for further development efforts.” Dec., at
`
`9 (quotation omitted). This requirement of “activity data” for identification of a
`
`lead compound conflicts with the Board’s decisions in, for example, Ex parte
`
`Dong, Appeal No. 2011-010047 (P.T.A.B. Jan. 28, 2013) (Ex. 1026); and Ex parte
`
`Cao, Appeal No. 2010-004081 (B.P.A.I. Sept. 19, 2011) (Ex. 1027).
`
`
`
`2
`
`

`
`
`
`The Board’s application of the “lead compound” analysis in Ex parte Dong
`
`follows the analysis required by Dillon and should be followed on reconsideration.
`
`In Ex parte Dong, the Board found claims to a compound obvious based on a
`
`structurally similar analog found in Example 378 of the reference (out of 411 total
`
`Examples). Ex. 1026, at 5-6. In doing so, the Board explicitly rejected the
`
`analysis employed by the panel in denying review in the present IPR. The Board
`
`dismissed the proposition that “Daiichi Sankyo, Otsuka, or other lead compound
`
`cases mandate that the only compounds useful for evaluating obviousness are those
`
`for which the prior art has provided specific comparative data.” Id. at 7. As the
`
`Board correctly noted, “accepting such an interpretation would effectively render
`
`[the reference] unavailable as prior art for determining obviousness, simply
`
`because [the reference] did not provide data comparing the biological properties of
`
`its compounds.” Id.
`
`The Board in Dong correctly upheld the Examiner’s rejection even though
`
`“[i]t may be true…that [the reference] provides no specific biological activity data
`
`for any of the exemplified GLP-1 analogues that might allow an ordinary artisan to
`
`choose one of [the reference’s] compounds over another as a lead compound.” Id.
`
`at 6. The lack of biological data was irrelevant to the Examiner’s selection of the
`
`compound of Example 378 because (1) there was “no evidence of record …
`
`suggesting that an ordinary artisan would have expected any of the exemplified
`
`
`
`3
`
`

`
`
`
`compounds, including the compound of Example 378, to lack the therapeutic
`
`properties described in [the reference]” and (2) there was “no evidence of record
`
`suggesting that an ordinary artisan would have ignored [the reference’s] general
`
`teaching of therapeutic efficacy, and instead only would have selected as lead
`
`compounds those compounds for which specific comparative data had been
`
`presented.” Id.
`
`The Board in Dong also correctly observed that “the Federal Circuit has
`
`tempered the rigorousness of the lead compound analysis by stating that ‘the lead
`
`compound analysis must, in keeping with KSR, not rigidly focus on the selection of
`
`a single, best lead compound ….’” Id., citing Daiichi Sankyo Co., Ltd. v. Matrix
`
`Labs., Ltd., 619 F.3d 1346, 1354 (Fed. Cir. 2010), citing Altana Pharma AG v.
`
`Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009). These decisions are
`
`consistent with earlier Federal Circuit precedent, including Merck & Co. Inc. v.
`
`Biocraft Laboratories Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). In the absence of a
`
`specific teaching away in the prior art from the closest structurally related
`
`compound, that compound is an appropriate lead compound for obviousness
`
`analysis, regardless of whether the prior art discloses any activity data for the
`
`compound. See Ex. 1026 at 6-7.
`
`B. A compound named in a reference may not be dismissed as a lead
`compound because the reference also discloses other compounds
`
`The Board’s conclusion that a skilled artisan would not have selected
`
`
`
`4
`
`

`
`
`
`aprepitant from the “laundry list of 600 other specific compounds,” “having no
`
`reported activity data on any of the 601 enumerated compounds” (Dec. at 11),
`
`clearly conflicts with Dong. Dorn ’699 provides a detailed description of the
`
`therapeutic effects of its disclosed compounds (Abstract; 42:34-44:6; Pet. 37-38.),
`
`and the fact that aprepitant is included in a list of less relevant compounds is
`
`irrelevant. The Board in Dong specifically confirmed this point, acknowledging
`
`that although “Example 378 is one of 411 exemplified compounds,” the reference
`
`disclosed “as a general principle, that ‘the administration of the compounds of this
`
`invention for purposes of eliciting an agonist effect can have the same effects and
`
`uses as GLP-1 itself.’” Ex. 1026, at 5-6 (emphasis in original) (internal citation
`
`omitted). Accordingly, the Board was “not persuaded that [the reference] failed to
`
`provide a reason to select any of its exemplified compounds, including Example
`
`378, as a compound suitable for further improvement.” Id. (emphasis added).
`
`Dorn ’699 likewise provides a reason to select any of its 601 compounds, including
`
`aprepitant, for further improvement.
`
`C.
`
`Structural similarity alone is sufficient to make a prior art
`compound a lead compound for obviousness
`
`The panel’s disregard of the structural similarity between the claimed
`
`prodrug fosaprepitant and the prior art parent compound aprepitant (Dec. at 9, 12),
`
`conflicts with the Board decision in Ex parte Cao (Ex. 1027). In Cao, the Board
`
`rejected the argument that the identification of a “lead compound” is an essential
`
`
`
`5
`
`

`
`
`
`step in the obviousness analysis. Ex. 1027, at 7. Rejecting such a per se rule, the
`
`Board confirmed the “long standing principles” of structural obviousness under
`
`which, “it is sufficient to show that the claimed and prior art compounds possess a
`
`‘sufficiently close relationship ... to create an expectation,’ in light of the totality of
`
`the prior art, that the new compound will have ‘similar properties’ to the old.’” Id.
`
`at 6, 7-8, quoting Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1357
`
`(Fed. Cir. 2008), quoting Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499
`
`F.3d 1293, 1301 (Fed. Cir. 2007), quoting Dillon, 919 F.2d at 692.
`
`IV. USING THE CORRECT STANDARD OF OBVIOUSNESS,
`INSTITUTION SHOULD BE GRANTED
`
`A. The Board erred in failing to consider the structural similarity
`between aprepitant and its prodrug fosaprepitant
`
`In denying the Petition based on the absence of “activity data” in Dorn ʼ699,
`
`the Board erred by disregarding the structure of aprepitant, which is the same
`
`pharmaceutically active ingredient present in fosaprepitant and is the closest prior
`
`art structural analog of the claimed prodrug disclosed in the reference. Pet., at 14-
`
`15; Hu Decl., Ex. 1002, at ¶¶ 10-13. Fosaprepitant is nothing more than aprepitant,
`
`modified with conventional phosphoryl groups to improve the solubility of the
`
`parent compound. Id. No other compound in the prior art has a closer structure to
`
`the claimed compound.
`
`In denying review, the Board erred in failing to apply the structural
`
`
`
`6
`
`

`
`
`
`obviousness analysis required by Federal Circuit precedent, including In re Dillon,
`
`919 F.2d 688 (Fed. Cir. 1990) (en banc). Under Dillon, structural similarity alone
`
`is sufficient to provide motivation to a person skilled in the art (“POSA”) to
`
`modify a prior art compound, particularly a compound having the same biological
`
`and therapeutic activity, like aprepitant. As the court reaffirmed in Dillon,
`
`“structural similarity between claimed and prior art subject matter, proved by
`
`combining references or otherwise, where the prior art gives reason or motivation
`
`to make the claimed compositions, creates a prima facie case of obviousness[.]”
`
`Id. at 692. Furthermore, “it is not necessary in order to establish a prima facie case
`
`of obviousness … that there be a suggestion in or expectation from the prior art
`
`that the claimed compound or composition will have the same or a similar utility as
`
`one newly discovered by applicant.” Id. at 693.
`
`The Federal Circuit cases cited by the Board confirm the long-standing
`
`principles of structural obviousness under which, “it is sufficient to show that the
`
`claimed and prior art compounds possess a ‘sufficiently close relationship ... to
`
`create an expectation,’ in light of the totality of the prior art, that the new
`
`compound will have ‘similar properties’ to the old.’” Eisai, 533 F.3d at 1357,
`
`quoting Aventis Pharma, 499 F.3d at 1301, quoting Dillon, 919 F.2d at 692.
`
`Where a patent claims a chemical compound, “the analysis of the third Graham
`
`factor (the differences between the claimed invention and the prior art) often turns
`
`
`
`7
`
`

`
`
`
`on the structural similarities and differences between the claimed compound and
`
`the prior art.” Eisai, 533 F.3d at 1356-57; Altana, 566 F.3d at 1007; Daiichi
`
`Sankyo, 619 F.3d at 1352 (“Whether a lead compound and a claimed compound
`
`have a sufficiently close relationship frequently turns on their ‘structural
`
`similarities and differences.’”).
`
`Under Dillon, the “lead compound” analysis necessarily begins with the
`
`most structurally similar compound disclosed in the prior art, unless the prior art
`
`provides a specific teaching away that would discourage a POSA from selecting
`
`that compound for an obvious modification. Patent Owner did not identify any
`
`disparagement of aprepitant in the prior art that would dissuade a POSA from
`
`selecting aprepitant as a lead compound, to produce a prodrug with improved
`
`solubility. Aprepitant and fosaprepitant have the same, expected pharmacological
`
`activity, as confirmed by the two drugs’ labels. Pet. at 5, 7, 16; Hu Decl., Ex.
`
`1002, at ¶¶ 14, 62. Fosaprepitant is more soluble in aqueous solution than
`
`aprepitant, but this additional, expected property of the prodrug does not “upset an
`
`already established motivation to modify a prior art compound based on the
`
`expected properties of the resulting compound.” Bristol-Myers Squibb Co. v. Teva
`
`Pharm. USA, Inc., 769 F.3d 1339, 1347 (Fed. Cir. 2014) (per curiam) (O’Malley,
`
`J., concurring in denial of rehearing en banc), citing Dillon, 919 F.2d at 693.
`
`
`
`
`
`8
`
`

`
`
`
`B.
`
`The Board erred in requiring the disclosure of “activity data” for
`aprepitant in Dorn ʼ699
`
`The Board erred in requiring biological data for the parent compound
`
`aprepitant in Dorn ʼ699, stating that “absent any reported activity data, compound
`
`96 could not have served as ‘a natural choice for further development efforts.’”
`
`Dec., at 9. Similarly, the Board considered that there was no reason “why a skilled
`
`artisan, having no reported activity data on any of the 601 enumerated compounds,
`
`would have picked compound 96 for further development.” Id. at 11.
`
`This was legal error. There is no requirement that the prior art must disclose
`
`“reported activity data” for a suitable lead compound. See Dillon, 919 F.2d at 693
`
`(“the statement that a prima facie obviousness rejection is not supported if no
`
`reference shows or suggests the newly-discovered properties and results of a
`
`claimed structure is not the law.”). Under Dillon, the compound having the closest
`
`structure to a claimed compound serves as “a natural choice for further
`
`development efforts” without the requirement of “reported activity data.”
`
`The Board’s analysis improperly eliminates the prior art compound closest
`
`in structure to the claimed compound from consideration, by adopting a rule
`
`requiring disclosure of “activity data” for a compound such as aprepitant to be
`
`considered as a “lead compound.” Under this analysis, without “activity data”
`
`Dorn ʼ699 is disqualified, in its entirety, as prior art in an obviousness analysis,
`
`even though the reference identifies the biological activity and therapeutic
`
`
`
`9
`
`

`
`
`
`applications of the preferred class of compounds “of the invention” including
`
`aprepitant (see Abstract and 42:34-44:6; see Pet. 37-38).
`
`C. The Board erred in concluding that aprepitant is not a lead
`compound because Dorn ʼ699 also discloses other compounds
`
`The Board erred in concluding that aprepitant is not a “lead compound”
`
`because Dorn ʼ699 discloses 600 other compounds. Dec., at 9 and 11. This is
`
`legal error, because a large disclosure of less-related compounds cannot eliminate a
`
`reference such as Dorn ʼ699 from consideration. The law is clear that even if a
`
`reference “discloses a multitude of effective combinations [that] does not render
`
`any particular formulation less obvious” where the claimed pharmaceutical
`
`composition “is used for the identical purpose taught by the prior art.” Merck, 874
`
`F.2d at 807 (where the prior art disclosed a genus of 1200 possible combinations of
`
`diuretic compounds, it would have suggested any of them to a POSA, including the
`
`claimed combination of two specific compounds for the same therapeutic purpose).
`
`The Board misapplied Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d
`
`1280, 1295 (Fed. Cir. 2012), to assert a bright-line rule, rejecting a “lead
`
`compound” “when the prior art lists the compound as one among hundreds of
`
`examples that may be useful.” See Dec., at 11. Otsuka does not support this
`
`general proposition and was instead based on the prior art’s failure to disclose the
`
`same pharmacological activity as the claimed drug.
`
`Otsuka dealt with the obviousness of aripiprazole, which is the active
`
`
`
`10
`
`

`
`
`
`ingredient in an antipsychotic drug. 678 F.3d at 1284. Pertinent to the Board’s
`
`citation here, the Federal Circuit affirmed the rejection of “2,3-dichloro propoxy”
`
`as a lead compound, because the prior art did not identify that compound as an
`
`antipsychotic, as opposed to a different type of central nervous system controlling
`
`agent (e.g., an antihistamine). Id. at 1295 (the prior art “lists the 2,3-dichloro
`
`propoxy compound as one among hundreds of examples that may be useful for an
`
`extensive list of potential central nervous system controlling activities, and fails to
`
`tie the 2,3-dichloro propoxy to any meaningful suggestion of antipsychotic
`
`activity.”). Otsuka thus stands only for the proposition that a compound may be
`
`rejected as a “lead compound” where the prior art does not identify it as having the
`
`pharmaceutical activity desired for further development.
`
`In contrast to Otsuka, Dorn ’699 discloses that aprepitant has the same
`
`pharmaceutical activity as fosaprepitant, as a tachykinin receptor antagonist, and is
`
`useful for treating the same disorders, including emesis. Pet., at 33-38; see Dorn
`
`’699 at Abstract, 42:34-44:6. Dorn ’699 is comparable to the reference in Ex Parte
`
`Dong, which the Board similarly relied on as disclosing compounds that elicit the
`
`general agonist effects of GLP-1. Ex. 1026, at 6. Just as the Board in Dong
`
`determined that the reference provided a reason to select any of its 411 compounds
`
`for further improvement, Dorn ’699 provides reason to select any of its 601
`
`compounds, including aprepitant, for further improvement.
`
`
`
`11
`
`

`
`
`
`D. Denial of review was based on an erroneous factual finding
`
`The panel assumed that “a skilled artisan would have pursued . . . more
`
`promising lead compounds, not compound 96, and thus, would not have arrived at
`
`fosaprepitant dimeglumine, the prodrug of compound 96.” Dec. at 9. This
`
`assumption is not supported by substantial evidence. In an obviousness analysis
`
`relating to a prodrug such as fosaprepitant, the closest structural analog and the
`
`most relevant “lead” compound to the prodrug is its parent compound aprepitant.
`
`Pet. at 15; Hu Decl., Ex. 1002, at ¶¶ 10-13. Both aprepitant and its derivative
`
`fosaprepitant have the same pharmacological functions and human therapeutic
`
`utility. Pet. at 5, 7, 16; Hu Decl., Ex. 1002, at ¶¶ 14, 62. To the extent that the
`
`Board’s decision considers that any other compound in the prior art is a more
`
`obvious “lead” compound than aprepitant, the Board has not identified that
`
`compound, and its decision is not supported by substantial evidence.
`
`Patent Owner refers to various studies describing the potential biological
`
`activity of other compounds as NK-1 inhibitors. But this is bare attorney
`
`argument, unsupported by expert testimony. These studies do not disclose the
`
`numerous, specific human therapeutic applications disclosed in Dorn ʼ699
`
`(Abstract and 42:34-44:6), that would have motivated those skilled in the art to
`
`pursue development of Dorn’s compounds including aprepitant. Patent Owner
`
`cannot now deny its own inventors’ statements in Dorn ʼ699 that the prior art
`
`
`
`12
`
`

`
`
`
`compounds, including aprepitant, were highly promising human therapeutic agents,
`
`by reliance on preliminary studies of unrelated compounds in vitro and in animal
`
`studies. No expert testimony or other evidence supports its assertion that a POSA
`
`would reject aprepitant as a lead compound, which is described in Dorn ʼ699 as a
`
`highly effective drug for treating human disorders including emesis, and instead
`
`pursue agents having only potential therapeutic utility based on activity as
`
`substance P antagonists (“SPAs”). Aprepitant, which can be effectively
`
`administered to humans in oral dosage forms (Dorn ʼ699, 46:5-19) was a far more
`
`promising lead compound than SPAs having only “reported modest oral
`
`availability,” including CP 99,994, as confirmed by inventors Hale, Mills and
`
`MacCoss. Ex. 1028, at 4607. The disclosure of one potential SPA cannot eliminate
`
`every other promising lead compound from consideration for further development.
`
`See Daiichi Sankyo, 619 F.3d at 1354. Drug discovery would cease under the
`
`rigid rule proposed by Patent Owner, which ignores the real-world process of
`
`pharmaceutical development involving multiple promising drug candidates.
`
`E.
`
`The inventors’ admissions confirm that the development of
`fosaprepitant would have been obvious
`
`As shown in the table below, the Patent Owner Preliminary Response
`
`(POPR) is inconsistent with statements made by the inventors of the ʼ366 patent,
`
`confirming that it would have been obvious to phosphorylate aprepitant and obtain
`
`fosaprepitant based on the same Murdock reference cited in the Petition:
`
`
`
`13
`
`

`
`The inventors’
`
`admissions (Hale Ex.
`
`1029 at 1235)
`
`Conespiggiggtisttiitfiments in
`
`Patent Owner’s
`
`inconsistent arguments in
`
`the Preliminary Response
`
`“Ignoring the scope and
`“The improved solubility of
`content of prodrug prior
`phosphate ester VII
`art, Apotex uses
`(fosphenytoin) would have
`hindsight to rely on
`been highly pertinent to a
`POSA who sought to develop Murdock, and then makes
`intravenous preparations of
`arguments contradicted
`water—insoluble drugs such as
`by Murdock itself”
`aprepitant.” Petition at 22.
`Section heading VI(A)(2).
`
`The recent example
`of the anticonvulsant
`fosphenytoinlo
`highlights one
`successful approach
`for introducing
`solubility—enhancing
`phosphate
`functionality into a
`bioactive nitrogenous M""dock (Exl005: which is
`heterocycle, 11 [Ref
`reference 11 in Hale)
`1 1; “pm. othe,
`“dtsclose[s] the direct
`examples, see: (a)
`I”_'0SPh0".Yl“1i0” 0f
`Murdock, [et a1_,
`nitrogenous drugs to produce
`1993]», Ex 10051
`prodrugs with enhanced water
`solubility.” Petition at 24.
`
`“Without support’ Apotex
`“A POSA would have been
`but we wished to
`argues that (1 P_0SA
`avoidfunctionalized motivated to avoidformation
`would have av_0'ded the
`Mannich adducts of
`ofan N-Mannich base, like
`2 which would
`fosphenytoin.” Petition at 23. mdmg chemistry taught
`necessitate the release
`“N—Mannich bases were
`'_” all ofthese references
`in vivo of
`disfavored due to their
`m 1995 out of“ supposed
`formaldehyde or
`unavoidable release of
`geslre to ‘wold the
`other low molecular
`formaldehyde during
`relfase 0ff°""“_"{"”'3""
`weight aliphatic
`decomposition or activation to d"r_mg_dec0mp0sltw" or
`aldehydes.
`the parent compound in vivo.”
`actwatwn to the parent
`Id. citing Ex. 1002 Ex. 1008
`“’"'1"”""’ 5” "5""-”
`EX 1009’ Ex_ 1014.
`Petition at 23.’ POPR at
`29.
`
`“Apotex fails to establish
`“When Murdock ’082 is
`The simplest
`that its cited references
`considered in view of
`approach to
`introduce phosphate Atanassova et al. and Van Den would have guided a
`functionality into 2
`Bos, a POSA would have
`POSA to Merck ’s novel
`would be the direct
`recognized that the simplest
`“direct phosphorylation”
`phosphorylation of
`a roach to introduce
`approach” Section
`
`14
`
`

`
`The inventors’
`
`admissions (Hale Ex.
`
`1029 at 1235)
`
`the l,2,4—triazol—3—
`one group, and we
`were encouraged to
`pursue this as a
`prodrug strategy on
`finding that the 0-
`thiophosphorylation
`of some structurally
`simple l,2,4—triazol—
`3—ones had been
`reported.”
`
`C0rreSp(:Illl:ilI;§tiSttia0t:mentS in
`
`Patent Owner’s
`
`inconsistent arguments in
`
`the Preliminary Response
`
`heading VI(A)(3).
`phosphate functionality into
`“Apmex relies on
`aprepitant would have been
`the direct phosphorylation of Anmassova and Van Den
`aprepitant’s l,2,4—triazolin—3— B03. But neither of these
`one group, and a POSA would
`have been encouraged to
`pursue this technique on
`finding that the
`phosphorylation of isoteres of
`l,2,3—triazolin—3—ones was
`known.” Petition at 51.
`
`be directly
`phosphorylated
`exclusively at its N1
`nitro zen? POPR at 47.
`
`references. . .provides a
`reasonable expectation
`that a triazolinone could
`
`The Petition’s statements concerning the knowledge and motivation of a
`
`POSA is confirmed by the inventors’ own admissions concerning Murdock and the
`
`obviousness of phosphorylating aprepitant to improve its solubility. These
`
`inconsistencies were not brought to the PTAB’s attention in the POPR, as required
`
`by Rule 42.5l(b)(l)(iii). On reconsideration, the Board should consider this
`
`information, which is clearly inconsistent with Patent Owner’s attorney arguments,
`
`and institute inter partes review for the reasons stated in the Petition.
`
`V.
`
`CONCLUSION
`
`It is respectfully requested that the Board reconsider its Decision and
`
`institute a trial for inter partes review of U.S. Patent No. 5,691,336 claims 1, 3-8,
`
`and 10-25.
`
`15
`
`

`
`
`
`
`
`Date: July 24, 2015
`
`SUGHRUE MION, PLLC
`2011 Pennsylvania Ave., N.W.
`Washington, DC 20037
`(202) 293-7060
`
`
`Respectfully submitted,
`
`/Kenneth Burchfiel/
`
`
`
`Kenneth J. Burchfiel
`Attorney for Petitioner Apotex Inc.
`Registration No. 31,333
`
`
`
`16
`
`

`
`CERTIFICATE OF SERVICE
`(37 C.F.R. §§ 42.6(e) and 42.105(a))
`
`The undersigned hereby certifies that the above-captioned APOTEX
`
`REQUEST FOR RECONSIDERATION UNDER 37 C.F.R § 42.71(d) was
`
`served on July 24, 2015 by filing these documents through the Patent Review
`
`Processing System as well as delivering copies via electronic mail upon the
`
`following attorneys of record for the Patent Owner:
`
`Bruce M. Wexler (brucewexler@paulhastings.com)
`
`Preston K. Ratliff, II (prestonratliff@paulhastings.com)
`
`Gregory A. Morris (gregorymorris@paulhastings.com)
`
`Naveen Modi (naveenmodi@paulhastings.com)
`
`Richard C. Billups (richard_billups@merck.com)
`
`Gerard M. Devlin, Jr. (gerard_devlin@merck.com)
`
`
`
`DATE: July 24, 2015
`
`
`/Grant Shackelford/
`Grant S. Shackelford
`Reg. No. 70,504
`SUGHRUE MION, PLLC
`2100 Pennsylvania Ave, NW
`Washington, DC 20037
`Telephone: (202) 293-7060
`Facsimile: (202) 293-7860