`Paper No. 9
`Date Filed: February 8, 2019
`
`Filed on behalf of: Sanofi Mature IP
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`NEPTUNE GENERICS, LLC
`Petitioner,
`v.
`AVENTIS PHARMA S.A.
`Patent Owner.
`________________
`
`Case IPR2019-00136
`U.S. Patent No. 5,847,170
`________________
`
`
`
`
`PATENT OWNER PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`

`

`
`
`
`
`I.
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`BACKGROUND ............................................................................................. 3
`
`A.
`
`Taxane Research Efforts ....................................................................... 4
`
`B.
`
`C.
`
`The Invention of Cabazitaxel ................................................................ 7
`
`The Prosecution History ........................................................................ 8
`
`D.
`
`The Prior Challenges ...........................................................................11
`
`1.
`
`2.
`
`The Prior IPR Petition ...............................................................12
`
`The Prior District Court Litigation ...........................................12
`
`III.
`
`POSA .............................................................................................................14
`
`IV. CLAIM CONSTRUCTION ..........................................................................15
`
`V.
`
`LEGAL STANDARD ...................................................................................15
`
`A.
`
`Institution Standard .............................................................................15
`
`B.
`
`Obviousness Standard .........................................................................16
`
`VI. THE PETITION SHOULD BE DENIED BECAUSE ITS
`ARGUMENTS HAVE ALREADY BEEN PRESENTED ...........................18
`
`A.
`
`B.
`
`The Board Should Reject the Petition Pursuant to Section
`325(d) ..................................................................................................18
`
`The Board Should Reject the Petition Pursuant to Section
`314 .......................................................................................................27
`
`VII. THE PETITION IS BASED ON IMPROPER HINDSIGHT .......................28
`
`VIII. NEPTUNE FAILS TO ESTABLISH PRIMA FACIE
`OBVIOUSNESS ............................................................................................30
`
`
`
`i
`
`

`

`A. Neptune fails to establish motivation to modify paclitaxel
`to obtain cabazitaxel ............................................................................31
`
`1.
`
`Neptune fails to establish that a POSA would have
`modified C-7 and C-10 .............................................................31
`
`(a) Neptune fails to establish that a POSA would have focused
`
`on modifying flexible positions ...........................................31
`
`(b) Neptune fails to establish that a POSA would have focused
`
`on modifying C-7 and C-10 based on ease of modification 35
`
`2.
`
`3.
`
`4.
`
`5.
`
`Neptune fails to establish a POSA would have
`modified taxanes in ways that would make them
`less water soluble ......................................................................35
`
`Neptune fails to establish that a POSA would have
`made a methoxy modification at C-10 ......................................38
`
`Neptune fails to establish that a POSA would have
`made a methoxy modification at C-7 ........................................41
`
`Neptune fails to establish that a POSA would have
`simultaneously modified the C-7 and C-10
`positions ....................................................................................44
`
`B.
`
`Neptune fails to establish that a POSA would have
`reasonably expected cabazitaxel to have improved
`properties .............................................................................................48
`
`IX. CONCLUSION ..............................................................................................49
`
`
`
`
`
`
`
`
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`
`No. IPR2017-01586 (P.T.A.B. Dec. 15, 2017)…………………………….18
`
`Cuozzo Speed Techs., LLC v. Lee,
`
`136 S. Ct. 2131 (2016)………..…………………………………………....15
`
`Daiichi Sankyo Co., Ltd. v. Matrix Labs., Ltd.,
`
`619 F.3d 1346 (Fed. Cir. 2010)……………………………………..……..17
`
`Gen. Plastic Indus. Co., Ltd. v. Canon Kabushiki Kaisha,
`No. IPR2016-01357 (P.T.A.B. Sept. 6, 2017)……………………………..27
`
`
`Harmonic Inc. v. Avid Tech., Inc.,
`
`815 F.3d 1356 (Fed. Cir. 2016)……………………………………………15
`
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd,
`
`No. IPR2013-00324 (P.T.A.B. Nov. 21, 2013)……………………………19
`
`KSR Int’l Co. v. Teleflex Inc.,
`
`550 U.S. 398 (2007)……………………………………………………16, 30
`
`Mylan Pharm. v. Bayer Intellectual Prop. GMBH,
`No. IPR2018-01143 (P.T.A.B. Dec. 3, 2018)……………………………...27
`
`
`Netapp, Inc. v. Realtime Data LLC,
`
`No. IPR2017-01354 (P.T.A.B. Nov. 14, 2017)…………………………….16
`
`Otsuka Pharm. Co., Ltd. v. Sandoz,
`
`678 F.3d 1280 (Fed. Cir. 2012)……………………………………….........17
`
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`
`566 F.3d 989 (Fed. Cir. 2009)……………………………………………...17
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`
`550 F.3d 1075 (Fed. Cir. 2008)………………………………………...17, 30
`
`Telebrands Corp. v. Tinnus Enters., LLC,
`
`No. PGR2017-00051 (P.T.A.B. Feb. 22, 2018)……………………………20
`
`
`
`iii
`
`

`

`
`Unified Patents Inc. v. Berman,
`
`No. IPR2016-01571 (P.T.A.B. Dec. 14, 2016)…………………………….19
`
`Yamanouchi Pharm. Co., Ltd. v. Danbury Pharmacal, Inc.,
`
`231 F.3d 1339 (Fed. Cir. 2000)…………………………………………….17
`
`Ziegmann, N.P.Z., Inc. v. Stephens,
`
`No. IPR2015-01860 (P.T.A.B. Sept. 6, 2017)……………………………..18
`
`
`Statutes
`
`35 U.S.C. § 103(a)………………………………………………………………..16
`
`35 U.S.C. § 314(a)………………………………………………………...15, 27, 28
`
`35 U.S.C. § 325…………………………………………………………………...15
`
`35 U.S.C. § 325(d)………………………………………………………...18-20, 27
`
`
`
`
`
`iv
`
`

`

`I.
`
`INTRODUCTION
`
`U.S. Patent No. 5,847,170 (“the ’170 patent”) claims the cabazitaxel
`
`molecule and pharmaceutical compositions containing cabazitaxel. Cabazitaxel
`
`(marketed under the brand name Jevtana®) is the first chemotherapy agent shown
`
`to prolong the lives of patients with castration resistant metastatic prostate cancer,
`
`which has progressed after treatment with docetaxel. In a phase III clinical trial,
`
`patients who were treated with cabazitaxel had a statistically significant increase in
`
`overall survival and a better disease response rate than those treated with a known
`
`commercial chemotherapy agent. (Exh. 2001 at 1154.) This led to fast-track FDA
`
`approval of Jevtana® in 2010 after only eleven weeks of FDA review. (Exh. 2002
`
`at 2.)
`
`As a result of cabazitaxel’s groundbreaking properties, the ’170 patent has
`
`faced, and survived, multiple attacks from generic manufacturers including an IPR
`
`petition (where institution and a motion for rehearing were denied) and a multi-
`
`defendant Hatch-Waxman litigation (where, after trial, patent validity was upheld).
`
`The instant petition comes from Neptune Generics, LLC (“Neptune” or
`
`“Petitioner”), who has made no application to the FDA to sell a competing
`
`cabazitaxel product. For at least the following reasons, the Board should deny
`
`institution of Neptune’s petition.
`
`
`
`1
`
`

`

`First, while the instant petition comes from a “new” petitioner, it uses the
`
`earlier proceedings to mount a substantively duplicative challenge to the ’170
`
`patent. Neptune recycles key prior art references and repeats arguments that have
`
`already been considered and rejected by one forum or another. Such tactics are
`
`contrary to Congress’s intent to avoid “lengthy and duplicative proceedings,”
`
`which have been characterized as “one of the worst evils” of administrative
`
`proceedings. 154 CONG. REC. S22620–32 (daily ed. Sept. 27, 2008) (statement of
`
`Sen. Kyl). The Board can, and should, exercise its discretion to deny the petition
`
`on this basis alone.
`
`Second, Neptune’s petition relies on impermissible hindsight. The taxane
`
`prior art comprises hundreds of patents and articles, which disclose thousands of
`
`taxane compounds. Neptune provides no reason a person of ordinary skill in the art
`
`(“POSA”) would have selected and combined the particular prior art references it
`
`relies upon from the sea of possibilities. As the patent challengers before it,
`
`Neptune has plainly done what a POSA could not have done, namely worked
`
`backwards from cabazitaxel to identify the references needed to support the
`
`specific molecular modifications required to arrive at cabazitaxel. Such hindsight
`
`reasoning is impermissible. And, again, the instant petition should be denied for
`
`this reason alone.
`
`
`
`2
`
`

`

`Lastly, Neptune fails to establish even prima facie obviousness. In
`
`particular, Neptune fails to adequately explain why a POSA would have modified
`
`paclitaxel, Neptune’s asserted lead compound, in the particular manner required to
`
`arrive at cabazitaxel. Nothing in the cited prior art suggests that a POSA would
`
`have sought to: make a taxane less water soluble; add the same chemical groups to
`
`both the C-7 and C-10 positions of the taxane core; and use only methoxy
`
`substituents at both the C-7 and C-10 positions. Cited prior art teaches that if a
`
`POSA had sought to increase activity, he or she would not have modified the
`
`“flexible” C-7 and C-10 positions because such changes did not substantially affect
`
`cytotoxicity. Neptune also fails to show that a POSA would have reasonably
`
`expected that cabazitaxel would have the properties that it does. There is nothing in
`
`the cited prior art showing that adding a methoxy group at the C-7 and/or C-10
`
`positions leads to improved cytotoxicity, or any other desirable property such as
`
`overcoming docetaxel drug resistance.
`
`II. BACKGROUND
`
`The ’170 patent claims the cabazitaxel molecule (depicted below) and
`
`pharmaceutical compositions containing cabazitaxel. Cabazitaxel is a type of
`
`taxane compound. Taxanes are a class of anticancer drugs that interfere with cell
`
`division by stabilizing microtubules. Cabazitaxel is only the third taxane that has
`
`
`
`3
`
`

`

`received FDA-approval, following Taxol® and Taxotere®.”1 Notably, cabazitaxel
`
`has “antitumour properties, and more especially activity against tumours which are
`
`resistant to Taxol® or to Taxotere®.” (Exh. 1001 at 11:59-61.)
`
`
`
`A. Taxane Research Efforts
`
`As Neptune acknowledges, worldwide taxane research “was well underway
`
`utilizing best laboratory practices” as of the time of the invention. (Petition at 20.)
`
`In fact, there were numerous publications disclosing thousands of taxane
`
`compounds that had been investigated by research groups around the world. This
`
`includes, among others, groups at Rhône-Poulenc Rorer (a predecessor company to
`
`Patent Owner, “RPR”) (Exhs. 1009, 1014, 1018), Bristol-Myers Squibb (see, e.g.,
`
`Exhs. 1010, 1011, 1012, 1013, 1036), Abbott Laboratories (see, e.g., Exh. 1016),
`
`Florida State University (see, e.g., Exhs. 1022, 2003), Virginia Tech University
`
`
`1
` Taxol’s® generic name is paclitaxel. Taxotere’s® generic name is docetaxel.
`
`
`
`4
`
`

`

`(see, e.g., Exh. 2004), SUNY Stony Brook (see, e.g., Exhs. 1026, 1052, 2005,
`
`2006), the National Cancer Institute (see, e.g., Exh. 1053), the French National
`
`Center for Scientific Research (see, e.g., Exhs. 1005, 1034, 1037, 1040), the
`
`Institute of Cancer Research (see, e.g., Exh. 1006), and the Rotterdam Cancer
`
`Institute (see, e.g., Exh. 1007).
`
`Many of these researchers used a trial-and-error method called structure-
`
`activity relationship (“SAR”) to search for improved taxanes. In SAR, a researcher
`
`systematically makes one chemical change at a time and then uses biological
`
`assays to see whether desirable or undesirable pharmacological or physical
`
`properties result. Despite its benefits, there is an inherent unpredictability to SAR,
`
`which limits its extrapolative value. (Exh. 2007 at 101-02 (describing drug design
`
`as “very much a case of groping in the dark”).)
`
`All told, as of the time of the invention, researchers had explored hundreds
`
`of different modifications all over the taxane molecule and made thousands of
`
`different compounds. (See, e.g., Exh. 2008 at 302-20 (summarizing taxane SAR as
`
`including “a plethora of analogues with core and side-chain modifications” and
`
`detailing modifications to C-1, C-2, C-4, C-5, C-6, C-7, C-9, C-10, C-14, C-19 and
`
`sidechain).) Many researchers identified modifications to positions other than C-7
`
`and C-10 as leading to promising compounds. For instance, references among
`
`Neptune’s exhibits alone identify that:
`
`
`
`5
`
`

`

` Commerçon focused on modifying the sidechain and, after
`
`summarizing the state of the art, states, “other modifications at C-3’
`
`might further improve the antitumor efficacy.” (Exh. 1009 at 236);
`
` Holton also focused on modifying the sidechain and described its
`
`analogs with a 2’ pyridyl substituted C-13 sidechain as “show[ing]
`
`remarkable properties, in vitro, and are valuable antileukemia and
`
`antitumor agents” and as having biological activity “comparable to
`
`that exhibited by taxol and taxotere.” (Exh. 1022 at 4:52-59);
`
` Ojima also focused on synthesizing sidechain analogs based on their
`
`likelihood to “have better bioavailability and cytotoxicity with lower
`
`undesired toxicity.” (Exh. 1052 at 6999);
`
` Klein focused on modifying C-9 and described its analogs as
`
`“show[ing] great promise as a second generation class of
`
`antimicrotubule agents,” as “hav[ing] increased water solubility and
`
`stability as compared to taxol,” and as “also exhibit[ing] excellent
`
`activity in tumor models.” (Exh. 1016 at 276);
`
` Margraff focused on modifying C-19 and concluded “chemical
`
`modifications at C-19 can be done without significant loss of
`
`biological activity.” (Exh. 1018 at 235).
`
`
`
`6
`
`

`

`Importantly, no researcher came up with cabazitaxel before the inventors of
`
`the ’170 patent.
`
`B.
`
`The Invention of Cabazitaxel
`
`In 1989, Patent Owner launched a medicinal chemistry program to search
`
`for taxane analogs. During the course of this ten-year program, nearly 450 taxane
`
`analogs were synthesized and tested. (Exh. 2009 at 2981.)
`
`In January 1993, Patent Owner began to try to synthesize cabazitaxel. (Exh.
`
`2023 at 1042-43.) Over the next 23 months, Patent Owner conducted a series of
`
`experiments directed at that objective. (Id. at 1043-58.) Cabazitaxel was first
`
`successfully synthesized in November 1994 but only through the use of aggressive
`
`and unusual reaction conditions. (Id. at 1042:23-1058:25.)
`
`Once made, cabazitaxel was subjected to extensive in vitro and in vivo
`
`testing to evaluate its biological properties. (Exh. 2009 at 2981.) Cabazitaxel was
`
`found to have unexpectedly high levels of activity across multiple cell lines,
`
`including cell lines that are resistant to other chemotherapy agents, including
`
`taxanes. (Id. at Tables S5, 4.)
`
`After discovering cabazitaxel, RPR’s scientists continued to make and test
`
`other taxane analogs, but were unable to find a single compound that was as
`
`promising.
`
`
`
`7
`
`

`

`C. The Prosecution History
`
`The ’170 patent issued on December 8, 1998 from U.S. Pat. Appl. No.
`
`08/622,011 (“the ’011 application”) filed on March 26, 1996. The ’011 application
`
`claims priority to U.S. Provisional Appl. No. 60/010,144 filed on January 17, 1996,
`
`which in turn claims priority to French Pat. Appl. Nos.: 95-03545 filed March 27,
`
`1995 and 95-15381 filed December 22, 1995. (Exh. 1001.)
`
`The claims of the ’170 patent were extensively reviewed. The Examiner
`
`considered multiple pieces of prior art including the Kant reference and the
`
`European counterpart to the Wong reference – both relied upon by Neptune. (Id. at
`
`References Cited; Exh. 1004 at 729.)
`
`During prosecution, Applicants demonstrated that cabazitaxel shows
`
`improved cytotoxicity in drug resistant cell lines when compared to docetaxel and
`
`other compounds synthesized by Applicants based on the prior art cited by the
`
`Examiner. In particular, Applicants provided data comparing the antitumor activity
`
`of cabazitaxel with docetaxel and two compounds that, like cabazitaxel, each had
`
`identical substituents at C-7 and C-10 in resistant and sensitive carcinoma cell
`
`lines. (Exh. 1004 at 582-87.)
`
`
`
`8
`
`

`

`
`
`
`
`As shown in replicated Table 1, this testing demonstrated that cabazitaxel
`
`“possesses superior in vitro and in vivo anti-tumor activity” to the comparative
`
`
`
`
`
`9
`
`

`

`
`
`compounds. (Id. at 582.) Indeed, cabazitaxel had a better T/C%2 and IC503 value
`
`than both comparative compounds.
`
`
`
`Applicants also reported that cabazitaxel was “very active in vivo against
`
`B16 melanoma giving a full inhibition of tumor growth (T/C% = 0) and [was]
`
`cytotoxic in vitro against KB cells at a concentration 0.029 µg/ml.” (Id. at 582.)
`
`Applicants also tested in vitro activity in resistant cell lines. (Id. at 583-85.)
`
`As seen in replicated Tables 2 and 3, this testing demonstrated that cabazitaxel was
`
`
`2 As Patent Owner explained during prosecution: “[t]he T/C value in percent is an
`
`indication of antitumor effectiveness . . . a T/C <42% is the minimal level to
`
`declare activity,” and “a T/C <10% is considered to indicate high anti-tumor
`
`activity.” (Exh. 1004 at 582.)
`
`3 The IC50 value reflects the drug concentration “required to inhibit cell
`
`proliferation to 50% versus untreated cells.” (Exh. 1010 at 5545.)
`
`
`
`10
`
`

`

`12-fold more active than docetaxel, and that Comparatives A and B showed no
`
`activity against the resistant cell line.
`
`Upon consideration of this evidence, the Examiner withdrew all rejections
`
`
`
`and allowed the claims. (Id. at 291-92.)
`
`D. The Prior Challenges
`
`The ’170 patent, and specifically claims 1 and 2, have survived previous
`
`validity challenges. In particular, the ’170 patent was the subject of both an IPR
`
`
`
`11
`
`

`

`challenge, which was denied institution and rehearing, and a Hatch-Waxman
`
`action before the District of New Jersey involving, at its peak, 10 defendants.
`
`1.
`
`The Prior IPR Petition
`
`The ’170 patent has survived a previous IPR challenge by Mylan, IPR No.
`
`2016-00627 (Exh. 2011). The Mylan IPR combined Kant (one of Neptune’s key
`
`references) and Klein (Exh. 1016) and argued that a POSA would have been
`
`motivated to modify a taxane in order to increase activity. (Exh. 2011 at 32, 34.) In
`
`particular, Mylan used Kant to argue a POSA would have been motivated by the
`
`allegedly improved activity of Kant Compound 20 to use a paclitaxel analog with a
`
`docetaxel sidechain and a C-10 methoxy group. (Id. at 30.) Mylan used Klein to
`
`argue that a POSA would have been motivated by the allegedly improved activity
`
`of a compound with a C-7 methoxy group to incorporate such a change to a taxane
`
`analog with a docetaxel sidechain. (Id. at 32.)
`
`The Board denied institution of Mylan’s petition and its request for
`
`rehearing. (See Exh. 2020 (denying institution); see also Exh. 2021 (denying
`
`rehearing following the Decision Denying Institution of the Petition challenging
`
`U.S. Patent No. 5,847,170).)
`
`2.
`
`The Prior District Court Litigation
`
`The district court litigation involved invalidity challenges explicitly based on
`
`Kant and Wong (two of Neptune’s key references). The district court defendants
`
`
`
`12
`
`

`

`asserted two separate obviousness challenges – the first combined Kant with Klein
`
`(Exh. 1016), and the second combined Wong with two BMS patents. The district
`
`court defendants also relied on Commerçon (another of Neptune’s key references)
`
`to argue that a POSA would have focused on modifying the “flexible” positions.
`
`(Exh. 2010 at 14-15.)
`
`The district court defendants asserted a POSA would have been motivated to
`
`modify a taxane in order to “improve its performance against both normal and
`
`resistant cancer cells . . . .” (Id. at 13.) Specifically, the district court defendants
`
`argued a POSA would have been motivated by the allegedly improved activity of
`
`Kant Compound 20 to methylate the C-10 position of a paclitaxel analog with a
`
`docetaxel sidechain. (Id. at 16-18.) Similarly, the district court defendants used
`
`Wong to argue a POSA would have been motivated by the allegedly improved
`
`activity of Wong Example 2 to methylate C-7. (Id. at 15-16.)
`
`The district court defendants also argued that a POSA would have
`
`reasonably expected cabazitaxel to have the activity it does in sensitive and
`
`resistant cell lines based on structural similarity to prior art compounds. (Id. at 25.)
`
`After an 8-day bench trial, which included fact and expert testimony as well
`
`as substantial pre- and post-trial briefing related to topics such as taxane drug
`
`development practices, the district court upheld the validity of the ’170 patent.
`
`
`
`13
`
`

`

`(Exh. 1049 at 43.) The district court defendants appealed and that appeal is now
`
`pending at the Federal Circuit.
`
`* * *
`
`Neptune has not advanced a novel challenge. Instead, as described in detail
`
`in Section VI, Neptune repeats arguments that have been previously presented to
`
`the Board and/or the District Court of New Jersey – some of which are now
`
`pending before the Federal Circuit. The Board can, and should, exercise its
`
`discretion to deny Neptune’s petition for this reason alone.
`
`III. POSA
`
`The ’170 patent relates to medicinal chemistry and small molecule drug
`
`development. Accordingly, a POSA at the relevant time would possess the
`
`following qualifications: (a) a Ph.D. in organic chemistry, medicinal chemistry, or
`
`a closely related discipline; (b) a master’s degree in organic chemistry, medicinal
`
`chemistry, or a closely related discipline, and at least two years of practical
`
`experience synthesizing and characterizing drug molecules; or (c) a bachelor’s
`
`degree in chemistry, or a closely related discipline, and at least four years of
`
`practical experience synthesizing and characterizing drug molecules.
`
`This is the same POSA definition Patent Owner proposed in the previous
`
`proceedings challenging the ’170 patent. It is also nearly identical to the definition
`
`now proposed by Neptune except that Neptune does not propose a definition in
`
`
`
`14
`
`

`

`which a POSA could have only a bachelor’s degree. Regardless, the analysis and
`
`outcome for an institution decision should not be affected by the POSA definition
`
`adopted by the Board. Institution should be denied under any definition of a POSA.
`
`IV. CLAIM CONSTRUCTION
`
`Patent Owner agrees with Neptune that for the purposes of this proceeding
`
`no term in claims 1 or 2 of the ’170 patent requires construction.
`
`V. LEGAL STANDARD
`
`A.
`
`Institution Standard
`
`To institute an IPR, Petitioner must show a reasonable likelihood of
`
`prevailing on invalidity. See 35 U.S.C. § 314(a) (IPR may not be instituted absent
`
`“a reasonable likelihood that the petitioner would prevail”). Nevertheless, the
`
`institution of IPR is discretionary. See, e.g., Cuozzo Speed Techs., LLC v. Lee, 136
`
`S. Ct. 2131, 2140 (2016) (“[T]he agency’s decision to deny a petition is a matter
`
`committed to the Patent Office’s discretion.”); Harmonic Inc. v. Avid Tech., Inc.,
`
`815 F.3d 1356, 1367 (Fed. Cir. 2016) (“[T]he PTO is permitted, but never
`
`compelled, to institute an IPR proceeding.”). Institution may be denied when “the
`
`same or substantially the same prior art or arguments were previously presented to
`
`the Office.” U.S.P.T.O., August 2018 Update to Trial Practice Guide 8 Section D.2
`
`(2018); see also 35 U.S.C. § 325. The Board’s discretion to deny a petition “is not
`
`limited to situations where the same party files multiple petitions” and may be
`
`exercised where “a different petitioner filed a petition challenging a patent that had
`
`
`
`15
`
`

`

`already been challenged by previous petitions.” Netapp, Inc. v. Realtime Data
`
`LLC, No. IPR2017-01354 Paper 16 (P.T.A.B. Nov. 14, 2017). Additionally:
`
`There may be other reasons besides the “follow-on”
`
`petition context where the “effect . . . on the economy, the
`
`integrity of the patent system, the efficient administration
`
`of the Office, and the ability of the Office to timely
`
`complete proceedings” . . . favors denying a petition . . .
`
`this includes, for example, events in other proceedings
`
`related to the same patent, either at the Office, in district
`
`courts, or the ITC.
`
`
`U.S.P.T.O., August 2018 Update to Trial Practice Guide 10 (2018).
`
`B. Obviousness Standard
`
`A patent claim is obvious “if the differences between the claimed invention
`
`and the prior art are such that the claimed invention as a whole would have been
`
`obvious before the effective filing date of the claimed invention to a person having
`
`ordinary skill in the art.” 35 U.S.C. § 103(a). A party asserting obviousness must
`
`show a person of ordinary skill had an “apparent reason” to combine known
`
`elements and a reasonable expectation of success. KSR Int’l Co. v. Teleflex, Inc.,
`
`550 U.S. 398, 416-19 (2007).
`
`For patents involving new chemical compounds, such as the ’170 patent,
`
`there must have been a reason to both: (1) select the prior art “most promising to
`
`modify” (often called the “lead compound”), and (2) to make all of the necessary
`
`
`
`16
`
`

`

`modifications to arrive at the claimed invention. Otsuka Pharm. Co., Ltd. v.
`
`Sandoz, Inc., 678 F.3d 1280, 1291-92 (Fed. Cir. 2012); see also Daiichi Sankyo
`
`Co., Ltd. v. Matrix Labs., Ltd., 619 F.3d 1346, 1354 (Fed. Cir. 2010) (“[T]he
`
`attribution of a compound as a lead compound after the fact must avoid hindsight
`
`bias; it must look at the state of the art at the time the invention was made to find a
`
`motivation to select and then modify a lead compound to arrive at the claimed
`
`invention.”). There must also have been a reasonable expectation of both making
`
`the new compound, and of its advantageous properties. Procter & Gamble Co. v.
`
`Teva Pharms. USA, Inc., 566 F.3d 989, 996 (Fed. Cir. 2009) (a POSA must have a
`
`“reasonable expectation . . . that [the claimed compound] would be a successful
`
`compound); Otsuka Pharm., 678 F.3d at 1292; Sanofi-Synthelabo v. Apotex, Inc.,
`
`550 F.3d 1075, 1088 (Fed. Cir. 2008) (“The application of hindsight is
`
`inappropriate where the prior art does not suggest that this [compound] could
`
`reasonably be expected to manifest the properties and advantages that were found.
`
`. . .”); Yamanouchi Pharm. Co., Ltd. v. Danbury Pharmacal, Inc., 231 F.3d 1339,
`
`1345 (Fed. Cir. 2000) (finding reasonable expectation of success requires showing
`
`an expectation of obtaining a compound having the desired properties of the
`
`claimed compound).
`
`
`
`17
`
`

`

`VI. THE PETITION SHOULD BE DENIED BECAUSE ITS
`ARGUMENTS HAVE ALREADY BEEN PRESENTED
`
`A. The Board Should Reject the Petition Pursuant to Section 325(d)
`
`As noted above, 35 U.S.C. § 325(d) provides that “[i]n determining whether
`
`to institute or order a proceeding under this chapter, chapter 30, or chapter 31, the
`
`Director may take into account whether, and reject the petition or request because,
`
`the same or substantially the same prior art or arguments previously were
`
`presented to the Office.” In doing so, the Board weighs the competing concerns of
`
`petitioner’s desire to be heard and improving patent quality, against the interests of
`
`patent owners, who seek to avoid harassment and enjoy quiet title to their rights.
`
`Ziegmann, N.P.Z., Inc. v. Stephens, No. IPR2015-01860, Paper 13 at 11 (P.T.A.B.
`
`Sept. 6, 2017) (expanded panel) (discussing H.R. Rep. No. 112-98, pt. 1, at 48
`
`(“[T]hese proceedings are not to be used as tools for harassment or a means to
`
`prevent market entry through repeated litigation and administrative attacks on the
`
`validity of a patent.”)).
`
`In the designated-as-informative decision in Becton, Dickinson & Co. v. B.
`
`Braun Melsungen AG, No. IPR2017-01586, Paper 8 at 17-18 (P.T.A.B. Dec. 15,
`
`2017) (informative), the Board listed non-exhaustive factors it will consider in
`
`determining whether to exercise its discretion to deny institution under § 325(d):
`
`(a) the similarities and material differences between the asserted art and the
`
`prior art involved during examination;
`
`
`
`18
`
`

`

`(b) the cumulative nature of the asserted art and the prior art evaluated
`
`during examination;
`
`(c) the extent to which the asserted art was evaluated during examination,
`
`including whether the prior art was the basis for rejection;
`
`(d) the extent of the overlap between the arguments made during
`
`examination and the manner in which Petitioner relies on the prior art or
`
`Patent Owner distinguishes the prior art;
`
`(e) whether Petitioner has pointed out sufficiently how the Examiner erred in
`
`its evaluation of the asserted prior art; and
`
`(f) the extent to which additional evidence and facts presented in the Petition
`
`warrant reconsideration of the prior art or arguments.
`
`The Board has repeatedly exercised its discretion under § 325(d) to deny
`
`institution where the petition relies on references that are cumulative to other
`
`literature expressly considered by the PTO. See Intelligent Bio-Systems, Inc. v.
`
`Illumina Cambridge Ltd., No. IPR2013-00324, Paper 19 at 6-7 (P.T.A.B. Nov. 21,
`
`2013) (informative) (institution denied pursuant to § 325(d) because the references
`
`relied upon, while not identical, contained “substantially the same teachings” as the
`
`references in the first petition); Unified Patents v. Berman, No. IPR2016-01571,
`
`Paper 10 at 11-12 (P.T.A.B. Dec. 14, 2016) (informative) (institution denied in part
`
`under § 325(d) when a reference not discussed by the examiner was still being
`
`
`
`19
`
`

`

`used in the same way as a reference the examiner had previously considered and
`
`allowed the claims over); Telebrands Corp. v. Tinnus Enters., LLC, No. PGR2017-
`
`00051, Paper 8 at 16-19 (P.T.A.B. Feb. 22, 2018) (institution denied under §
`
`325(d) even though a reference had not been before the examiner because the
`
`disclosure of the new reference was similar to those considered by the examiner,
`
`and therefore the petitioner was making substantially the same arguments as those
`
`already considered).
`
`As in those cases, the Board should exercise its discretion and deny
`
`institution here because the arguments and prior art are cumulative to, and
`
`substantially the same as, those presented in the rejected Mylan IPR petition.
`
`Although Neptune summarily states that “the Mylan petition relied upon
`
`completely different lead compounds . . . and different prior art and obviousness
`
`combinations” (Petition at 78), Neptune fails to show that these alleged differences
`
`actually result in a different argument from the one already rejected by the Board.
`
`To the contrary, as discussed below, Neptune merely recycles Mylan’s failed
`
`arguments.
`
`Neptune starts its lead compound analysis with paclitaxel; whereas Mylan
`
`started with docetaxel or Kant Compound 20. However, this is a superficial
`
`difference that does not substantially alter the ultimate analysis. As explained
`
`below, both Neptune’s and Mylan’s lead compound analyses arrive at the same
`
`
`
`20
`
`

`

`compound: paclitaxel having a C-10 methoxy group and a BOC sidechain, i.e.,
`
`Kant Compound 20.
`
`Indeed, Neptune suggests a POSA would have immediately modified its lead
`
`compound, paclitaxel, to add the docetaxel sidechain:
`
`The improved biological activity of analog 20 in Kant
`
`would motivate a POSA in March 1995 to improve
`
`paclitaxel’s activity by: (1) using a BOC rather than a
`
`benzoyl group in paclitaxel’s side-chain . . . . (Petition at
`
`47.)4
`
`Neptune then turns to Kant for the exact same reason Mylan did – to
`
`rationalize the substitution of the C-10 hydroxy of paclitaxel with a methoxy group
`
`on a compound with the docetaxel sidechain based on the allegedly improved
`
`activity of Kant Compound 20. Specifically, Neptune argues:
`
`Kant Table II disclosed that among the compounds
`
`tested, the paclitaxel analog with the BOC side-chain and
`
`methoxy group at C-10 [i.e., Compound 20] provided the
`
`
`4 Moreover, while Neptune adopts the sidechain modification from docetaxel, it
`
`does not adopt the second critical change made to paclitaxel, namely replacing the
`
`C-10 acetoxy group in paclitaxel with a hydroxyl group, which improved water
`
`solub