Paper No. 47
`
`Filed: December 22, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________________
`
`NEPTUNE GENERICS, LLC,
`APOTEX INC., APOTEX CORP.,
`TEVA PHARMACEUTICALS USA, INC.,
`and FRESENIUS KABI USA, LLC,
`
`PETITIONERS,
`
`V.
`
`ELI LILLY & COMPANY,
`
`PATENT OWNER.
`
`
`
`___________________
`
`Case IPR2016-002401, 2
`Patent 7,772,209
`___________________
`
`
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`1 Cases IPR2016-01191 and IPR2016-01343 have been joined with the instant
`proceeding.
`2 An identical Reply has been filed in IPR2016-00237 under that IPR caption. All
`paper and exhibit numbers herein refer to IPR2016-00237’s papers and exhibits
`unless otherwise noted.
`
`

`
`
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................ 1
`I.
`DR. CHABNER APPLIES THE WRONG OBVIOUSNESS
`II.
`STANDARDS TO REACH HIS OPINIONS. ....................................................... 2
`III. DR. CHABNER’S OPINIONS ARE INCONSISTENT WITH
`CONTEMPORANEOUS EVIDENCE OF HOW A POSA WOULD
`INTERPRET THE PRIOR ART. .......................................................................... 6
`IV. A POSA WOULD HAVE BEEN MOTIVATED TO ADDRESS
`PEMETREXED’S KNOWN TOXICITIES. ....................................................... 11
`V.
`FOLIC ACID IS NOT PEMETREXED’S ANTIDOTE. ....................... 12
`1. A POSA Would Have Understood that Folic Acid is Not
`Pemetrexed’s Antidote. ............................................................................. 12
`2. A POSA Would Have Reasonably Expected Folic Acid Pretreatment
`to Improve Pemetrexed’s Therapeutic Index. ........................................ 14
`3. A POSA Would Not Have Compared Hammond and Rinaldi for the
`Efficacy of Folic Acid Supplementation. ................................................. 16
`4. A POSA Would Have Understood that Folic Acid Supplementation
`Does Not Cause Tumor Growth. ............................................................. 17
`VI. A POSA WOULD HAVE BEEN MOTIVATED TO SUPPLEMENT
`PEMETREXED WITH FOLIC ACID AND B12 WITH A REASONABLE
`EXPECTATION OF SUCCESS. .......................................................................... 18
`A. The Prior Art Taught that Pretreatment Elevated Homocysteine
`Predicts Pemetrexed Toxicity. ................................................................... 18
`B. A POSA Would Have Had a Reasonable Expectation that B12
`Supplementation with FA Would Successfully Reduce Pemetrexed
`Toxicity. ....................................................................................................... 23
`C. A POSA Would Not Have Been Concerned about a B12 Methyl Trap . 27
`D. A POSA Would Have Understood that B12 Supplementation Would
`Not Cause Tumor Growth. ........................................................................ 28
`
`
`
`i
`
`

`
`
`
`VII. THE ’209 PATENT’S CLAIMED DOSE AND SCHEDULE ARE NOT
`CRITICAL AND WERE STANDARD IN THE ART. ...................................... 30
`VIII. LILLY’S ALLEGED SECONDARY CONSIDERATIONS ARE
`INSUFFICIENT TO DEFEAT OBVIOUSNESS. .............................................. 31
`
`
`
`
`
`
`
`
`
`
`ii
`
`

`
`
`
`Cases 
`
`TABLE OF AUTHORITIES
`
`Amazon.com, Inc. v. Barnesandnoble.com,
`239 F.3d 1343 (Fed. Cir. 2001) .............................................................................. 3
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
` 713 F.3d 1369 (Fed. Cir. 2013) ........................................................................... 33
`Custom Accessories, Inc. v. Jeffrey-Allan Indus.,
`807 F.2d 955 (Fed. Cir. 1986) ................................................................................ 3
`Ex Parte Erlich,
`1992 Pat. App. Lexis 2,
`(Bd. Pat. App. & Interferences Jan. 16 1992) ........................................................ 7
`Ex Parte McGaughey,
`1988 Pat. App. LEXIS 2,
`(Bd. Pat. App. & Interferences Mar. 4, 1988)........................................................ 7
`Ex Parte Raychem,
`1992 Pat. App. LEXIS 21,
`(Bd. Pat. App. & Interferences June 30, 1992) ...................................................... 7
`Hoffman-LaRoche Inc. v. Apotex, Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .............................................................................. 3
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) ............................................................................ 25
`In re Hogan,
`559 F.2d 595 (C.C.P.A. 1977) ............................................................................... 7
`In re Wilson,
`311 F.2d 266 (C.C.P.A. 1962) ............................................................................... 6
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................... 4
`Medichem S.A. v. Rolabo S.I.,
`437 F.3d 1157 (Fed. Cir. 2006) ............................................................................ 15
`Organik Kimya AS v. Rohm & Haas Co.,
`IPR2014-00185, Paper 42-2 (P.T.A.B. Dec. 18, 2014) ....................................... 32
`Ortho-McNeil Pharm., Inc. v. Teva Pharms. Indus., Ltd.,
`344 F. App’x 595 (Fed. Cir. 2009) ...................................................................... 11
`
`
`
`iii
`
`

`
`
`
`Pharmastem Therapeutics, Inc. v. Viacell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) ............................................................... 11, 32, 33
`Randall Mfg. v. Rea,
`733 F.3d 1355 (Fed. Cir. 2013) ............................................................................ 19
`Std. Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ................................................................................ 3
`Thomas & Betts Corp. v. Litton Sys., Inc.,
`720 F.2d 1572 (Fed. Cir. 1983) .............................................................................. 6
`ViiV Healthcare UK Ltd. v. Lupin Ltd.,
`6 F. Supp. 3d 461 (D. Del. 2013) ......................................................................... 32
`Rules 
`
`Fed. R. Evid. 801(d)(2) .............................................................................................. 7
`
`
`
`iv
`
`

`
`
`
`I.
`
`INTRODUCTION
`
`Lilly’s Response is based on Dr. Chabner’s testimony. But Dr. Chabner’s
`
`opinions are fatally flawed for a host of reasons because he: (1) failed to analyze
`
`obviousness from the perspective of a POSA; (2) admits he is the only person that
`
`adheres to his unusual views of the prior art; (3) applied a legally erroneous
`
`standard for reasonable expectation of success; (4) applied different standards
`
`depending on whether it helped or hurt Lilly’s case; and (5) inexplicably
`
`contradicted Lilly’s contemporaneous admissions about the prior art’s teachings.
`
`Neptune’s experts’ opinions—and the explicit teachings of the prior art on
`
`which they are based—disagree with Dr. Chabner. For good reason. The prior art
`
`establishes that a POSA in June 1999 would have been motivated to address the
`
`known problem of pemetrexed’s toxicity, particularly for patients presenting with
`
`elevated homocysteine levels known to strongly correlate with such toxicity. And
`
`the prior art taught a POSA to address toxicity for at least those patients by
`
`administering folic acid and B12 vitamins prior to treatment with pemetrexed.
`
`Based on those teachings a POSA in June 1999 had a reasonable expectation
`
`that such a combination would succeed in ameliorating toxicity while preserving
`
`pemetrexed’s antitumor effects.
`
`
`
`1
`
`

`
`
`
`II. DR. CHABNER APPLIES THE WRONG OBVIOUSNESS
`STANDARDS TO REACH HIS OPINIONS.
`
`When Lilly’s oncologist expert, Dr. Chabner, was asked what methodology
`
`he used to distinguish between his knowledge acquired over 50 years (30 years of
`
`which came prior to June 1999) and a POSA’s knowledge in June 1999, he
`
`testified that he “really can’t answer that question,” and admitted he did not
`
`“employ methodologies” because he used “his own personal experience” and did
`
`not conduct his analysis based on a POSA “less informed than myself.” (Ex. 1075-
`
`233:15-234:12, 228:11-229:3.)
`
`When asked how he applied the reasonable expectation of success standard
`
`in his declaration, Dr. Chabner testified, “I looked at what I knew as of 1999, and
`
`what the literature said and what was publicly available, and I concluded that it
`
`was not obvious that – that using these vitamins would make a difference, would
`
`improve therapy.” (Id., 88:25-89:8.) When asked what criteria he employed, he
`
`testified, “I think, you know, it’s like pornography. When it’s reasonable, you
`
`understand it when you see it. Scientifically, I was skeptical about it.” (Id., 1075-
`
`89:20-25.) He further testified, “I was skeptical about this working, based on my
`
`30 years of experience as an antifolate researcher”—while conceding a POSA need
`
`not have such experience. (Id., 227:20-228:24.)
`
`When pressed to explain how reasonably successful the claimed
`
`combination needed to be for obviousness, Dr. Chabner testified, “I think it would
`
`
`
`2
`
`

`
`
`
`need to be something that I could endorse”— admitting “my standard for saying
`
`what’s obvious and reasonable is my personal standard. And that’s why I have 50
`
`years in the field.” (Id., 90:19-94:3.)
`
`Dr. Chabner’s failure to opine from a POSA’s perspective is fatal to his non-
`
`obviousness opinions. The Board should give his opinions little, if any, weight.
`
`Amazon.com, Inc. v. Barnesandnoble.com, 239 F.3d 1343, 1364 (Fed. Cir. 2001)
`
`(what an expert “did or did not personally realize at the time based on his actual
`
`knowledge is irrelevant”); Custom Accessories, Inc. v. Jeffrey-Allan Indus., 807
`
`F.2d 955, 962 (Fed. Cir. 1986) (inquiry is whether challenged claims are obvious
`
`to a POSA, “not to the judge, or to a layman . . . or to geniuses in the art.”); Std.
`
`Oil Co. v. Am. Cyanamid Co., 774 F.2d 448, 454 (Fed. Cir. 1985) (POSA follows
`
`the “conventional wisdom” of the prior art).
`
`Separately, Dr. Chabner admitted that his personal standard for reasonable
`
`expectation of success required “evidence that it worked in the clinical setting” and
`
`“what was really needed was clinical evidence” of success. (Ex. 1075-214:9-
`
`215:4.) But “[c]onclusive proof of efficacy is not necessary to show obviousness.
`
`All that is required is a reasonable expectation of success.” Hoffman-LaRoche Inc.
`
`v. Apotex, Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014). Dr. Chabner did not use the
`
`proper standard for determining whether a POSA would have a reasonable
`
`expectation of success, and his opinions should be afforded little, if any, weight.
`
`
`
`3
`
`

`
`
`
`Dr. Chabner further opines that rather than administering folic acid and B12
`
`to address pemetrexed’s known toxicity to patients with elevated homocysteine, a
`
`POSA would have instead addressed toxicity for such patients by (1) adjusting
`
`pemetrexed’s dose and schedule, or (2) administering post-treatment leucovorin
`
`(folinic acid), or (3) using granulocyte colony stimulating factors. (Ex. 1075-
`
`149:18-152:4.) He also admitted that these were the only options for these patients
`
`known in the prior art. (Id., 308:20-310:1.)
`
`First, given Dr. Chabner’s admission that there were a limited number of
`
`options for addressing pemetrexed toxicity for patients presenting with elevated
`
`homocysteine, this testimony is evidence that a POSA would have found it
`
`obvious—or at least obvious to try—the folic acid/B12 combination to address
`
`those patients’ toxicity. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421
`
`(2007) (when there is a need “to solve a problem and there are a finite number of
`
`identified, predictable solutions, a person of ordinary skill has good reason to
`
`pursue the known options within his or her technical grasp. If this leads to the
`
`anticipated success, it is likely the product not of innovation but of ordinary skill
`
`and common sense.”)
`
`Second, with respect to the three prior art alternatives, Dr. Chabner
`
`admitted: (1) a POSA had no clinical data establishing dose reduction preserved
`
`antitumor activity (102:3-103:16); (2) no prior art reference disclosed efficacy or
`
`
`
`4
`
`

`
`
`
`toxicity data for a dose reduction for patients presenting with elevated
`
`homocysteine (105:8-12); (3) it would take further study to determine the well-
`
`tolerated dose for patients with elevated homocysteine and to determine the
`
`amount of dose reduction required (101:7-24, 109:24-110:4, 111:5-15, 112:20-
`
`113:6); (4) he assumed without data that three-quarters of a dose would avoid
`
`toxicity (103:17-104:13); and (5) the therapeutic window for the dose of
`
`pemetrexed alone for patients presenting with elevated homocysteine was “not
`
`actually known” (286:12-16). Despite these prior art shortfalls, Dr. Chabner
`
`nonetheless would have been “very encouraged to undertake further investigation
`
`[of these alternatives].” (Ex. 1075-136:2-6.)
`
`When asked, with respect to these alternatives, “[d]oes being encouraged to
`
`undertake further investigation satisfy your understanding and application of a
`
`reasonable expectation of success?”—Dr. Chabner answered “Yes.” (Id., 136:7-
`
`13.)
`
`Dr. Chabner’s use of a lower standard (encouraged to undertake
`
`investigation) for a reasonable expectation of success for his alternatives—and a
`
`heightened standard (proof from clinical data) when evaluating reasonable
`
`expectation of success for the claimed folic acid/B12 pretreatment—entitles both
`
`opinions to little weight.
`
`
`
`5
`
`

`
`
`
`III. DR. CHABNER’S OPINIONS ARE INCONSISTENT WITH
`CONTEMPORANEOUS EVIDENCE OF HOW A POSA WOULD
`INTERPRET THE PRIOR ART.
`
`Three documents produced during these proceedings provide further
`
`powerful evidence undermining the credibility of Dr. Chabner’s opinions, and
`
`further support Neptune’s obviousness Grounds.
`
`Lilly produced two documents it submitted to the FDA prior to the earliest
`
`effective filing date of the ’209 Patent. (Exs. 2103 and 2017.) Although these
`
`documents are not technically prior art, they are admissible for a POSA’s
`
`knowledge of the state of the art at the time of the ’209 patent’s effective filing
`
`date. Thomas & Betts Corp. v. Litton Sys., Inc., 720 F.2d 1572, 1580-81 (Fed. Cir.
`
`1983) (finding unpublished internal documents “were, in effect, properly used as
`
`indicators of the level of ordinary skill in the art to which the invention
`
`pertained”); In re Wilson, 311 F.2d 266, 268-69 (C.C.P.A. 1962) (approving
`
`citation to document that was not prior art to show a fact about the prior art).
`
`Lilly submitted a third document (Ex. 1047) to The Oncologist.3 Although
`
`Exhibit 1047 was submitted six months after the effective filing date, it is relevant
`
`
`3 Dr. Chabner has always been Editor-in-Chief of The Oncologist. (Ex. 1075-
`
`34:13-20.) He testified certain characterizations of the prior art in Exhibit 1047 that
`
`contradict his sworn opinions were inaccurate and wished he would have corrected
`
`
`
`6
`
`

`
`
`
`to obviousness. See e.g., Ex Parte Raychem, 1992 Pat. App. LEXIS 21, *10-11 &
`
`n. 4 (Bd. Pat. App. & Interferences June 30, 1992) (later-published reference
`
`“relevant evidence” concerning a POSAs knowledge about the prior art reference’s
`
`teaching); Ex Parte Erlich, 1992 Pat. App. Lexis 2, *6 (Bd. Pat. App. &
`
`Interferences Jan. 16 1992) (later-published reference citing many prior art
`
`references relevant to POSAs knowledge about the prior art references on patent
`
`filing date); In re Hogan, 559 F.2d 595, 605 & n. 17 (C.C.P.A. 1977) (later-
`
`published reference permissible evidence of art-related facts existing on the filing
`
`date). These documents also constitute party admissions concerning the content of
`
`the prior from a POSAs perspective. Fed. R. Evid. 801(d)(2); Ex Parte
`
`McGaughey, 1988 Pat. App. LEXIS 2, 13-15 (Bd. Pat. App. & Interferences Mar.
`
`4, 1988) (“An admission is defined as an acknowledged, declared, conceded or
`
`recognized fact or truth.”)
`
`
`them (Ex. 1075-147:148:14)—but before he knew that line of questioning was
`
`coming, he admitted that when the article published in 2001 pemetrexed “was an
`
`established drug” that people know about it and its “pathway” and the article was
`
`“bread-and-butter oncology.” (Id., 82:25-84:20.)
`
`
`
`7
`
`

`
`
`
`These documents are evidence Lilly created long before the patentability of
`
`the ’209 patent was an issue, and uniformly contradict Dr. Chabner’s opinions of
`
`the pertinent prior art.4
`
`In Exhibit 2103, Lilly submitted a brief to the FDA, where patient health
`
`turns on the importance of candor and scientific rigor, explaining the rationale for
`
`administering folic acid and B12 before pemetrexed treatment. In doing so, Lilly
`
`cited the teachings of several prior art references at issue here, including Niyikiza
`
`(Ex. 1008), Calvert (Ex. 1013, Laohavinij (Ex. 2031), Worzalla (Ex. 1005),
`
`Bronstrup 1999 (Ex. 1099), and Hammond (Ex. 1022). (Ex. 2103-19-20; Ex. 1077
`
`¶¶69-71.)
`
`In Exhibit 2107, Lilly explained to the FDA that the teachings of the prior
`
`art justified pretreating with folic acid and B12 before and during pemetrexed
`
`
`4 Neptune is not arguing that Lilly’s path to the invention or how it achieved the
`
`invention is evidence of obviousness. Rather, Neptune cites the three documents as
`
`evidence solely for: (1) how POSAs interpreted specific prior art references at
`
`issue here around the priority date, and (2) to show Dr. Chabner’s interpretation of
`
`the prior art contradicts how POSAs around the priority date interpreted the same
`
`references. Neptune’s use for this narrow evidentiary purpose has been approved
`
`by the Board and the Federal Circuit, as shown in the cases cited in this section.
`
`
`
`8
`
`

`
`
`
`treatment. This prior art included Worzalla (Ex. 1005), Laohavinij (Ex. 2031),
`
`Bronstrup 1999 (Ex. 1099), Morgan 1990 (Ex. 1023). (Ex. 2107, passim; Ex. 1077
`
`¶¶69-71.)
`
`Exhibit 1047 is a Lilly publication that discusses the teachings of several
`
`prior art references at issue here, including Niyikiza (Ex. 2015), Rusthoven (Ex.
`
`1011), Morgan 1990 (Ex. 1023), Worzalla (Ex. 1005), and Hammond (Ex. 1022).
`
`(Ex. 1047-372-73; Ex. 1077 ¶¶69-71)
`
`During his deposition, Dr. Chabner was shown Lilly’s interpretation of the
`
`relevant prior art cited in these three documents. Although Lilly’s interpretations
`
`and admissions (made years earlier) are consistent with the references themselves,
`
`Dr. Chabner repeatedly rejected them.
`
`The documents admit Hammond taught a POSA that the addition of folic
`
`acid supplementation permits pemetrexed dose escalation and ameliorates toxicity.
`
`(Ex. 1077 ¶69.) Dr. Chabner’s Declaration, in contrast, states that Hammond
`
`teaches that folic acid undermines pemetrexed’s efficacy (Ex. 2120 ¶ 96), and he
`
`also disagreed with Lilly’s representations that Hammond encouraged use of folic
`
`acid. (Ex. 1075-141:25-142:19, 146:11-148:14, 167:14-168:21, 180:13-184:15.)
`
`Amazingly, Dr. Chabner “disagree[s] with everyone,” including Lilly scientists,
`
`who interpreted Hammond as supporting the use of folic acid pretreatment with
`
`pemetrexed. (Ex. 1075-160:5-20.) Not surprisingly, Dr. Chabner stands alone and
`
`
`
`9
`
`

`
`
`
`could not identify a single reference interpreting Hammond the way he does. (Id.,
`
`160:22-161:12.)
`
`Likewise, Lilly admitted Worzalla teaches that folic acid supplementation
`
`reduced pemetrexed’s toxicities while maintaining antitumor efficacy. (Ex. 1077
`
`¶70.) Dr. Chabner, in contrast, said Worzalla teaches that folic acid compromises
`
`pemetrexed’s efficacy. (Ex. 2120 ¶ 157.) Dr. Chabner also disagreed with Lilly’s
`
`interpretation of Worzalla evidencing that folic acid can ameliorate pemetrexed
`
`toxicities without a reduction in antitumor efficacy. (Ex. 1075-157:5-159:20,
`
`165:5-167:13, 219:23-221:5, 249:12-250:20, 269:3-277:2.) When asked “are you
`
`aware of any publication that sides with your interpretation of Worzalla and not the
`
`one that is disclosed in The Oncologist article – or these reports?” He unabashedly
`
`responded under oath: “No.” (Ex. 1075-251:19-24.) Again, Dr. Chabner stands
`
`alone.
`
`Lilly also admitted that Laohavinij teaches “it is possible to decrease the
`
`toxicity [of lometrexol] to healthy tissue while maintaining antitumor effect
`
`through careful adjustment of folic acid intake.” (Ex. 2107-10.) Dr. Chabner says
`
`the opposite (Ex. 2120 ¶ 157) and disagrees with Lilly’s contemporaneous
`
`understanding. (Ex. 1075-254:3-258:20.)
`
`Dr. Chabner’s opinions regarding Hammond, Worzalla, and Laohavinij are
`
`unsupported by any other reference and are inconsistent with contemporaneous
`
`
`
`10
`
`

`
`
`
`statements made by Lilly to the FDA and a peer-reviewed journal—and should be
`
`rejected as not credible.
`
`In sum, Lilly’s own prior art disclosures (confirmed by Lilly’s subsequent
`
`confirmation of the teachings of those disclosures), explicitly taught a POSA in
`
`June 1999 to ameliorate toxicity associated with antifolates in general, and
`
`pemetrexed in particular, by administering folic acid and B12 before pemetrexed
`
`treatment to ensure that the patient had adequate folate levels—a known biomarker
`
`for pemetrexed toxicity. Dr. Chabner’s declaration and deposition testimony flies
`
`in the face of these explicit teachings. Consequently, his opinions should be given
`
`little, if any, weight. See, e.g., Pharmastem Therapeutics, Inc. v. Viacell, Inc., 491
`
`F.3d 1342, 1361-63 (Fed. Cir. 2007); Ortho-McNeil Pharm., Inc. v. Teva Pharms.
`
`Indus., Ltd., 344 F. App’x 595, 603 (Fed. Cir. 2009) (expert opinions given little
`
`weight when they fly in the face of explicit prior art disclosures).
`
`IV. A POSA WOULD HAVE BEEN MOTIVATED TO ADDRESS
`PEMETREXED’S KNOWN TOXICITIES.
`
`Lilly contends pemetrexed’s toxicities “were considered tolerable, and
`
`manageable through…adjustments to the dose and schedule of pemetrexed
`
`administration” or through “a rescue therapy.” (Paper 33-10, 28.) Lilly is wrong.
`
`Both Calvert 1998 and Hammond taught pemetrexed’s toxicities were
`
`serious. (See, e.g., Exs. 1013-38-39; 1022-129.) Likewise, Rinaldi taught that
`
`“[t]hree patients [8%] died during the study related to [pemetrexed] toxicity”. (Ex.
`
`
`
`11
`
`

`
`
`
`2030-86.) Thödtmann similarly taught that two patients (4%) died “due to
`
`[pemetrexed]-related toxicities.” (Ex. 1021-129.) Rusthoven taught, despite dose
`
`and schedule modifications, that 30% of pemetrexed patients had to stop treatment
`
`because of the drug’s toxicity, (Ex. 1011-1198) and explicitly taught a POSA that
`
`“dietary supplementation with folic acid may improve therapeutic index by
`
`reducing toxicity.” (Id. -1195.)
`
`Contrary to Lilly’s assertions, a POSA would have focused on addressing
`
`pemetrexed’s toxicities so more patients could tolerate treatment. (Ex. 1077 ¶16.)
`
`Pemetrexed’s anti-tumor activity was considered “‘remarkable and unusual’”
`
`(Paper 33-10), and the most promising antifolate for cancer treatment as of June
`
`1999. (Ex. 1075-13:2-14.) Thus, a POSA would have been motivated to reduce
`
`pemetrexed’s toxicities.
`
`V.
`
`FOLIC ACID IS NOT PEMETREXED’S ANTIDOTE.
`1.
`
`A POSA Would Have Understood that Folic Acid is Not
`Pemetrexed’s Antidote.
`First, Lilly argues that folic acid supplementation “would have been
`
`understood by the POSA to act as pemetrexed’s antidote.” (Paper 33-1.) This is
`
`based on an inaccurate understanding of pemetrexed’s mechanism of action. (Exs.
`
`1077 ¶19-20; 1078 ¶22-35.) Pemetrexed acts, in part, by decreasing the amount of
`
`tetrahydrofolate (FH4) available for DNA synthesis. (Exs. 1077 ¶19; 1078 ¶46.)
`
`The body converts folic acid (FA) to FH4 through dihydrofolate reductase (DHFR).
`
`
`
`12
`
`

`
`
`
`(Ex. 2118 ¶23.) Prior to this reduction to FH4, FA remains unusable for DNA
`
`synthesis. (Exs. 1077 ¶19; 1078 ¶46.) Because a POSA would have known that
`
`pemetrexed is “a very potent inhibitor for human DHFR (Ki = 7.0 nM),” and that
`
`FA is a very poor substrate for DHFR, (Exs. 2078-142; 2107-11; 1077 ¶19; 1078
`
`¶¶40-45.) a POSA would have understood that, in the presence of pemetrexed, FA
`
`cannot reduce to FH4, as shown on the following page:
`
`Pemetrexed
`
`Pemetrexed
`
`DNA
`
`DHFR
`
`FA
`
`Pemetrexed
`
`(Ex. 1077 ¶19.)
`
`This is in contrast to leucovorin (folinic acid), which is already in reduced
`
`form, and so does not need DHFR to increase the amount of FH4 in the body and
`
`prevent pemetrexed’s efficacy. (Exs. 1077 ¶20; 1078 ¶46.) Thus, leucovorin’s
`
`preventative (rescue) effect does not apply to folic acid. (Exs. 1077 ¶20; 1078 ¶46;
`
`2107-11.)
`
`Second, Lilly argues that “if DHFR inhibition were sufficiently complete
`
`such that the folic acid could not be converted to a usable form that would compete
`
`
`
`13
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`

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`
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`with the antifolate, then the folic acid would not have a beneficial effect on
`
`toxicity.” (Paper 33-24.) This assumes concurrent treatment with folic acid and
`
`pemetrexed, ignoring the prior art’s teaching that it is the patient’s pretreatment
`
`homocysteine and nutritional status that predicts pemetrexed toxicity. (Ex. 1008.)
`
`Thus, a POSA would expect pretreatment folic acid to have its beneficial effect on
`
`toxicity prior to pemetrexed administration. (Exs. 1077 ¶22; 1063-1276S (citing
`
`Ex. 1017); 2107-10.)
`
`Third, Lilly argues if folic acid is given prior to pemetrexed, folic acid could
`
`be converted to other usable folates and undermine pemetrexed’s efficacy. (Paper
`
`33-24-25.) However, any reduced folates remaining at pemetrexed inhibition
`
`would be insufficient to compete with pemetrexed and lower its therapeutic index.
`
`This is true because, as Dr. Chabner admits, pemetrexed also acts by inhibiting TS
`
`and GARFT in addition to the DHFR enzyme that blocks folic acid’s reduction.
`
`(Ex. 1077 ¶¶23, 50; 2120 ¶ 164.) Additionally, because the claimed single dose of
`
`folic acid approximates the normal daily dietary level of folic acid, a POSA would
`
`have been even less concerned about interfering with pemetrexed. (Exs. 1077 ¶23;
`
`1078 ¶83; see Ex. 1076-83:18-20.)
`
`2.
`
`A POSA Would Have Reasonably Expected Folic Acid
`Pretreatment to Improve Pemetrexed’s Therapeutic Index.
`A POSA would have been further convinced that folic acid is not
`
`pemetrexed’s antidote by the prior art’s conclusion that folic acid
`
`
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`14
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`

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`
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`“supplementation increases the therapeutic index of MTA” by “permit[ting] MTA
`
`dose escalation by ameliorating toxicity.” (Exs. 1022-129; 1011-1195; see Exs.
`
`1005-3237-39; 1013-39; 1014-7; 1016-256a; 2035-225a; 1077 ¶24.)
`
`A POSA uses the therapeutic index to find “a window in which there is a
`
`therapeutic response and tolerable toxicity.” (Ex. 1075-184:17-21.) A POSA would
`
`understand that decreasing a drug’s toxicity can allow a patient to receive
`
`higher/more doses of the drug, which can improve the drug’s response, even if the
`
`toxicity reduction results in a lower efficacy per mg of drug administered. (Ex.
`
`1077 ¶¶24, 41, 45.) See Medichem S.A. v. Rolabo S.I., 437 F.3d 1157, 1165 (Fed.
`
`Cir. 2006) (“[A] given course of action often has simultaneous advantages and
`
`disadvantages, and this does not necessarily obviate motivation to combine.”).
`
`Lilly disregards the prior art’s teachings that folic acid supplementation
`
`improves pemetrexed’s therapeutic index. Instead, Lilly relies on two references
`
`concerning other antifolates (methotrexate and Tomudex). (Paper 33-19.)
`
`First, a POSA would not have ignored teachings specific to pemetrexed in
`
`favor of contrary teachings relating to methotrexate and Tomudex. (Ex. 1077 ¶¶37-
`
`38.)
`
`Second, while one reference states that “folic acid or its derivatives may
`
`decrease response to systemically administered methotrexate,” it also teaches that
`
`“[f]olate deficiency states may increase methotrexate toxicity.” (Ex. 2020-1398-
`
`
`
`15
`
`

`
`
`
`99.) Because the therapeutic index balances a drug’s response with toxicity, this
`
`reference is at best inconclusive regarding folic acid’s effect on methotrexate’s
`
`therapeutic index. (Ex. 1077 ¶37.)
`
`Finally, because Tomudex is not a DHFR inhibitor like pemetrexed, a
`
`POSA would not expect Tomudex to prevent folic acid reduction to a usable form
`
`as pemetrexed does. (Compare Paper 33-26 with Paper 33-5; Ex. 1077 ¶38.)
`
`3.
`
`A POSA Would Not Have Compared Hammond and Rinaldi for
`the Efficacy of Folic Acid Supplementation.
`
`Lilly argues that, when compared with Rinaldi, “[t]he Hammond abstracts
`
`teach the POSA that folic acid pretreatment does exactly what the POSA would
`
`expect—it reduces toxicity, but it also reduces efficacy.” (Paper 33-24.) Not so.
`
`First, a POSA would not have compared efficacies between Hammond and
`
`Rinaldi because both describe phase I trials. (Ex. 1077 ¶¶27-28; see Ex. 1080 ¶¶27-
`
`28.) Lilly’s experts admit a POSA would not attempt to quantify and then compare
`
`responses from Phase I trials, because they are designed to establish a safe and
`
`effective dose, not measure or compare efficacy. (Exs. 1076-124:20-125:15; 1075-
`
`172:23-25, 178:2-179:13; 2043-274, 19; 2031-326; 1077 ¶27; 1080 ¶¶27-28.)
`
`Second, a POSA would not compare Hammond and Rinaldi, because the
`
`abstracts do not fully describe their testing protocols, and because the treatment
`
`regimens and patient populations differ. (Ex. 1077 ¶28.) Because neither the
`
`pemetrexed dosing nor schedule is disclosed, no meaningful comparison can be
`
`
`
`16
`
`

`
`
`
`made between responders versus non-responders. (Exs. 1075-179:3-18; 1077 ¶28;
`
`compare Ex. 2022 with Ex. 2035.) Additionally, Hammond and Rinaldi treated
`
`different cancers with different pretreatment regimens. (Exs. 1075-179:3-13; 1077
`
`¶28; compare Ex. 2022 with Ex. 2035.). Moreover, a POSA would not have
`
`compared Hammond’s efficacy to Rinaldi’s because Hammond’s study was not yet
`
`complete upon publication. (Exs. 2035-225a; 1077 ¶28.)
`
`Third, Hammond concluded that “folic acid supplementation appears to
`
`permit MTA dose escalation.” (Ex. 2035-225a.) Lilly concurred. (Ex. 2103-14.) A
`
`POSA would have understood this to be consistent with an improvement in the
`
`therapeutic index. (Ex. 1077 ¶28.)
`
`4.
`
`A POSA Would Have Understood that Folic Acid
`Supplementation Does Not Cause Tumor Growth.
`
`Lilly argues that “folic acid would have been expected to feed the tumor and
`
`cause it to grow,” relying on Dr. Farber’s studies from 1948. (Paper 33-2, 20.) Dr.
`
`Farber’s studies treated cancer growth—with an antifolate and a liver extract
`
`containing folic acid and B12. (Exs. 2042-787; 1064-4022; 1066-620; 1077 ¶29.) A
`
`POSA would have known that cancer growth has never been reported to be caused
`
`by folic acid supplementation in conjunction with any antifolate. (Ex. 1077 ¶29;
`
`see, e.g., Exs. 1005; 1022; 1011; 1020; 2031.)
`
`Further, Lilly’s reliance on Laohavinij to support the notion that folic acid
`
`prior to and during treatment could aid tumor progression is misplaced. (Ex. 2120 ¶
`
`
`
`17
`
`

`
`
`
`67.) Laohavinij did not warn against tumor proliferation, instead it taught that
`
`“lometrexol toxicity can be modulated by folic acid supplementation in patients,”
`
`and encouraged to use its study data to “facilitate the future development and
`
`evaluation of this class of compounds [antifolates] in the treatment of human
`
`cancer.” (Ex. 2031-330-31.) Lilly admitted this is how a POSA would understand
`
`Laohavinij. (Ex. 2107-10; Ex. 1077 ¶¶30-31.)
`
`VI. A POSA WOULD HAVE BEEN MOTIVATED TO SUPPLEMENT
`PEMETREXED WITH FOLIC ACID AND B12 WITH A
`REASONABLE EXPECTATION OF SUCCESS.
`
`Lilly contends “the POSA would have no reason to administer vitamin B12
`
`pretreatment.” (Paper 33-30.) The prior art explicitly provides a host of reasons.
`
`A.
`
`The Prior Art Taught that Pretreatment Elevated Homocysteine
`Predicts Pemetrexed Toxicity.
`
`Lilly concedes that the Niyikiza abstracts taught a POSA that pretreatment
`
`homocysteine levels ≥10µM strongly correlate with severe pemetrexed toxicity.
`
`(Paper 33-10-11; Ex. 1008-127.) (See also Exs. 2015-558a; 1014-7; 1073-71-72;
`
`1077 ¶40.)
`
`For IPR2016-240, Lilly contends Neptune’s argument fails because the
`
`instituted Ground does not include Niyikiza. (IPR2016-240, Paper 32-19.) Not so.
`
`Just as in IPR2016-237, Neptune included a section, “Overview of the State of the
`
`Art and Motivation to Combine,” which explained, “Niyikiza reported…that there
`
`was a strong correlation between elevated homocy