Trials@uspto.gov
`571.272.7822
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` Paper No. 43
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`Entered: September 11, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`OSI PHARMACEUTICALS, LLC
`and GENENTECH, INC.,
`
`Petitioner,
`
`v.
`
`ARCH DEVELOPMENT CORP. and
`DANA-FARBER CANCER INSTITUTE, INC.,
`
`Patent Owner.
`____________
`
`Case IPR2016-01034
`Patent 7,838,512 B1
`____________
`
`
`Before LORA M. GREEN, TINA E. HULSE, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`Claims 1–3, 5, and 6 Shown to Be Unpatentable
`35 U.S.C. § 318(a); 37 C.F.R. § 42.73
`
`
`
`
`

`

`IPR2016-01034
`Patent 7,838,512 B1
`
`INTRODUCTION
`
`This is a Final Written Decision in an inter partes review challenging
`the patentability of claims 1–3, 5, and 6 (collectively, “the challenged
`claims”) of U.S. Patent No. 7,838,512 B1 (Ex. 1001, “the ’512 patent”).
`We have jurisdiction under 35 U.S.C. § 6. For the reasons that follow, we
`determine that Petitioner has shown, by a preponderance of the evidence,
`that claims 1–3, 5, and 6 of the ’512 patent are unpatentable.
`
`A.
`
`Procedural History
`OSI Pharmaceuticals, LLC and Genentech, Inc., (“Petitioner”)1 filed
`a Petition requesting an inter partes review of claims 1–3, 5, and 6 of the
`’512 patent. Paper 3 (“Pet.”). Arch Development Corp. and Dana-Farber
`Cancer Center Institute, Inc. (“Patent Owner”) filed a Preliminary Response
`to the Petition. Paper 8 (“Prelim. Resp.”). Based on these submissions, we
`instituted an inter partes review of claims 1–3, 5, and 6 on the following
`grounds of unpatentability alleged in the Petition. Paper 9 (“Inst. Dec.”).
`
`
`1 Petitioner further identifies Astellas US LLC, Astellas US Holding, Inc.,
`Astellas Pharma Inc., and Roche Holdings, Inc. as real parties in interest.
`Pet. 4
`
`2
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`IPR2016-01034
`Patent 7,838,512 B1
`Ground References
`II
`Honma2, in view of the knowledge of a person of
`ordinary skill in the art (“POSA”), Honma 1992,3
`and McGahon4
`Akinaga,5 in view of the knowledge of a POSA,
`Seynaeve,6 Friedman,7 and Tam8
`
`IV
`
`Basis
`§ 103
`
`§ 103
`
`After institution of trial, Patent Owner filed a Patent Owner Response
`(Paper 16, “PO Resp.”), to which Petitioner filed a Reply (Paper 34,
`“Reply”).
`In support of its challenges, Petitioner relies on the Declaration of
`Alan Eastman, Ph.D. (Ex. 1002). Patent Owner relies on the Declaration of
`first named inventor, Donald W. Kufe, M.D. (Ex. 2011).
`
`
`2 Yoshio Honma et al., Induction of Erythroid Differentiation of K562
`Human Leukemic Cells by Herbimycin A, an Inhibitor of Tyrosine Kinase
`Activity, 49 CANCER RES. 331–34 (1989). Ex. 1003.
`3 Yoshio Honma et al., Herbimycin A, an Inhibitor of Tyrosine Kinase,
`Prolongs Survival of Mice Inoculated with Myeloid Leukemia C1 Cells with
`High Expression of v-abl Tyrosine Kinase, 52 CANCER RES. 4017–20 (1992).
`Ex. 1022.
`4 Anne McGahon et al., BCR-ABL Maintains Resistance of Chronic
`Myelogenous Leukemia Cells to Apoptotic Cell Death, 83 BLOOD 1179–87
`(1994). Ex. 1029.
`5 Shiro Akinaga et al., Enhancement of Antitumor Activity of Mitomycin C In
`Vitro and In Vivo by UNC-01, a Selective Inhibitor of Protein Kinase C, 32
`CANCER CHEMOTHERAPY AND PHARMACOLOGY 183–89 (1993). Ex. 1004.
`6 Caroline M. Seynaeve et al., Cell Cycle Arrest and Growth Inhibition by
`the Protein Kinase Antagonist UCN-01 in Human Breast Carcinoma Cells,
`53 CANCER RES. 2081–86 (1993). Ex. 1014.
`7 BethAnn Friedman et al., Regulation of the Epidermal Growth Factor
`Receptor by Growth-Modulating Agents: Effects of Staurosporine, a Protein
`Kinase Inhibitor, 50 CANCER RES. 533–38 (1990). Ex. 1031.
`8 Sun W. Tam and Robert Schlegel, Staurosporine Overrides Checkpoints
`for Mitotic Onset in BHK Cells, 3 CELL GROWTH & DIFFERENTIATION 811–
`17 (1992). Ex. 1012.
`
`3
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`IPR2016-01034
`Patent 7,838,512 B1
`Patent Owner filed a Motion to Exclude. Paper 37. Petitioner filed an
`Opposition (Paper 38), and Patent Owner filed a Reply (Paper 40). An oral
`hearing was held on June 20, 2017. A transcript of the hearing has been
`entered into the record. Paper 42 (“Tr.”).
`
`B.
`
`Related Proceedings
`The ’512 Patent is at issue in Arch Development Corp. v. Genentech,
`Inc., No. 1:15-cv-6597 (N.D. Ill.), which is currently stayed. Pet. 4;
`Paper 6; Paper 20, 1.
`
`The ’512 Patent and Relevant Background
`C.
`The ’512 patent is directed to the use of DNA damaging agents in
`
`combination with tyrosine kinase inhibitors (TKIs) to enhance cancer cell
`death. See generally Ex. 1001, Title, Abstract, 4:12–40, 5:28–38.
`According to Petitioner’s expert, Dr. Eastman, tyrosine kinases are enzymes
`that catalyze the phosphorylation of a substrate protein by attaching a
`phosphoryl group to a tyrosine amino acid residue on the substrate.
`Ex. 1002 ¶ 31. Tyrosine kinases were known to be involved in cell signaling
`pathways that control cell growth, differentiation, and cell death. Pet. 7
`(citing Ex. 1002 ¶¶ 31–38). Elevated tyrosine kinase activity has also been
`associated with cancers because it can promote abnormal cell proliferation.
`Id. (citing Ex. 1002 ¶ 37).
`According to the Specification, the treatment of cancer cells with
`ionizing radiation or chemotherapeutic agents such as the DNA alkylating
`agent, mitomycin C, results in DNA damage. Ex. 1001, 1:32–35, 3:51–65,
`4:41–54. “The cellular response to DNA damage includes activation of
`DNA repair, cell cycle arrest, and lethality (Hall, 1988).” Id. at 1:32–35. As
`explained by Petitioner:
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`Patent 7,838,512 B1
`By 1994, it was well known that the cell cycle involves
`progression through four phases: G1 (growth phase); S (copying
`of DNA); G2 (rapid growth in preparation for mitosis/cell
`division); M (mitosis/cell division). (Eastman Decl. ¶¶40-41
`(Ex. 1002).) The cell cycle can arrest in G1, S and G2 to allow
`cells with damaged DNA to repair their DNA. (Id. ¶42.) In part,
`these “checkpoints” are regulated by tyrosine kinases. (Id. ¶44.)
`Cells with damaged DNA that advance to the M phase, however,
`cannot properly divide and instead die. (Id.)
`Pet. 8. Consistent with this summary, the Specification points to prior art
`showing that environmental conditions following exposure to DNA
`damaging agents can influence cell survival. Ex. 1001, 1:38–55, 2:50–63.
`For example,
`cell survival can be increased if the cells are arrested in the cell
`cycle for a protracted period of time following radiation
`exposure, allowing repair of DNA damage. (Hall, 1988). Thus
`[potentially lethal damage] is repaired and the fraction of cells
`surviving a given dose of x-rays is increased if . . . cells do not
`have to undergo mitosis while their chromosomes are damaged.”
`Id. at 2:56–63. The Specification further states that “available evidence
`suggests that G2 arrest is necessary for repair of DNA damage before entry
`into mitosis.” Id. at 1:37–44; see also id. at 3:43–46. In particular, “[c]ells
`that are irradiated or treated with DNA damaging agents halt in the cell cycle
`at G2, so that an inventory of chromosome damage can be taken and repair
`initiated and completed before mitosis is initiated.” Id. at 3:3–7. “By
`preventing delays in G2, cells will enter mitosis before the DNA is repaired
`and therefore the daughter cells will likely die.” Id. at 3:46–48.
`Recognizing that DNA damaging agents result in the activation of
`p56/p53lyn tyrosine kinase, a protein implicated in cell cycle control,9 the
`
`9 Example 1 of the Specification discloses that the DNA damaging agent
`mitomycin C activates (via autophosphorylation) the tyrosine kinase
`
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`Patent 7,838,512 B1
`Specification proposes that tyrosine kinase inhibitors, such as genistein or
`herbimycin A, could force damaged cells to override the G2 arrest
`checkpoint and enter mitosis before completing DNA repairs, and thereby
`enhance cell killing. Id. at 3:38–42, 5:28–32, 19:10–27. Accordingly, the
`’512 patent teaches “contact[ing] the cell with a DNA damaging agent and a
`tyrosine kinase inhibitor in a combined amount effective to kill the cell,” i.e.,
`such that “cell death is induced.” Id. at 3:66–4:5.
`
`D. Challenged Claims
`Claims 1–3, 5, and 6 are in independent format. Claim 1 is illustrative
`(paragraphing and footnote added):
`1. A method of improving chemotherapeutic intervention in a
`patient, the method comprising:
`(a) administering a chemotherapeutic10 DNA damaging agent to
`the patient;
`(b) administering a therapeutically effective amount of a low
`molecular weight tyrosine kinase inhibitor to the patient,
`wherein the low molecular weight inhibitor binds intracellularly
`to inhibit the activity of more than one tyrosine kinase protein,
`and
`wherein the agent and the inhibitor act in combination by
`effecting a series of intracellular events to enhance cell death,
`thereby improving chemotherapeutic intervention.
`
`
`p56/p53lyn, which, in turn, associates with and phosphorylates the tyrosine
`15 residue (Tyr 15) of the p34cd2 polypeptide chain. See generally id. at 9:4–
`14:5. The cellular protein p34cd2 is a serine/threonine protein kinase that
`controls entry of cells into mitosis. Id. at 1:45–55, 13:21–22.
`Phosphorylation of p34cd2 at Tyr 15 inhibits the entry of cells into mitosis
`and, thus, promotes G2 arrest. Id. at 13:27–32.
`10 See Ex. 1001, Certificate of Correction dated November 23, 2010 (adding
`the modifier “chemotherapeutic” to all claims).
`
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`Patent 7,838,512 B1
`Claims 2, 3, and 5 further specify that the tyrosine kinase inhibitor
`intracellularly inhibits phosphorylation of downstream effector molecules
`(claims 2, 3, and 5), “inhibit[s] the activity of [epidermal growth factor
`receptor] EGFR” (claim 3), and acts in combination with the DNA
`damaging agent “to enhance apoptosis” (claim 5).
`In contrast to claims 1–3 and 5, claim 6 does not recite the
`enhancement of either cell death or apoptosis, but more broadly requires that
`the DNA damaging agent and the low molecular weight tyrosine kinase
`inhibitor “act in combination to alter the cell’s response to the agent.”
`
`
`
`DISCUSSION
`
`A.
`
`Principles of Law
`Petitioner bears the burden of proving unpatentability of the
`challenged claims, and the burden of persuasion never shifts to Patent
`Owner. Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375,
`1378 (Fed. Cir. 2015). To prevail, Petitioner must establish the facts
`supporting its challenge by a preponderance of the evidence. 35 U.S.C.
`§ 316(e); 37 C.F.R. § 42.1(d).
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which that
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations including (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and (4) objective evidence of
`
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`Patent 7,838,512 B1
`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). A
`decision on the ground of obviousness must include “articulated reasoning
`with some rational underpinning to support the legal conclusion of
`obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). The
`obviousness analysis “should be made explicit” and it “can be important to
`identify a reason that would have prompted a person of ordinary skill in the
`relevant field to combine the elements in the way the claimed new invention
`does.” KSR, 550 U.S. at 418.
`
`B.
`
`Person of Ordinary Skill in the Art.
`The parties agree that a person of ordinary skill in the art as of the
`effective filing date of the ’512 patent, “would have held an M.D. or Ph.D.
`in molecular biology, biochemistry, pharmacology, or a related field and
`have had several years of experience working in cancer research.” Pet. 17
`(citing Ex. 1002 ¶ 19); PO Resp. 4. This level of ordinary skill is consistent
`with the prior art asserted in the Petition. See Chore-Time Equip., Inc. v.
`Cumberland Corp., 713 F.2d 774, 779 n.2 (Fed. Cir. 1983) (indicating that
`the prior art itself may reflect the appropriate level of ordinary skill in the
`art). Accordingly, we adopt the parties’ definition for the purpose of this
`Decision.
`
`C.
`
`Claim Construction
`Petitioner asserts, and Patent Owner does not contest, that the ’512
`patent expired as of April 8, 2015. Pet. 17; Prelim. Resp. 8–9. Although we
`accord claims of an unexpired patent their broadest reasonable interpretation
`in light of the specification, our review of claims of an expired patent is
`similar to that of a district court. See In re Rambus, Inc., 694 F.3d 42, 46
`(Fed. Cir. 2013). Specifically, claim terms are given their ordinary and
`
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`Patent 7,838,512 B1
`customary meaning, as would be understood by a person of ordinary skill in
`the art at the time of the invention in light of the language of the claims, the
`specification, and the prosecution history of record. Phillips v. AWH Corp.,
`415 F.3d 1303, 1313–17 (Fed. Cir. 2005) (en banc).
`i. Administering a Therapeutically Effective Amount of a Low
`Molecular Weight Tyrosine Kinase Inhibitor
`Petitioner proposes that the term “therapeutically effective amount,”
`as used in the claim phrase “administering a therapeutically effective amount
`of a low molecular weight tyrosine kinase inhibitor,” be accorded its plain
`and ordinary meaning of “an amount that would be sufficient to have a
`desired therapeutic effect.” Pet. 19–21 (citing, e.g., Ex. 1002 ¶¶ 79–80).
`Patent Owner admits that Petitioners’ proposed definition of the plain and
`ordinary meaning of the term “may be correct” (Prelim. Resp. 7), but
`contends that the Board should instead apply an express definition of
`“therapeutically effective amount” set forth in the Specification (PO Resp.
`5–8).
`Patent Owner points to column 4, lines 16 to 19 of the Specification,
`which defines a “therapeutically effective amount” as “an amount of a DNA
`damaging agent and tyrosine kinase inhibitor that, when administered to an
`animal in combination, is effective to kill cells within the animal.” Id. at 5.
`The challenged claims, however, use “therapeutically effective amount” in a
`context different from the express definition set forth in the Specification.
`As noted by Petitioner, the definition at column 4, lines 16 to 19 of the
`Specification refers to “a combined amount of the DNA damaging agent and
`the tyrosine kinase inhibitor, while the claims require that only the tyrosine
`kinase inhibitor be administered in a ‘therapeutically effective amount.’”
`See Pet. 20.
`
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`IPR2016-01034
`Patent 7,838,512 B1
`In response, Patent Owner points to the Specification’s teaching that
`“[t]herapeutically effective combinations are thus generally combined
`amounts of DNA damaging agents and tyrosine kinase inhibitors that
`function to kill more cells than either element alone and that reduce the
`tumor burden” (Ex. 1001, 4:21–25), which, according to Patent Owner,
`indicates that “the inventors of the ’512 patent expressly contemplated that
`both the claimed tyrosine kinase inhibitor and chemotherapeutic damaging
`agent are each capable of killing cells, i.e., each may be administered in a
`‘therapeutically effective amount.’” PO Resp. 5. We do not find this
`argument persuasive.
`First, the term “therapeutically effective combinations,” as defined in
`the cited passage, is not found in any of the challenged claims. Second, that
`the tyrosine kinase inhibitor and the chemotherapeutic DNA damaging agent
`are each capable of killing cells is not dispositive as to whether the
`challenged claims require them to be present in individually cytotoxic
`amounts. Similarly, that the combination of agents “function to kill more
`cells than either element alone” does not indicate that either agent is
`necessarily present in an individually cytotoxic amount, particularly in light
`of the Specification’s teaching that the combination may have synergistic
`effects on cell death. See Ex. 1001, 4:5–10; see also id. at 4:42–15 (“The
`term ‘in a combined amount effective to kill the cell’ means that the amount
`of the DNA damaging agent and inhibitor are sufficient so that, when
`combined within the cell, cell death is induced.”). Thus, the passage relied
`on by Patent Owner (column 4, lines 21–25) encompasses an amount of
`tyrosine kinase inhibitor that is insufficient to kill cells alone, yet enhances
`cell killing in combination with a chemotherapeutic damaging agent.
`
`10
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`Patent 7,838,512 B1
`Patent Owner also contends that its proposed definition of “a
`therapeutically effective amount” is “consistent with the stated aim of the
`claimed invention, i.e., the ‘synergistic cancer cell killing effects.’” PO
`Resp. 6. We, however, agree with Petitioner, “[E]ven if one of the stated
`purposes of the invention is as Patent Owners contend . . . , this cannot
`overcome the ordinary meaning of the term as used in the claims.” Reply 6
`(citing E-Pass Techs., Inc. v. 3Com Corp., 343 F.3d 1364, 1370 (Fed. Cir.
`2003) (“An invention may possess a number of advantages or purposes, and
`there is no requirement that every claim directed to that invention be limited
`to encompass all of them.”)).
`Patent Owner further argues that we should adopt its construction to
`maintain internal consistency among the claims. See PO Resp. 7–8. As we
`understand the argument, Patent Owner contends that each of claims 1–3
`and 5 require “cell death” or apoptosis (defined as “a series of intracellular
`events that lead to cell death”) such that “the express ‘desired therapeutic
`effect’ is cell death.” Id. at 8. We are not persuaded that internal
`consistency informs the meaning of “administering a therapeutically
`effective amount of a low molecular weight tyrosine kinase inhibitor”
`because, although claims 1–3 and 5 require that the chemotherapeutic agent
`and the tyrosine kinase inhibitor “act in combination to enhance cell death
`[or apoptosis],” claim 6 recites that “the agent and the inhibitor act in
`combination to alter the cell’s response to the agent.” Emphasis added.
`Accordingly, the “desired therapeutic effect” in claim 6 is potentially
`broader than that of claims 1–3 and 5.
`Where the Specification reveals a special definition for a claim term,
`the inventors’ lexicography governs. Phillips, 415 F.3d at 1316. Any such
`special definition must be set forth in the specification with reasonable
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`Patent 7,838,512 B1
`clarity, deliberateness, and precision. See In re Paulsen, 30 F.3d 1475, 1480
`(Fed. Cir. 1994). On the present record, we are not convinced that the
`inventors’ express definition of “therapeutically effective amount” applies to
`the tyrosine kinase inhibitor as set forth in the challenged claims, as opposed
`to the combination of inhibitor and DNA damaging agent referenced at
`column 4, lines 16 to 19 of the Specification. Accordingly, we construe
`“therapeutically effective amount” as used in the claim phrase,
`“administering a therapeutically effective amount of a low molecular weight
`tyrosine kinase inhibitor” according to its plain and ordinary meaning of “an
`amount that would be sufficient to have a desired therapeutic effect.”
`ii. Cell Death and Apoptosis
`Claims 1–3 of the ’512 Patent recite that “the [chemotherapeutic]
`agent and the [tyrosine kinase] inhibitor act in combination to enhance cell
`death”; in claim 5, the two components “act in combination to enhance
`apoptosis.” Noting that the ’512 patent expressly provides that “[t]he terms,
`‘killing’, ‘programmed cell death’ and ‘apoptosis’ are used interchangeably”
`to describe “a series of intracellular events that lead to target cell death”
`(Ex. 1001, 5:35–38), we previously agreed with the parties’ proposed
`construction of “apoptosis” as meaning “a series of intracellular events that
`lead to target cell death.” See Dec. 11.11 In light of the same passage in the
`Specification, we likewise construe “cell death” as also meaning “a series of
`intracellular events that lead to target cell death.” It is our understanding
`
`
`11 While we recognize Patent Owner’s argument that “not all cell death is
`apoptotic in nature” (PO Resp. 14), we rely here on the express definition in
`the Specification. Moreover, for purposes of this Decision, we need not
`distinguish apoptosis from cell death generally, as the result would be the
`same.
`
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`that the parties do not oppose this construction. See Tr. 13:9–17, 19:5–12,
`22:18–20, 51:4–52:1.
`The parties vigorously disagree, however, whether cell death and
`apoptosis should be understood as the proximal cause of a low molecular
`weight tyrosine kinase inhibitor acting in combination with a
`chemotherapeutic agent, or whether these terms further include the induction
`of differentiation processes, wherein cancer cells are rendered “mortal and
`naturally die after a limited lifespan.” See, e.g., Tr. 26:20–27:4; Pet. 31; PO
`Resp. 12–14; Reply 7–8.
`Petitioner contends that the challenged claims “have no immediacy
`limitation,” such that the terms “enhanc[ing] cell death” and “enhancing
`apoptosis” encompass inducing an otherwise immortal cancer cell to
`differentiate and, eventually, die. Reply 7; Pet. 29; see Ex. 1002 ¶¶ 125–
`128. According to Petitioner, “[d]ifferentiation is the process by which
`precursor cells undergo a series of changes—including intracellular events—
`to become a more specialized cell. When cells reach the point that they can
`differentiate no more, they are terminally differentiated, in which state they
`live out their days and die.” Pet. 29 (citations and footnote omitted).
`Patent Owner argues that the ’512 Patent is directed to “enhancing
`cancer cell death,” which does not include “natural cell death,” i.e., “waiting
`for . . . differentiated cells to die naturally.” PO Resp. 12–13 (citing
`Ex. 1001, Abstract). According to Patent Owner, “[n]ot a single
`embodiment disclosed in the ’512 patent results in . . . cell differentiation”
`(PO Resp. 6), and moreover, “the Specification of the ‘512 patent uses the
`terms “cell death” or “cell killing” 30 times but only once uses the word
`“differentiation” (Tr. 42:15–43:5; see Ex. 1001, 2:26–27 (“Protein tyrosine
`
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`phosphorylation contributes to the regulation of cell growth and
`differentiation.”)).
`Consistent with Patent Owner’s analysis, nowhere does the
`Specification suggest that the inventors contemplated the induction of a
`differentiation pathway. See Ex. 2011 ¶ 4. To the contrary, and as discussed
`above in Section 1(C), the Specification focuses on the use of DNA
`damaging agents in combination with tyrosine kinase inhibitors to force
`damaged cells to override the G2 arrest checkpoint and enter mitosis before
`completing DNA repairs. See, e.g., Ex. 1001, 3:46–48 (“By preventing
`delays in G2, cells will enter mitosis before the DNA is repaired and
`therefore the daughter cells will likely die.”). Accordingly, we agree with
`Patent Owner that, in light of the Specification, one of ordinary skill in the
`art would not understand the terms “enhanc[ing] cell death” and “enhancing
`apoptosis” to encompass the a process by which cancer cells are
`differentiated, become mortal, and, subsequently, “live out their days and
`die.” See Pet. 29; Ex. 1002, ¶ 127.
`In reaching this determination, we recognize Petitioner’s argument
`that the challenged claims include no mechanism of action. Reply 8. We
`disagree with that assessment to the extent the plain language of the claims
`requires that the chemotherapeutic agent and the low molecular weight
`tyrosine kinase inhibitor generally “act in combination by effecting a series
`of intracellular events.” Although Petitioner may be correct that nothing in
`the claims requires that “‘enhance[d] cell death’ must be due to the TKI
`‘acting as a tyrosine kinase inhibitor’” (see id.), our reviewing court instructs
`that “we strive to capture the scope of the actual invention, rather than . . .
`allow the claim language to become divorced from what the specification
`conveys is the invention.” Retractable Techs., Inc. v. Becton, Dickinson &
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`Co., 653 F.3d 1296, 1305 (Fed. Cir. 2011) (citing Phillips, 415 F.3d at
`1323–34). In the present case, we do not find that the Specification conveys
`to one of ordinary skill in the art that “enhanc[ing] cell death” or “enhancing
`apoptosis” encompasses a process involving differentiation and eventual cell
`death.
`We also find persuasive the following passage from the prosecution
`history of the ’512 Patent in which Applicants made clear that inducing
`differentiation is not the same as cell killing:
`Watanabe et al. appears to be concerned only with showing that
`inhibitors of tyrosine kinases, such as genistein, are able to
`induce, in combination with mitomycin C, the differentiation of
`mouse erythroleukemia cells. A skilled artisan, reading
`Watanabe, would merely conclude that such treatment is useful
`only for forcing cells into a terminally differentiated state. There
`is no teaching or suggestion that such a combination would be
`useful for increasing cell killing.
`Ex. 1016, 6; see also id. at 8 (“[U]nlike the results shown in Watanabe
`wherein a protein tyrosine kinase inhibitor induced differentiation, the
`instant invention shows increased cell killing in combination with DNA
`damaging agents.”). Applicants’ assertion was repeatedly discussed during
`this proceeding. See PO Resp. 3; Pet. 29 n.3; Reply 6 n.4; Tr. 12:2–13:19.
`Petitioner takes the position that 1) irrespective of the Applicants’
`statements during prosecution, “the specification is the controlling
`interpretation”; moreover, 2) the file history is less relevant because “the
`word ‘killing’ is not actually used in any of the challenged claims.”
`Tr. 13:3–16. With respect to Petitioner’s first argument, there is no dispute
`that apoptosis and cell death refer to “a series of intracellular events that lead
`to target cell death,” as set forth in column 5, lines 35–38 of the
`Specification. To the extent that definition is “controlling,” it provides only
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`the general outlines of the claim term. In order to determine whether the
`expressly recited definition encompasses cellular differentiation processes
`that render cancer cells mortal, as Petitioner contends, we consider all of the
`intrinsic evidence, including the prosecution history. See Phillips, 415 F.3d
`at 1317.
`With respect to Petitioner’s argument that “the word ‘killing’ is not
`actually used in any of the challenged claims,” we note that the Specification
`uses interchangeably the terms “killing,” “programmed cell death,” and
`“apoptosis.” The following passage of the Specification expressly sets forth
`this equivalency:
`To achieve cell killing, both agents are delivered to a cell in a
`combined amount effective to kill the cell, i.e., to induce
`programmed cell death or apoptosis. The terms, “killing”,
`“programmed
`cell death”
`and
`“apoptosis”
`are used
`interchangeably in the present text to describe a series of
`intracellular events that lead to target cell death.
`Ex. 1001, 5:32–38. Read in the context of the Specification, we conclude
`that one of ordinary skill in the art would understand “cell killing” in the
`prosecution history as synonymous with the claim terms “cell death” and
`“apoptosis.” Petitioner presents no evidence to the contrary. Thus, to the
`extent the Specification provides a controlling, albeit general, definition of
`the claim terms, it does not convey to one of ordinary skill in the art that
`“cell death” or “apoptosis” encompasses a process involving differentiation
`and eventual cell death.
`iii. Non-limiting Elements
`The parties agree that the preamble of each challenged claim, as well
`as the “thereby” clause of claims 1–3 (“thereby improving chemotherapeutic
`intervention”), are non-limiting. Pet. 17–18, 21–22; Prelim. Resp. 5, 8;
`Ex. 2001, 15. On the present record, we adopt the parties’ proposed
`
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`Patent 7,838,512 B1
`interpretation of these claim elements. See Vivid Techs., Inc. v. Am. Sci. &
`Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (instructing that only those
`terms that are in controversy need be construed, and only to the extent
`necessary to resolve the controversy).
`
`D. Ground II: Obviousness over Honma, in view of the knowledge of a
`POSA, Honma 1992, and McGahon
`Petitioner asserts that claims 1–3, 5, and 6 would have been obvious
`over the combination of Honma, in view of the knowledge of a person of
`ordinary skill in the art, Honma 1992, and McGahon. See Pet. 2, 22–41;
`Reply 10–17. Having considered the full trial record, we determine that
`Petitioner has not shown by a preponderance of evidence that claims 1–3
`and 5 are unpatentable as obvious over the cited references, but we
`determine that Petitioner has met its burden with respect to claim 6.
`Petitioner addresses the individual limitations of the challenged claims
`at length, including in a detailed claim chart. See Pet. 2, 22–41; Reply 10–
`17. We begin with an overview of the asserted references.
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`Patent 7,838,512 B1
`i. Overview of Asserted References
`1. Honma (Ex. 1003)
`Honma teaches that herbimycin A, “a selective inhibitor of
`intracellular tyrosine kinase,” induces erythroid differentiation of K562
`human leukemic cells in a dose-dependent manner, as measured by
`benzidine staining. Ex. 1003, Abstract, 331–332. Herbimycin A was also
`found “to inhibit the growth of K562 cells at concentrations higher than
`6 x 10-8 M, [with] 50% inhibition of growth occurring at 9.5 x 10-8 M” and
`65% inhibition of growth at 1 x 10-7 M. Id. at 332, Fig. 1. According to
`Honma, “the effective concentration [of herbimycin A] was noncytotoxic.”
`Id. at 333. In investigating the mechanism for these effects, Honma
`determined that “[w]hen K562 cells were labeled with 32Pi in the presence of
`5 x 10-8 M herbimycin A, the level of all tyrosine-phosphorylated proteins
`was greatly reduced,” including a reduction of approximately 55% of the
`tyrosine kinase p210c-abl. Id. at 333.
`Honma also examined the effect of herbimycin A in combination with
`other inducers of erythroid differentiation in K562 cells, including the DNA
`damaging agent Adriamycin. Id. at 333. Honma concludes that “a low
`concentration of herbimycin A increases inhibition of cell growth of K562
`cells by Adriamycin,” and the combination has “additive or more than
`additive effects on [erythroid differentiation].” Id.; see id. at Figs. 4, 5.
`Honma concludes that “herbimycin A and the other differentiation inducers
`have additive or more than additive effects on induction of benzidine-
`positive cells in suboptimal concentrations (Fig. 4).” Id.
`In light of these results, Honma suggests that “tyrosine kinase activity
`may be critically involved in growth control mechanism of K562 cells,
`possibly as a result of induction of terminal differentiation.” Id.
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`“Herbimycin A and its derivatives might be useful as cancer
`chemotherapeutic agents against some types of leukemia oncogenesis where
`tyrosine kinase activities are implicated.” Id. And, “[s]ince herbimycin A
`can have an additive or more than additive effect with some well-known
`antitumor agents such as Adriamycin . . . [,] these combinations may be
`useful for the treatment of some types of leukemia.” Id.
`2. Honma 1992 (Ex. 1022)
`According to Honma 1992:
`Chronic myelogenous leukemia and some cases of acute
`lymphocytic leukemia are characterized by the Philadelphia
`t(9;22)(q32;q11) chromosome translocation, in which the 5’
`sequences of the bcr gene bec