Case 1:16-cv-01221-LPS Document 58-1 Filed 06/13/18 Page 1 of 5 PageID #: 535
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`Exhibit A
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`Case 1:16-cv-01221-LPS Document 58-1 Filed 06/13/18 Page 2 of 5 PageID #: 536
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`BRISTOL-MYERS SQUIBB CO.,
`E. R. SQUIBB & SONS, L.L.C.,
`ONO PHARMACEUTICAL CO., LTD., and
`TASUKU HONJO,
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`Plaintiffs,
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`v.
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`MERCK & CO., INC. and
`MERCK SHARP & DOHME CORP.,
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`Defendants.
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`Civil Action No. 14-1131-GMS
`Civil Action No. 15-560-GMS
`Civil Action No. 15-572-GMS
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`ORDER CONSTRUING THE TERMS OF U.S. PATENT NOs. 8,728,474, 9,067,999 &
`9,073,994
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`After having considered the submissions of the parties and hearing oral argument on the
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`matter, IT IS HEREBY ORDERED, ADJUDGED, and DECREED that, as used in the asserted
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`claims of U.S. Patent Nos. 8,728,474 ("the '474 patent"), U.S. Patent No. 9,067,999 ("the '999
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`patent"), and U.S. Patent No. 9,073,994 ("the '994 patent"):
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`1.
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`The terms "[for the treatment of/ of treating] a [tumor/ melanoma/ lung cancer/
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`metastatic melanoma]" and "treats the [lung cancer/ metastatic melanoma]" are construed
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`to have their plain and ordinary meaning. 1
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`1 The court rejects the proposed constructions of"to reduce proliferation or metastasis of cancer cells in the
`[tumor I melanoma I lung cancer I melanoma and melanoma metastases]" and "reduces proliferation or metastasis of
`cancer cells in the [lung cancer] I [melanoma and melanoma metastases]" submitted by the defendants Merck & Co.,
`Inc. and Merck Sharp & Dahme Corp. (collectively "Merck"). The parties agree that the treatment involves, as the
`claims state, administering an "anti-PD-I antibody." The parties' dispute focuses primarily on whether a limitation
`should be incorporated in the terms that indicates the goal of the treatment. In the patents at issue, the claims
`explain what the method of treatment consists of, yet Merck would also have the court construe treatment to require
`the attempted result based upon the goal identified in the preamble: suppression of metastasis or proliferation of
`cancer cells. (D.I. 82 at 10.) The court declines to limit the terms in this way. While Merck claims that it is unclear
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`Case 1:16-cv-01221-LPS Document 58-1 Filed 06/13/18 Page 3 of 5 PageID #: 537
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`2.
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`The term "pharmaceutically effective amount" is construed to mean an "amount
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`sufficient to reduce proliferation or metastasis of cancer cells in the [tumor I melanoma I
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`metastatic melanoma and melanoma metastases]."2
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`which kind of anti-PD-I antibodies are claimed, the court declines to define these agents entirely based upon their
`intended effect on the patient. (See DJ. 121 at 2.)
`Merck also argues that the "wherein" clauses are limiting because they require a particular effect on the
`disorder specified in the claim. (DJ. 82 at 11.) The plaintiffs Bristol-Myers Squibb Co., E. R. Squibb & Sons,
`L.L.C., Ono Pharmaceutical Co., Ltd. and Tasuku Honjo (collectively "Bristol-Myers") point out that Merck's
`proposed construction is redundant because claims 12 and 13 of the '4 7 4 patent are dependent claims that recite
`"wherein tumor proliferation is suppressed" and "wherein tumor metastasis is suppressed." (DJ. 84 at 8.) Merck
`responds that while claims 12 and 13 require proliferation or metastasis to be suppressed, its proposed construction
`simply requires a reduction in proliferation or metastasis. (DJ. 121 at 5.) In support of its construction, Merck
`relies on the case Griffin v. Bertina. 285 F.3d 1029 (Fed. Cir. 2002). In that case, the court was asked to address a
`patent that claimed a test to diagnose thrombosis by "assaying for the presence of a point mutation ... " Id. at 1033.
`The court determined that without explaining the objective of the test, the list of steps in isolation had no meaning.
`While that case did feature "wherein" clauses like the patents at issue, the court is persuaded that in this case there
`will not be confusion about the reason for administering anti-PD-1 antibodies.
`The dispute presently before the court is more like that in Novartis Pharm. Corp. v. Actavis, Inc., 2013 WL
`6142747 (D. Del. Nov. 21, 2013). There, the court determined that treatment means to try to cause a therapeutic
`improvement, without necessarily having assurance of what the outcome will be. Id at * 11. Similarly, here the
`court declines to adopt a construction that conflates treatment and efficacy. According to Merck, "The claim
`language expressly identifies what is being treated in each of the claimed methods: a particular manifestation of
`cancer." (DJ. 82 at 9.) However, as Bristol-Myers points out, "The term 'effective' is used in the claims of the
`'474 and '994 Patents, yet the patentees chose not to use the word 'effective' to describe the 'treatment' terms,
`indicating a clear intent not to import an efficacy limitation." (D.I. 84 at 7-8) (citing the '474 Patent at Cls. 1, 8;
`'994 Patent at Cl. 1). While treatment implies the goal of achieving results, it does not require a successful outcome.
`See Schering Corp. v. Mylan Pharm., Inc., No. 09-6383, 2011 U.S. Dist. LEXIS 63825, at *16 (D.N.J. June 15,
`2011). It goes without saying that treatment is not always effective, "especially for a disease as dangerous and as
`complicated as cancer." (See DJ. 122 at 2.)
`Finally, Bristol-Myers proposes a more specific construction of the ordinary meaning of the term treatment:
`"attempting to cause therapeutic improvement." The court finds this additional clarification unnecessary and
`concludes that in this case, plain and ordinary meaning suffices. See Thorner v. Sony Computer Entm 't Am. LLC,
`669 F.3d 1362, 1367 (Fed. Cir. 2012) (observing that the court construes claim terms to have their plain and
`ordinary meaning "unless the patentee explicitly redefines the term").
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`2 The court adopts Merck's proposed construction of an "amount sufficient to reduce proliferation or
`metastasis of cancer cells in the [tumor I melanoma I metastatic melanoma and melanoma metastases]." Bristol(cid:173)
`Myers' proposed construction is "An amount sufficient to exert the pharmacological action of the drug." However,
`as Merck asserts, "Without a construction of the 'treat' terms, one does not know what a pharmacological action is."
`(DJ. 121 at 8.)
`The customary usage of "effective amount" is not a term of art that the court needs assistance in
`understanding. See Abbott Labs. v. Baxter Pharm. Products, Inc., 334 F.3d 1274, 1277-78 (Fed. Cir. 2003) (holding
`that the customary usage of"effective amount" was an amount sufficient to achieve the claimed effect). However,
`here the parties dispute what the claimed effect is. Thus, reliance on 'plain and ordinary meaning' would be
`inadequate because it would not resolve the parties' dispute." 02 Micro Int'/ Ltd. v. Beyond Innovation Tech.
`Co., 521F.3d1351, 1361 (Fed. Cir. 2008). Bristol-Myers argues that "Defendants' construction not only
`improperly seeks to import an effectiveness limitation into the claims, it improperly seeks to impose a specific
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`Case 1:16-cv-01221-LPS Document 58-1 Filed 06/13/18 Page 4 of 5 PageID #: 538
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`3.
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`4.
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`The term "binds to ... PD-1" is construed to mean "interacts with . . . PD-1. "3
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`The term "tumor proliferation" is construed to mean "increase in the number of
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`tumor cells."4
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`restriction on how effectiveness is demonstrated." (D.I. 84 at 8.) Bristol-Myers insists that there are additional
`ways of measuring efficacy based on the specification including "life prolongation of an individual," "suppression
`of proliferation, invasion and metastasis," "tumor growth and survival rate." (Id. at 8-9.) Merck responds that what
`Bristol-Myers claims are measurements of efficacy are in fact downstream benefits from reducing the proliferation
`or metastasis of cancer, the factor that actually determines efficacy. (D.I. 124 at 7.) Merck also argues that even if
`there are multiple ways of measuring efficacy, this weighs against leaving the term undefined. (Id.)
`Bristol-Myers acknowledges that when the claim language is read in view of the specification, there can be
`no doubt that the effective amount is the amount sufficient to achieve "the pharmacologic action of the drug-the
`inhibition of the inhibitory signal of PD-1." (D.I. 122 at 6.) The claimed effect of this action is to reduce
`proliferation or metastasis of cancer cells. '474 Patent at col. 2:58-67, 20:51-55; (D.I. 121 at 9). The court finds that
`Merck's proposed construction is consistent with the claims and the specification. Adopting this construction will
`ensure that there is no confusion about the meaning of the claim term.
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`3 The parties dispute whether "binds to ... PD-1" requires a direct or indirect interaction with PD-1. The
`court finds that Merck's proposed construction, "interacts with ... PD-1;'' sufficiently describes the binding action
`and the "direct" modifier is not necessary. Bristol-Myers asserts that" To say an antibody binds indirectly is the
`same as saying an antibody does not bind at all." (D.I. I84 at I4.) Chemical bonds must form directly with amino
`acids. (Id. at 9.) Merck responds that the specification uses the word "interaction" to describe the binding of "PD- I
`to PD-Ll" and "PD-I to PD-L2." (D.I. 82 at 14.) "Plaintiffs' proposed construction would improperly limit the
`scope of the claims to one of the two types of binding interactions disclosed in the specification." (Id.) Bristol(cid:173)
`Myers responds that the citations that Merck provides do not describe direct and indirect binding, but instead
`inhibition. (D.I. 122 at 10.) Bristol-Myers also cites to the testimony of Dr. von Andrian which describes how
`binding requires the molecules to be touching. (D.I. 122 at 8.) According to Bristol-Myers, direct interaction is
`evident from the patents' reference to selectivity and specificity.
`Ultimately, the court is not persuaded that the modifier "directly" accurately captures what it means for
`molecules to touch. Nor is the court persuaded that "directly" conveys that an anti-PD-1 antibody will specifically
`recognize and selectively bind to PD-I and not other proteins, as Bristol-Myers suggests. (Id.) The court is
`convinced by the fact that, as Merck points out, the prosecution history uses the term interaction without modifiers
`to describe how the claimed inhibition occurs. (D.I. 82 at 14.) Thus, the court concludes that the intrinsic evidence
`does not clearly support the importation of "directly" as an additional limitation.
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`4 The parties dispute whether "tumor proliferation" is an "increase in the number of tumor cells" as Bristol(cid:173)
`Myers proposes or an "increase in the number of cancer cells in the tumor" as Merck proposes. The court rejects
`Merck's assertion that tumor proliferation is an increase in the number of cancer cells only. Merck argues that cells
`in a tumor that are not cancer cells are not the target of treatment. (D.I. 82 at I6.) However, as Bristol-Myers points
`out, tumors are not solely made of cancer cells and depend on normal cells to grow. (D.I. 84 at I 6.) "As described
`in the specification, tumor proliferation can be evaluated as a numerical calculation of the number of cells in the
`tumor or as the weight or volume of the tumor after it is removed from the body." (Id. at 15.) The court declines to
`adopt a narrow construction of the term tumor proliferation based upon the intended goal of treatment.
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`3
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`Case 1:16-cv-01221-LPS Document 58-1 Filed 06/13/18 Page 5 of 5 PageID #: 539
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`5.
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`The term ''tumor metastasis" is construed to mean "the development of a tumor
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`derived from the primary tumor at a location outside the primary tumor site."5
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`6.
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`The term "expresses [PD-Ll/PD-L2]" is construed to mean "produces a product of
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`the [PD-Ll/PD-L2] gene."6
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`Dated: June b , 2016
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`~The court rejects Bristol-Myers proposed construction of"The spread of cancer cells from a primary site
`of disease to other parts of the body." (D.I. 84 at 16.) Merck argues that Bristol-Myers' proposed construction
`conflates tumor metastasis and tumor prolif'eration. (DJ. 82at16.) Merck also objects that Bristol-Myers' proposal
`would eliminate the requirement that a secondary tumor form. (Id.) Merck points out that the lead inventor, Honjo,
`testified that "metastasis is the stage of cancer that [a] small number of cancer cells released from the original tumor
`and [sic] normally circulate the vessel or sometimes lymphatics and arrive to the other organ and settle there and
`starts growing and form another tumor." (D.I. 151 at 4.) In addition, Dr. von Andrian testified based on the
`textbook Alberts et al. that tumor metastasis refers to a process where cancer cells within a tumor move to different
`locations and create secondary tumors. (D.I. 83 at 9-12.) Bristol Myers' responds that the definition in Alberts does
`not require development of a second tumor, (D.I. 122-5 at 5), nor does the definition in Taber's Medical Dictionary.
`(D.I. 83-11at52.) However, the definitions that Bristol Myers' cites to refer to "metastasis" and not "tumor
`metastasis." The court is convinced that Merck's construction is the most scientifically accurate. Thus, the court
`adopts Merck's proposed construction of"the development ofa tumor derived from the primary tumor.at a location
`outside the primary tumor site." (D.I. 82at16.)
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`6 The court rejects Merck's proposed construction of"produces a detectable an1ount of [PD-Ll!PD-L2]
`protein." The parties dispute whether PD-Ll!PD-L2 expression must be detectable and whether PD-Ll!PD-L2
`expression is only detected through PD-Ll!PD-L2 proteins. According to Merck, the claim language clearly
`indicates that cancer cells produce a detectable amount of the PD-Ll or PD-L2 protein. (D.I. 82 at 19.) Bristol(cid:173)
`Myers responds that "Defendants' proposed construction wrongly conflates whether a gene is expressed with the
`degree to which a gene is expressed - these are two fundamentally distinct concepts that are described using different
`terminology." (Id.) The court agrees with Bristol-Myers that gene expression is a "zero-sum game" and not limited
`by the degree that a gene is detectable. (Id.)
`The court declines to read in the limitation that PD-Ll!PD-L2 expression is a protein. According to
`Bristol-Myers, the products of the PD-Ll and PD-L2 genes include things other than the PD-Ll and PD-L2 proteins
`set forth in the claims, such as DNA and RNA. (D.I. 122 at 15-18.) -Bristol-Myers argues that the patent discloses
`that the expression of the PD-Ll!PD-L2 protein can be identified by methods that detect RNA. '474 Patent at col.
`11 :40-42. Additionally, according to Bristol-Myers, RT-PCR can determine the presence and amount of the
`relevant cytokine mRNA. The court must agree with Bristol-Myers that the proper construction is not limited to a
`single means of detecting PD-Ll!PD-L2. The court is not persuaded that the intrinsic evidence clearly supports the
`importation of"protein" as a limitation. Omega Eng'g, Inc, v. Raytek Corp., 334 F.3d 1314, 1329 (Fed. Cir. 2003)
`("It is axiomatic that, unless expressly compelled by the intrinsic evidence, courts must avoid the addition of a novel
`limitation.").
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`4
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