Baxalta Incorporated v. Genentech, Inc.

Case: 22-1461    Document: 53     Page: 1   Filed: 09/20/2023




   United States Court of Appeals
       for the Federal Circuit
                  ______________________

   BAXALTA INCORPORATED, BAXALTA GMBH,
              Plaintiffs-Appellants

                             v.

                   GENENTECH, INC.,
                    Defendant-Appellee
                  ______________________

                        2022-1461
                  ______________________

     Appeal from the United States District Court for the
 District of Delaware in No. 1:17-cv-00509-TBD, Circuit
 Judge Timothy B. Dyk.
                 ______________________

                Decided: September 20, 2023
                  ______________________

     WILLIAM R. PETERSON, Morgan, Lewis & Bockius LLP,
 Houston, TX, argued for plaintiffs-appellants. Also repre-
 sented by MICHAEL J. ABERNATHY, CHRISTOPHER JOHN
 BETTI, MARIA DOUKAS, KARON NICOLE FOWLER, Chicago,
 IL; JULIE S. GOLDEMBERG, Philadelphia, PA.

     ERIC ALAN STONE, Groombridge, Wu, Baughman &
 Stone LLP, New York, NY, argued for defendant-appellee.
 Also represented by NICHOLAS P. GROOMBRIDGE, NAZ
 WEHRLI, JOSEPHINE YOUNG.
                 ______________________
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 2                 BAXALTA INCORPORATED v. GENENTECH, INC.




     Before MOORE, Chief Judge, CLEVENGER and CHEN,
                     Circuit Judges.
 MOORE, Chief Judge.
     Baxalta Inc. and Baxalta GmbH (collectively, Baxalta)
 appeal the United States District Court for the District of
 Delaware’s grant of summary judgment that claims 1–4,
 19, and 20 of 

U.S. Patent No. 7,033,590

 are invalid for lack
 of enablement. For the following reasons, we affirm.
                        BACKGROUND
                               A
     Blood clots are formed through a series of enzymatic
 activations known as the coagulation cascade. ’590 patent
 at 1:6–10. In a “key step” of the cascade, an enzyme known
 as activated Factor VIII (Factor VIIIa) complexes with an-
 other enzyme known as activated Factor IX (Factor IXa) to
 activate Factor X. 

Id.

 at 1:17–19. Hemophilia A is a blood
 clotting disorder where the activity of Factor VIII is func-
 tionally absent, thereby impeding the coagulation cascade
 and the body’s ability to effectively form blood clots. 

Id.

 at
 1:19–27. Historically, Hemophilia A has been treated by
 intravenously administering Factor VIII. 

Id.

 at 1:28–30.
 However, approximately 20–30% of Hemophilia A patients
 cannot benefit from this traditional treatment because
 their bodies develop Factor VIII inhibitors (i.e., antibodies
 against Factor VIII). 

Id.

 at 1:30–35.
     Recognizing these drawbacks, the ’590 patent sought to
 provide alternative means to treat Hemophilia A, particu-
 larly in patients who develop Factor VIII inhibitors. 

Id.

 at
 2:22–28. Such preparations comprise antibodies or anti-
 body derivatives that bind to Factor IX/IXa to increase the
 procoagulant activity of Factor IXa. 

Id.

 at 2:29–38. These
 antibodies allow Factor IXa to activate Factor X in the ab-
 sence of Factor VIII/VIIIa. 

Id.

 at 1:61–67, 2:39–44. Inde-
 pendent claim 1 is representative and recites:
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 BAXALTA INCORPORATED v. GENENTECH, INC.                   3



         1.   An isolated antibody or antibody fragment
         thereof that binds Factor IX or Factor IXa and in-
         creases the procoagulant activity of Factor IXa.
 

Id.

 at claim 1.
      Antibodies are proteins that bind to antigens (foreign
 molecules in the body). More specifically, an antibody is a
 Y-shaped immunoglobulin molecule having a specific
 amino acid sequence comprising two heavy chains and two
 light chains. Each chain includes two regions: a variable
 region and a constant region. The variable region—the
 amino acid sequence at the tips of the “Y”—is the portion
 of the chain that varies between antibodies of the same iso-
 type. 1 The variable region contains complementarity-de-
 termining regions (CDRs), which are the amino acid
 sequences primarily responsible for the antibody’s binding
 and functional properties. The remaining constant region
 is identical across antibodies of the same isotype.
      The inventors generated the antibodies claimed in the
 ’590 patent using a prior art method known as the hybrid-
 oma technique. 

Id.

 at 9:62–10:37. This process involves
 first immunizing mice with human Factor IX/IXa to gener-
 ate anti-Factor IX/IXa antibody-secreting B-cells. 

Id.

 The
 antibody-secreting B-cells are then removed and fused to
 myeloma cells to create hybridomas that secrete anti-Fac-
 tor IX/IXa antibodies.
     The inventors performed four such hybridoma fusion
 experiments. 

Id.

 at 10:11–13. Using routine techniques,
 the inventors screened the candidate antibodies from the
 four fusion experiments to determine whether the antibod-
 ies bind to Factor IX/IXa and increase procoagulant activ-
 ity, as claimed. 

Id.

 at 10:39–12:56. The inventors


     1   Antibodies are grouped into five classes known as
 “isotypes”: IgA, IgD, IgE, IgG, and IgM. “Ig” stands for im-
 munoglobulin, and the following letter specifies the class.
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 4                  BAXALTA INCORPORATED v. GENENTECH, INC.




 discovered that only 1.6% of the thousands of screened an-
 tibodies increased the procoagulant activity of Factor IXa.
 J.A. 17684. The ’590 patent discloses the amino acid se-
 quences of eleven antibodies that bind to Factor IX/IXa and
 increase the procoagulant activity of Factor IXa. See ’590
 patent at 12:36–49. These disclosed antibodies are all mon-
 ospecific (i.e., bind to a single antigen) and monoclonal (i.e.,
 produced by a single cell line). The written description of
 the ’590 patent explains that a skilled artisan may use
 well-known antibody engineering techniques to transform
 the resulting antibody into different structural formats.
 See 

id.

 at 6:15–7:50 (discussing “technically modified anti-
 bodies”). For example, scientists can create “bispecific an-
 tibodies” by combining a heavy and light chain of one
 antibody with a heavy and light chain of a different anti-
 body. In bispecific antibodies, unlike monospecific antibod-
 ies, each arm binds to a different antigen. 

Id.

 at 7:32–34.
 As another example, scientists can create “humanized an-
 tibodies” in which animal CDRs are inserted into an other-
 wise human antibody. 

Id.

 at 6:49–57.
                                B
      Baxalta sued Genentech, Inc. alleging Genentech’s
 Hemlibra® (emicizumab) product infringes the ’590 patent.
 Emicizumab is a humanized bispecific antibody that binds
 to Factor IXa with one arm and Factor X with the other
 arm, thereby mimicking the function of Factor VIIIa. Fol-
 lowing the district court’s construction of the claim terms
 “antibody” and “antibody fragment” to exclude bispecific
 antibodies, the parties stipulated to non-infringement sub-
 ject to appeal.
      On a prior appeal, we held the proper construction of
 “antibody” was “an immunoglobulin molecule having a spe-
 cific amino acid sequence comprising two heavy chains (H
 chains) and two light chains (L chains),” and the proper
 construction of “antibody fragment” was “a portion of an
 antibody.” Baxalta Inc. v. Genentech, Inc., 

972 F.3d 1341

,
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 BAXALTA INCORPORATED v. GENENTECH, INC.                   5



 1345–49 (Fed. Cir. 2020). Because the district court’s con-
 struction erroneously excluded bispecific antibodies, we va-
 cated the judgment of non-infringement and remanded for
 further proceedings. 

Id. at 1349

. On remand, Genentech
 moved for summary judgment of, inter alia, invalidity of
 claims 1–4, 19, and 20 for lack of enablement. The district
 court granted summary judgment. Baxalta Inc. v. Genen-
 tech, Inc., 

579 F. Supp. 3d 595

 (D. Del. 2022). Baxalta ap-
 peals. We have jurisdiction under 

28 U.S.C. § 1295

(a)(1).
                        DISCUSSION
     We review summary judgment rulings under the law of
 the regional circuit, here the Third Circuit. Junker v. Med.
 Components, Inc., 

25 F.4th 1027, 1032

 (Fed. Cir. 2022).
 The Third Circuit reviews the grant of summary judgment
 de novo. Melrose, Inc. v. City of Pittsburgh, 

613 F.3d 380, 387

 (3d Cir. 2010). Summary judgment is appropriate
 when, drawing all reasonable inferences in the non-
 movant’s favor, there is no genuine issue of material fact
 and the movant is entitled to judgment as a matter of law.
 Fed. R. Civ. P. 56(a); Anderson v. Liberty Lobby, Inc., 

477 U.S. 242, 255

 (1986).
     A patent’s specification must describe the invention
 and “the manner and process of making and using it, in
 such full, clear, concise, and exact terms as to enable any
 person skilled in the art to which it pertains . . . to make
 and use the same.” 

35 U.S.C. § 112

(a). As the Supreme
 Court recently reaffirmed in Amgen Inc. v. Sanofi, “the
 specification must enable the full scope of the invention as
 defined by its claims,” allowing for “a reasonable amount of
 experimentation.” 

598 U.S. 594

, 610–12 (2023). In other
 words, “the specification of a patent must teach those
 skilled in the art how to make and use the full scope of the
 claimed invention without undue experimentation.” Mag-
 Sil Corp. v. Hitachi Glob. Storage Techs., Inc., 

687 F.3d 1377, 1380

 (Fed. Cir. 2012) (internal quotation marks and
 citation omitted). Enablement is a question of law based
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 6                  BAXALTA INCORPORATED v. GENENTECH, INC.




 on underlying factual findings. 

Id.

 “Because patents are
 presumed valid, lack of enablement must be proven by
 clear and convincing evidence.” ALZA Corp. v. Andrx
 Pharms., LLC, 

603 F.3d 935, 940

 (Fed. Cir. 2010).
     Baxalta argues summary judgment of invalidity for
 lack of enablement was improper because, when viewing
 the evidence in the light most favorable to Baxalta, skilled
 artisans can obtain the full scope of claimed antibodies
 without undue experimentation. Specifically, Baxalta ar-
 gues skilled artisans can make and identify new claimed
 antibodies (with new variable regions) using the routine
 hybridoma-and-screening process disclosed in the ’590 pa-
 tent and that such routine screening does not amount to
 undue experimentation. In light of the Supreme Court’s
 recent decision in Amgen, we cannot agree.
     In Amgen, the patents claimed all antibodies that (1)
 bind to specific amino acid residues on a protein known as
 PCSK9; and (2) block PCSK9 from binding to LDL recep-
 tors. 598 U.S. at 602. The full scope of the claims covered
 potentially millions of antibodies, but the specification only
 disclosed the amino acid sequences of twenty-six antibodies
 that performed the two claimed functions. Id. at 612–13.
 To make and use the undisclosed claimed antibodies,
 skilled artisans could either follow the “roadmap” disclosed
 in the patent or employ a technique known as “conservative
 substitution.” Id. at 603. The roadmap directed skilled ar-
 tisans to:
     (1) generate a range of antibodies in the lab; (2) test
     those antibodies to determine whether any bind to
     PCSK9; (3) test those antibodies that bind to
     PCSK9 to determine whether any bind to the sweet
     spot as described in the claims; and (4) test those
     antibodies that bind to the sweet spot as described
     in the claims to determine whether any block
     PCSK9 from binding to LDL receptors.
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 BAXALTA INCORPORATED v. GENENTECH, INC.                     7



 Id. The conservative substitution technique directed
 skilled artisans to: “(1) start with an antibody known to
 perform the described functions; (2) replace select amino
 acids in the antibody with other amino acids known to have
 similar properties; and (3) test the resulting antibody to see
 if it also performs the described functions.” Id.
      The Supreme Court held these methods “amount to lit-
 tle more than two research assignments” and fail to enable
 the full scope of the claims. Id. at 612–15. The Court rea-
 soned Amgen’s roadmap “merely describes step-by-step
 Amgen’s own trial-and-error method for finding functional
 antibodies—calling on scientists to create a wide range of
 candidate antibodies and then screen each to see” which
 practice the claims. Id. at 614. Similarly, the conservative
 substitution technique simply “requires scientists to make
 substitutions to the amino acid sequences of antibodies
 known to work and then test the resulting antibodies to see
 if they do too—an uncertain prospect given the state of the
 art.” Id. Such approaches leave skilled artisans to “engage
 in ‘painstaking experimentation’ to see what works,” which
 “is not enablement.” Id. (quoting Consol. Elec. Light Co. v.
 McKeesport Light Co., 

159 U.S. 465, 475

 (1895)). The Su-
 preme Court acknowledged, however, that methods like a
 roadmap or conservative substitution might be sufficient to
 enable other claims under different circumstances, such as
 where the patent discloses “a quality common to every
 functional embodiment.” Id.; see also 

id. at 611

 (“[I]t may
 suffice to give an example (or a few examples) if the speci-
 fication also discloses ‘some general quality . . . running
 through’ the class that gives it ‘a peculiar fitness for the
 particular purpose.’ In some cases, disclosing that general
 quality may reliably enable a person skilled in the art to
 make and use all of what is claimed, not merely a subset.”
 (quoting Consol. Elec. Light Co., 

159 U.S. at 475

)).
     The facts of this case are materially indistinguishable
 from those in Amgen. Claim 1 of the ’590 patent covers all
 antibodies that (1) bind to Factor IX/IXa; and (2) increase
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 8                 BAXALTA INCORPORATED v. GENENTECH, INC.




 the procoagulant activity of Factor IXa. 2 There are mil-
 lions of potential candidate antibodies, J.A. 18754–55 ¶ 22,
 but the written description discloses the amino acid se-
 quences for only eleven antibodies with the two claimed
 functions. See ’590 patent at 12:36–49. To obtain the un-
 disclosed but claimed antibodies, the written description
 directs skilled artisans to: (1) immunize mice with human
 Factor IX/IXa; (2) form hybridomas from the antibody-se-
 creting spleen cells of those mice; (3) test those antibodies
 to determine whether they bind to Factor IX/IXa; and (4)
 test those antibodies that bind to Factor IX/IXa to deter-
 mine whether any increase procoagulant activity. 

Id.

 at
 9:62–12:56. Just like the roadmap rejected by the Supreme
 Court in Amgen, the ’590 patent’s roadmap simply directs
 skilled artisans to engage in the same iterative, trial-and-
 error process the inventors followed to discover the eleven
 antibodies they elected to disclose. See Amgen, 598 U.S. at
 613–14. In both cases, “nothing in the specification
 [teaches] how to identify any antibodies complying with the
 claim limitations other than by repeating the same process
 the inventors used to identify the . . . examples disclosed in
 the specification.” Baxalta, 579 F. Supp. 3d at 619.
     Moreover, it is undisputed the ’590 patent contains no
 disclosures—such as “a quality common to every functional



     2   The parties do not raise distinct arguments with
 respect to dependent claims 2–4, 19, and 20. Rather, the
 parties agree that practicing the challenged claims re-
 quires two steps: (1) obtaining new antibodies with new
 variable regions that bind to Factor IX/IXa and increase
 procoagulant activity; and (2) engineering these variable
 regions into the isotypes and formats recited in the depend-
 ent claims. Because, as discussed infra, we hold it requires
 unreasonable experimentation to practice the first step, we
 need not consider whether it would require unreasonable
 experimentation to practice the second step.
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 BAXALTA INCORPORATED v. GENENTECH, INC.                     9



 embodiment,” Amgen, 598 U.S. at 614—that would allow a
 skilled artisan to predict which antibodies will perform the
 claimed functions. The patent does not disclose any com-
 mon structural (or other) feature delineating which anti-
 bodies will bind to Factor IX/IXa and increase procoagulant
 activity from those that will not. Nor does the patent de-
 scribe why the eleven disclosed antibodies perform the
 claimed functions, or why the other screened antibodies do
 not. The only guidance the patent provides is “to create a
 wide range of candidate antibodies and then screen each to
 see which happen to bind” to Factor IX/IXa and increase
 procoagulant activity. Id. Amgen makes clear that such
 an instruction, without more, is not enough to enable the
 broad functional genus claims at issue here. Id. at 614–15
 (“[T]he . . . problem we see [is that] Amgen offers persons
 skilled in the art little more than advice to engage in ‘trial
 and error.’”).
     In an attempt to distinguish Amgen, Baxalta argues
 the hybridoma-and-screening process disclosed in the ’590
 patent does not require trial and error but instead predict-
 ably and reliably generates new claimed antibodies every
 time it is performed. Even accepting as true that skilled
 artisans will generate at least one claimed antibody each
 time they follow the disclosed process, this does not take
 the process out of the realm of the trial-and-error ap-
 proaches rejected in Amgen. 3         Amgen made clear
 that § 112(a) requires inventors to enable the “full scope”
 of the claimed invention without unreasonable



     3   Indeed, the same was apparently true in Amgen.
 See Brief for Petitioners at 49, Amgen, 

598 U.S. 594

 (No.
 21-757) (“It was undisputed that, by following the patents’
 roadmap, skilled artisans can generate other claimed anti-
 bodies every time.”). Yet, the Supreme Court still held
 Amgen’s roadmap required trial and error. See Amgen, 598
 U.S. at 614–15.
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 10                BAXALTA INCORPORATED v. GENENTECH, INC.




 experimentation. 

Id.

 at 610–12. Here, it is undisputed
 that to practice the full scope of the claimed invention,
 skilled artisans must make candidate antibodies and
 screen them to determine which ones perform the claimed
 functions. See J.A. 16451, 17340–41 (Baxalta’s experts tes-
 tifying the only way for skilled artisans to identify a new
 embodiment of the genus “is to make antibodies and test
 them”). This is the definition of trial and error and leaves
 the public no better equipped to make and use the claimed
 antibodies than the inventors were when they set out to
 discover the antibodies over which they now have an exclu-
 sive right. Under Amgen, such random trial-and-error dis-
 covery,    without    more,    constitutes     unreasonable
 experimentation that falls outside the bounds required by
 § 112(a). 598 U.S. at 613–15.
     Finally, Baxalta argues the district court’s enablement
 determination is inconsistent with In re Wands, 

858 F.2d 731

 (Fed. Cir. 1988). We do not agree. We have previously
 explained the factual distinction between Wands and
 Amgen. Amgen Inc. v. Sanofi, Aventisub LLC, 

987 F.3d 1080

, 1085–86 (Fed. Cir. 2021). The facts of this case are
 more analogous to—and are, in fact, indistinguishable
 from—those in Amgen. We do not interpret Amgen to have
 disturbed our prior enablement case law, including Wands
 and its factors. 4
      In light of the foregoing, we hold the ’590 patent fails
 to teach skilled artisans how to make and use the full scope
 of     claimed      antibodies     without     unreasonable


      4 At oral argument, both parties agreed the Supreme
 Court did not disturb the Wands factors. Oral Arg. at
 00:40–1:16, 30:31–31:15, available at https://cafc.uscourts.
 gov/home/oral-argument/listen-to-oral-arguments. We see
 no meaningful difference between Wands’ “undue experi-
 mentation” and Amgen’s “[un]reasonable experimentation”
 standards.
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 BAXALTA INCORPORATED v. GENENTECH, INC.               11



 experimentation. We therefore affirm the district court’s
 grant of summary judgment that claims 1–4, 19, and 20 are
 not enabled.
                       CONCLUSION
    We have considered the parties’ remaining arguments
 and find them unpersuasive. For the reasons given above,
 we affirm the district court’s grant of summary judgment.
                       AFFIRMED