Trials@uspto.gov
`571-272-7822
`
`
`
`
`
` Paper No. 15
` Entered: February 5, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`SANOFI-AVENTIS U.S. LLC AND
`REGENERON PHARMACEUTICALS, INC.,
`Petitioners,
`v.
`
`GENENTECH, INC. AND CITY OF HOPE,
`Patent Owners.
`____________
`
`Case IPR2015-01624
`Patent 6,331,415 B1
`____________
`
`
`
`
`
`Before LORA M. GREEN, ERICA A. FRANKLIN, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`PAULRAJ, Administrative Patent Judge.
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`571-272-7822
`
`
`
`
`
` Paper No. 15
` Entered: February 5, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`SANOFI-AVENTIS U.S. LLC AND
`REGENERON PHARMACEUTICALS, INC.,
`Petitioners,
`v.
`
`GENENTECH, INC. AND CITY OF HOPE,
`Patent Owners.
`____________
`
`Case IPR2015-01624
`Patent 6,331,415 B1
`____________
`
`
`
`
`
`Before LORA M. GREEN, ERICA A. FRANKLIN, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`PAULRAJ, Administrative Patent Judge.
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`IPR2015-01624
`Patent 6,331,415 B1
`
`I.
`
`INTRODUCTION
`
`Sanofi-Aventis U.S. LLC. and Regeneron Pharmaceuticals, Inc.
`
`(collectively, “Petitioners”) filed a Petition (Paper 1, “Pet.”), requesting
`
`institution of an inter partes review of claims 1–4, 9, 11, 12, 14–20, and 33
`
`of U.S. Patent No. 6,331,415 B1 (Ex. 1001, “the ’415 patent”). Genentech,
`
`Inc. and City of Hope (collectively, “Patent Owners”) timely filed a
`
`Preliminary Response (Paper 14, “Prelim. Resp.”). We have jurisdiction
`
`under 35 U.S.C. § 314, which provides that an inter partes review may not
`
`be instituted “unless . . . there is a reasonable likelihood that the petitioner
`
`would prevail with respect to at least 1 of the claims challenged in the
`
`petition.”
`
`Upon consideration of the Petition and the Preliminary Response, and
`
`for the reasons explained below, we determine that Petitioners have shown
`
`that there is a reasonable likelihood that they would prevail with respect to at
`
`least one of the challenged claims. We thus institute an inter partes review
`
`of claims 1–4, 11, 12, 14, 18–20, and 33 of the ’415 patent.
`
`A. Related Proceedings
`
`The parties have identified several district court and PTO proceedings
`
`related to the ’415 patent. Pet. 7–17; Paper 6, 1–4.
`
`Of particular relevance, the ’415 patent was the subject of a merged ex
`
`parte reexamination proceeding, Control Nos. 90/007,542 and 90/007,859.
`
`Id. During the course of the reexamination, the claims of the ’415 patent
`
`were initially rejected based on prior art 4,399,216 (“Axel,” Ex. 1018) and
`
`5,840,545 (“Moore,” Ex. 1019), Rice & Baltimore (Ex. 1020), and Ochi (I)
`
`(Ex. 1021) on the grounds including obviousness-type double patenting,
`
`anticipation and obviousness. These rejections were overcome and a
`
`
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`IPR2015-01624
`Patent 6,331,415 B1
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`reexamination certificate issued on May 19, 2009, which confirmed the
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`patentability of claims 1–20 and 33–36, and determined that claims 21–32
`
`are patentable as amended. Ex. 1026, Reexam Cert.
`
`B.
`
`The ’415 Patent (Ex. 1001)
`
`The ’415 patent issued on December 18, 2001, and claims priority to
`
`an application filed on April 8, 1983. See Ex. 1001, Title Page. It names
`
`Shmuel Cabilly, Herbert L. Heyneker, William E. Holmes, Arthur D. Riggs,
`
`and Ronald B. Wetzel as the inventors. Id.
`
`The ’415 patent relates generally to processes for producing
`
`immunoglobulin molecules in a host cell transformed with a first DNA
`
`sequence encoding the variable domain of the heavy chain and a second
`
`DNA sequence encoding the variable domain of the light chain, as well as
`
`vectors and transformed host cells used in such processes. More
`
`specifically, the first and second DNA sequences are present in either
`
`different vectors or in a single vector, and independently expressed so that
`
`the immunoglobulin heavy and light chains are produced as separate
`
`molecules in the transformed single host cell. See id., cols. 1, 15, 18, 21, and
`
`33.
`
`According to the specification of the ’415 patent, there were two
`
`major sources of vertebrate antibodies that could be generated in situ by the
`
`mammalian B lymphocytes or in cell culture by B-cell hybrids
`
`(hybridomas). Id. at 1:42–45. The specification notes, however, that
`
`monoclonal antibodies produced by these two sources suffer from
`
`disadvantages, including contamination with other cellular materials,
`
`instability, production of an undesired glycosylated form, high cost, and an
`
`inability to manipulate the genome. Id. at 2:40–66. The specification
`
`
`
`3
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`IPR2015-01624
`Patent 6,331,415 B1
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`recognizes that “the use of recombinant DNA technology can express
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`entirely heterologous polypeptides—so-called direct expression—or
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`alternatively may express a heterologous polypeptide fused to a portion of
`
`the amino acid sequence of a homologous polypeptide.” Id. at 4:33–37.
`
`The specification states that “[t]he invention relates to antibodies and
`
`to non-specific immunoglobulins (NSIs) formed by recombinant techniques
`
`using suitable host cell cultures,” which can “be manipulated at the genomic
`
`level to produce chimeras of variants which draw their homology from
`
`species which differ from each other.” Id. at 4:53–59. The specification
`
`further indicates that “[t]he ability of the method of the invention to produce
`
`heavy and light chains or portions thereof, in isolation from each other offers
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`the opportunity to obtain unique and unprecedented assemblies of
`
`immunoglobulins, Fab regions, and univalent antibodies.” Id. at 12:58–62.
`
`C. Illustrative Claims
`
`Petitioners challenge claims 1–4, 9, 11, 12, 14–20, and 33 of the ’415
`
`patent. Independent claims 1 and 18 are illustrative, and reproduced below:
`
`1. A process for producing an immunoglobulin molecule or an
`immunologically functional immunoglobulin fragment comprising at
`least the variable domains of the immunoglobulin heavy and light
`chains, in a single host cell, comprising the steps of:
`
`(i) transforming said single host cell with a first DNA sequence
`encoding at least the variable domain of the immunoglobulin heavy
`chain and a second DNA sequence encoding at least the variable
`domain of the immunoglobulin light chain, and
`
`(ii) independently expressing said first DNA sequence and said
`second DNA sequence so that said immunoglobulin heavy and light
`chains are produced as separate molecules in said transformed single
`host cell.
`
`
`
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`18. A transformed host cell comprising at least two vectors, at least
`one of said vectors comprising a DNA sequence encoding at least a
`variable domain of an immunoglobulin heavy chain and at least
`another one of said vectors comprising a DNA sequence encoding at
`least the variable domain of an immunoglobulin light chain.
`
`D. The Asserted Grounds of Unpatentability
`
`Petitioners challenge the patentability of the claims of the ’415 patent
`
`on the following grounds:
`
`References
`
`Bujard1
`
`Basis
`
`§ 102(e)
`
`Bujard and Riggs & Itakura2
`
`§ 103(a)
`
`§ 103(a)
`
`§ 103(a)
`
`Bujard and Southern3
`
`Cohen & Boyer4 and Riggs &
`Itakura
`
`
`II. DISCUSSION
`
`A. Claim Construction
`
`Claims challenged
`
`1, 3, 4, 9, 11, 15, 16, 17,
`19, and 33
`1, 3, 4, 11, 12, 14, 19,
`and 33
`1, 2, 18, 20 and 33
`
`1, 3, 4, 11, 12, 14, and
`33
`
`We interpret claims using the “broadest reasonable construction in
`
`light of the specification of the patent in which [they] appear[].” 37 C.F.R.
`
`
`1 Bujard (Ex. 1002) Bujard et al., US 4,495,280, issued Jan. 22, 1985 (Ex.
`1002).
`2 Arthur D. Riggs and Keiichi Itakura, Synthetic DNA and Medicine, 31 Am
`J. Hum Genet, 531–538 (1979) (Ex. 1003).
`Riggs & Itakura (Ex. 1003)
`3 P.J. Southern and P. Berg, Transformation of Mammalian Cells to
`Antibiotic Resistance with a Bacterial Gene Under Control of the SV40
`Early Region Promoter, J. Molecular and Applied Genetics, Vol.1, 327–341
`(1982) (Ex. 1004).
`4 Cohen et al., US 4,237,224, issued Dec. 2, 1980 (Ex. 1005).
`
`
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`§ 42.100(b); see also In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1278–
`
`79 (Fed. Cir. 2015), cert. granted, No. 15-446 (U.S. Jan. 15, 2016)
`
`(“Congress implicitly approved the broadest reasonable interpretation
`
`standard in enacting the AIA,” 5 and “the standard was properly adopted by
`
`PTO regulation.”). Under the broadest reasonable construction standard,
`
`claim terms are given their ordinary and customary meaning, as would be
`
`understood by one of ordinary skill in the art at the time of the invention. In
`
`re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). “Absent
`
`claim language carrying a narrow meaning, the PTO should only limit the
`
`claim based on the specification . . . when [it] expressly disclaim[s] the
`
`broader definition.” In re Bigio, 381 F.3d 1320, 1325 (Fed Cir. 2004).
`
`“Although an inventor is indeed free to define the specific terms used to
`
`describe his or her invention, this must be done with reasonable clarity,
`
`deliberateness, and precision.” In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
`
`1994).
`
`Neither party has proposed the construction of any particular claim
`
`terms. See Pet. 16–17; Prelim. Resp. 9–10. Petitioners and Patent Owners
`
`agree that the term “immunoglobulin” is interchangeable with “antibody.”
`
`Pet. at 4 n.1; Prelim. Resp. 9 n.2. Moreover, while we note some ambiguity
`
`with respect to the term “independently expressing” recited in claims 1 and
`
`33, both parties have treated that term as synonymous with “co-expressing”
`
`the first and second DNA sequences in a single host cell. See Pet. 50 (noting
`
`that claims 1 and 33 “are both directed to co-expression of heavy and light
`
`chains in a single host cell”); Prelim. Resp. 46 (arguing that “Petitioners
`
`
`5 The Leahy-Smith America Invents Act, Pub. L. No. 11229, 125 Stat. 284
`(2011) (“AIA”).
`
`
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`have failed to establish that Bujard necessarily discloses the co-
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`transformation and co-expression of an immunoglobulin heavy chain and
`
`light chain from the same host cell.”). In other words, there does not appear
`
`to be any requirement that either the heavy or light chain should be capable
`
`of being expressed without the concomitant expression of the other chain.
`
`We apply that common understanding in our analysis here.
`
`We determine that no explicit construction of any other claim term is
`
`necessary to determine whether to institute a trial in this case. See, e.g.,
`
`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011)
`
`(“[C]laim terms need only be construed ‘to the extent necessary to resolve
`
`the controversy.’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`
`200 F.3d 795, 803 (Fed. Cir. 1999)). At this stage of the proceeding, we
`
`have not made a final determination as to the construction of any claim term.
`
`B. Principles of Law
`
`We analyze the proposed grounds of unpatentability in accordance
`
`with the following stated principles.
`
`An inter partes review may be instituted only if “the information
`
`presented in the [Petition and Preliminary Response] shows that there is a
`
`reasonable likelihood that the petitioner would prevail with respect to at
`
`least 1 of the claims challenged in the petition.” 35 U.S.C. § 314(a).
`
`1. Law of Anticipation
`
`The Court of Appeals for the Federal Circuit summarized the
`
`analytical framework for determining whether prior art anticipates a claim as
`
`follows:
`
`
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`To anticipate a claim, a single prior art reference must expressly
`or inherently disclose each claim limitation. Celeritas Techs.,
`Ltd. v. Rockwell Int’l Corp., 150 F.3d 1354, 1361 (Fed. Cir.
`1998). But disclosure of each element is not quite enough—this
`court has long held that “[a]nticipation requires the presence in a
`single prior art disclosure of all elements of a claimed invention
`arranged as in the claim.” Connell v. Sears, Roebuck & Co., 722
`F.2d 1542, 1548 (Fed. Cir. 1983) (citing Soundscriber Corp. v.
`United States, 175 Ct. Cl. 644, 360 F.2d 954, 960 (1966)
`(emphasis added)).
`
`Finisar Corp. v. DirecTV Grp., Inc., 523 F.3d 1323, 1334–35 (Fed. Cir.
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`2008). “Thus, it is not enough that the prior art reference discloses part of
`
`the claimed invention, which an ordinary artisan might supplement to make
`
`the whole, or that it includes multiple, distinct teachings that the artisan
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`might somehow combine to achieve the claimed invention.” Net MoneyIN,
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`Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 n.5 (Fed. Cir. 2008). “The
`
`requirement that the prior art elements themselves be ‘arranged as in the
`
`claim’ means that claims cannot be ‘treated … . . as mere catalogs of
`
`separate parts, in disregard of the part-to-part relationships set forth in the
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`claims and that give the claims their meaning.’” Therasense, Inc. v. Becton,
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`Dickinson & Co., 593 F.3d 1325, 1332 (Fed. Cir. 2010) (quoting Lindemann
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`Maschinenfabrik GMBH v. Am. Hoist & Derrick Co., 730 F.2d 1452, 1459
`
`(Fed. Cir. 1984)).
`
`2. Law of Obviousness
`
`The legal 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 skill in the art; and (4) objective evidence of
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`
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`nonobviousness, i.e., secondary considerations. See Graham v. John Deere
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`Co., 383 U.S. 1, 17–18 (1966).
`
`In KSR International Co. v. Teleflex Inc., the Supreme Court stated
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`that, under certain circumstances, an invention may be found obvious if
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`trying a course of conduct would have been considered obvious to a person
`
`having ordinary skill:
`
`When there is a design need or market pressure 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. In that
`instance the fact that a combination was obvious to try might
`show that it was obvious under § 103.
`
`550 U.S. 398, 421 (2007). In this regard, “[o]bviousness does not require
`
`absolute predictability of success . . . all that is required is a reasonable
`
`expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009)
`
`(citing In re O'Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988)).
`
`As the court noted in Kubin, “[t]he Supreme Court’s admonition
`
`against a formalistic approach to obviousness in this context actually
`
`resurrects this court’s own wisdom in In re O'Farrell . . . .” Id. In
`
`O’Farrell, the court outlined two classes of situations where “obvious to try”
`
`is erroneously equated with obviousness under § 103. First, obviousness is
`
`not shown when
`
`what would have been “obvious to try” would have been to
`vary all parameters or try each of numerous possible choices
`until one possibly arrived at a successful result, where the prior
`art gave either no indication of which parameters were critical
`or no direction as to which of many possible choices is likely to
`be successful.
`
`
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`
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`O’Farrell, 853 F.2d at 903. Second, obviousness is also not shown when
`
`what was “obvious to try” was to explore a new technology or
`general approach that seemed to be a promising field of
`experimentation, where the prior art gave only general guidance
`as to the particular form of the claimed invention or how to
`achieve it.
`
`
`Id.
`
`C. Prior Art Relied Upon
`
`Petitioners rely upon the following prior art in its challenges.
`
`1. Bujard (Ex. 1002)
`
`Bujard relates to a process for producing polypeptides in a
`
`transformed host cell using a plasmid vector that is optimized to have a high
`
`signal strength T5 phage promoter and a balanced terminator. Ex. 1002,
`
`Abstract, 5:11–12. More particularly, the structure of the vector taught by
`
`Bujard is “a strong promoter, followed by a DNA sequence of interest,
`
`optionally followed by one or more translational stop codons in one or more
`
`reading frames, followed by a balanced terminator, followed by a marker
`
`allowing for selection of transformants.” Id. at 2:8–13.
`
`Bujard explains that the plasmid vector may have the strong promoter
`
`and terminator separated by “more than one gene, that is, a plurality of
`
`genes, including multimers and operons.” Id. at 3:45–48. Further, Bujard
`
`indicates that “[d]esirably, the gene is followed by one or a plurality of
`
`translational stop codons e.g. oop or nonsense codons, or preferably a
`
`plurality, usually up to about six, more usually from about two to five, where
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`there is at least one stop codon in each reading frame.” Id. at 3:15–19.
`
`
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`These stop codons aid in the efficiency of termination at both the
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`transcription and expression levels. Id. at 3:19–21. Bujard also states:
`
`For hybrid DNA technology it would be useful to have a
`plasmid having a unique restriction site between a T5 promoter
`and a terminator, desirably having at least one stop codon on
`the upstream side of the terminator. In this manner, one or
`more structural genes may be introduced between the promoter
`and terminator.
`
`Id. at 7:57–63. This strategy described in Bujard “provides a vehicle which
`
`can be used with one or more hosts for gene expression.” Id. at 8:1–3. The
`
`host cells employed for Bujard’s process may be either bacterial or
`
`mammalian cells. Id. at 6:23–35.
`
`Bujard indicates that a “wide variety of structural genes are of interest
`
`for production of proteins,” and that “[t]he proteins may be prepared as a
`
`single unit or as individual subunits and then joined together in appropriate
`
`ways.” Id. at 4:14–21. Among the “proteins of interest,” Bujard includes
`
`“immunoglobulins e.g. IgA, IgD, IgE, IgG and IgM and fragments thereof,”
`
`and further spells out the “molecular formula” for each of those
`
`immunoglobulins. Id. at 4:30–5:27. For example, Bujard identifies
`
`immunoglobulin G (IgG) as having the formula γ2λ2 or γ2κ2, which
`
`corresponds to the two light chains and two heavy chains of the antibody
`
`molecule. Id. at 5:11–14. Bujard also lists “[f]ree light chains” separately.
`
`Id. at 5:27.
`
`2. Riggs & Itakura (Ex. 1003)
`
`Riggs & Itakura discusses the bacterial production of human insulin.
`
`Specifically, Riggs & Itakura made two E. coli strains, each constructed by
`
`cloning vectors containing chemically synthesized genes encoding the
`
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`insulin A chain or B chain, and further showed that the separately purified
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`chains can be joined by air oxidation in vitro to produce active insulin. Ex.
`
`1003, 532 (FIG. 1). Among the potential practical applications, Riggs &
`
`Itakura states that the recombinant DNA techniques discussed therein can be
`
`used to produce antibodies from hybridoma, stating “[h]ybridomas will
`
`provide a source of mRNA for specific antibodies. Bacteria may then be
`
`used for the production of the antibody peptide chains, which could be
`
`assembled in vitro and used for passive immunization.” Id. at 537–38.
`
`3. Southern (Ex. 1004)
`
`Southern describes the transformation of mammalian host cells to
`
`confer resistance to neomycin-kanamycin antibiotics. Ex. 1004, 327
`
`(Summary). In particular, Southern utilized known selection markers for co-
`
`expressing the bacterial genes gpt and neo using two separate vectors—
`
`pSV2-gpt and pSV2-neo—within a single host cell. Id. at 337, Table 3.
`
`Southern teaches that “vectors containing these markers provide a way to
`
`cotransduce other genes whose presence and/or expression can not be
`
`selected.” Id. at 338. Southern concludes that “[c]otransformation with
`
`nonselectable genes can be accomplished by inserting genes of interest into
`
`vector DNAs designed to express neo or gpt,” and further states that “[t]he
`
`schemes used to select for the expression of gpt and neo [described therein]
`
`are complementary and experiments that exploit the possibilities of a double
`
`and dominant selection are now in progress.” Id. at 339.
`
`4. Cohen & Boyer (Ex. 1005)
`
`Cohen & Boyer describes generally the replication and expression of
`
`exogenous (foreign) genes in a microorganism for protein synthesis. Ex.
`
`1005, 1:34–42. Cohen & Boyer teaches that host cells can be transformed
`
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`by introducing a plasmid vehicle bound to the foreign gene in order to
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`produce proteins of interest. Id. at 1:56–59, 4:29–38, 5:59–65, 6:43–47,
`
`claim 1. In particular, Cohen states that “[b]y introducing one or more
`
`exogenous genes into a unicellular organism, the organism will be able to
`
`produce polypeptides and proteins (‘poly(amino acids)’) which the organism
`
`could not previously produce.” Id. at 9:12–15. Cohen & Boyer lists
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`antibodies among the “poly(amino acids) of interest.” Id. at 9:28–34.
`
`Cohen & Boyer further notes: “the subject method provides means for
`
`preparing enzymes and enzymic products from bacteria where the natural
`
`host is not as convenient or efficient a source of such product. . . . Besides
`
`enzymes, other proteins can be produced such as antibodies.” Id. at 16:54–
`
`64.
`
`D. Analysis of Petitioners’ Patentability Challenges
`
`1. Anticipation of Claims 1, 3, 4, 9, 11, 12, 15–17, 19, and 33
`Based on Bujard
`
`Petitioners contend that claims 1, 3, 4, 9, 11, 12, 15–17, 19, and 33 are
`
`anticipated by Bujard. Pet. 35–44. In support, Petitioners rely upon the
`
`teachings of Bujard, as well as the Declaration of Jefferson Foote, Ph.D. (Ex.
`
`1006). Petitioners include a claim chart for claims 1, 15, 17, and 33, but
`
`point to the same disclosures in Bujard for each of these claims. Pet. 41–43.
`
`Independent claims 1 and 33 require the recombinant production of an
`
`immunoglobulin molecule (i.e., an antibody) or immunologically functional
`
`fragment by “independently expressing” DNA sequences encoding at least
`
`the variable domains of the immunoglobulin heavy and light chains within a
`
`“single host cell,” while independent claim 15 requires a vector comprising
`
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`the DNA sequences encoding the variable domains of the heavy and light
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`chains located “at different insertion sites.”
`
`Patent Owners argue that Bujard fails to teach a) transforming a single
`
`host cell with DNA sequences encoding the heavy and light chains of an
`
`immunoglobulin, b) independently expressing those sequences within the
`
`single host cell as separate molecules, and c) assembling the
`
`immunoglobulin chains to produce an intact antibody or an immunologically
`
`functional fragment. Prelim. Resp. 39–40. According to Patent Owners,
`
`“[t]he cited passages from Bujard make clear that the techniques being
`
`described by Petitioners are general ones; they do not show a particular
`
`application of the techniques to produce immunoglobulins in the manner
`
`required by the claims of the Cabilly ‘415 patent.” Id. at 41. Patent Owners
`
`assert that the Petition does not establish that the claim elements missing
`
`from Bujard are necessarily present, and that Petitioner improperly relied
`
`upon the testimony of Dr. Foote to fill in the missing elements. Id. at 43.
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`Patent Owners also contend that, as the PTO found in the prior
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`reexamination with respect to the Axel6 reference, “the mere use of the
`
`words ‘genes’ and ‘immunoglobulin’ in a reference does not convey to the
`
`skilled person an actual description of how to produce a functional
`
`immunoglobulin or fragment by independent expression of its constituent
`
`heavy and light chains in a single transformed host cells.” Id. at 29. Patent
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`Owners assert that Petitioners rely upon the same “linguistic” arguments
`
`with respect to Bujard’s disclosure of “genes” and “immunoglobulins” that
`
`have already been rejected. Id. at 31–38.
`
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`6 Axel et al., US 4,399,216, issued Aug. 16, 1983 (Ex. 1018).
`
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`14
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`Patent 6,331,415 B1
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`
`We determine that Petitioners have not demonstrated a reasonable
`
`likelihood of prevailing with respect to this anticipation challenge. Bujard
`
`describes generally the expression of “structural genes” using a vector
`
`containing a high signal strength promoter, and further identifies
`
`immunoglobulins among a “representative list of proteins of interest.” Ex.
`
`1002, 4:14–37. Bujard, however, does not describe a specific process or a
`
`vector that is “arranged as in the claim[s]” of the ’415 patent. Connell, 722
`
`F.2d at 1548. Although Bujard identifies the structure of immunoglobulins
`
`as including heavy and light chains (e.g., IgG with a molecular formula of
`
`γ2λ2 or γ2κ2), Bujard does not teach—either expressly or inherently—that
`
`genes encoding for both the heavy and light chains must be incorporated into
`
`the same vector or otherwise expressed within a single host cell. Ex. 1002,
`
`5:10–27.
`
`Petitioners’ anticipation arguments require us to draw inferences that
`
`are not required by Bujard’s generalized teachings. In particular, Petitioners
`
`assume, based on “common knowledge,” “simple logic,” and “common
`
`sense,” that the skilled artisan would interpret Bujard’s listing of
`
`immunoglobulins to mean that the different genes encoding for the heavy
`
`and light chains should both be present in the same vector and expressed
`
`within the same host cell. Pet. 38 (citing Ex. 1006 ¶ 91). But that type of
`
`analysis falls within the purview of obviousness, not anticipation. We
`
`recognize that Bujard suggests that a “plurality of genes, including
`
`multimers and operons” can be inserted between the promoter and
`
`terminators sequences of the vector. Ex. 1002, 3:46–48. We further
`
`recognize that Bujard suggests that it is “desirabl[e to] hav[e] at least one
`
`stop codon on the upstream side of the terminator” so that “one or more
`
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`15
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`IPR2015-01624
`Patent 6,331,415 B1
`
`structural genes may be introduced between the promoter and terminator.”
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`Id. at 7:60–63; see also id. at 3:15–21. Petitioners, however, do not point to
`
`any teaching that all the genes encoding for the different subunits
`
`(polypeptides) of the “proteins of interest” identified in Bujard must
`
`necessarily be expressed within the same host cell. To the contrary, Bujard
`
`indicates that “[t]he strategy described above . . . can be used with one or
`
`more hosts for gene expression . . . .” Id. at 8:1–3.
`
`We find Bujard’s teachings to be more specific and robust than the
`
`Axel reference that was previously considered by the PTO. Contra Prelim.
`
`Resp. 36–37. As explained below, we determine that Petitioners have
`
`demonstrated a reasonable likelihood of prevailing in their assertion that
`
`Bujard, in combination with the Riggs & Itakura or Southern references,
`
`renders certain of the challenged claims obvious. Nonetheless, in order to
`
`arrive at the claimed invention, a skilled artisan would have been required to
`
`selectively apply the general teachings of Bujard to the specific production
`
`of immunoglobulins and, in doing so, would have made choices based on
`
`inferences gleaned from outside the reference. This is insufficient for
`
`anticipation. See Therasense, 593 F.3d at 1332 (prior art disclosure of
`
`individual elements that merely “could have been arranged” in the claimed
`
`manner is not anticipatory).
`
`We, therefore, determine that Petitioners have not demonstrated a
`
`reasonable likelihood of prevailing with respect to this anticipation
`
`challenge.
`
`
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`16
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`2. Obviousness of Claims 1, 3, 4, 11, 12, 14, 19, and 33 Based
`on Bujard and Riggs & Itakura
`
`Petitioners contend that claims 1, 3, 4, 11, 12, 14, 19, and 33 are
`
`obvious based on the combined teachings of Bujard and Riggs & Itakura.
`
`Pet. 44–47. In addition to the teachings of the references, Petitioners also
`
`rely upon Dr. Foote’s Declaration in support of this challenge. For this
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`obviousness challenge, Petitioners focus on those claims of the ’415 patent
`
`that require (or broadly allow for) the first and second DNA sequences to be
`
`present in a single vector within a host cell.
`
`Petitioners assert that “even if a [skilled artisan] would not interpret
`
`Bujard to teach assembly of the chains into an immunoglobulin tetramer,
`
`[the skilled artisan] would nevertheless be motivated to combine Bujard with
`
`the in vitro assembly disclosures in Riggs & Itakura.” Id. at 45. In
`
`particular, based on Bujard’s suggestion that “individual [protein] subunits”
`
`can be “joined together in appropriate ways,” Petitioners rely upon Riggs &
`
`Itakura as teaching a specific in vitro assembly technique that is applicable
`
`to Bujard. Id. at 45–46 (citing Ex. 1002, 4:20–21; Ex. 1002, 537–38; Ex.
`
`1006, ¶¶ 99–101). Although Riggs & Itakura demonstrated the in vitro
`
`assembly of insulin A and B chains, and not immunoglobulin heavy and
`
`light chains, Petitioners assert that the reference is nonetheless relevant
`
`because it “addresses the same problem of joining unassociated
`
`[polypeptide] chains separately produced in microorganism host cells.” Id.
`
`at 46. Petitioners also point to the conclusion in Riggs & Itakura that the in
`
`vitro recombinant DNA techniques disclosed therein are applicable for
`
`antibodies, wherein hybridomas would be a source of mRNA for the
`
`antibody peptide chains (i.e., heavy and light chains) that are produced in
`
`
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`17
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`bacteria and assembled in vitro. Id. at 47 (citing Ex. 1003, 537; Ex. 1006 ¶
`
`102).
`
`Patent Owners contend that Riggs & Itakura does not cure the
`
`deficiencies of Bujard. More specifically, Patent Owners assert that
`
`“nothing in Riggs & Itakura suggests that the in vitro techniques described
`
`therein to combine proteins expressed in separate host cells would also be
`
`suitable for combining in vitro different proteins expressed in the same host
`
`cell.” Prelim. Resp. 49. Because Riggs & Itakura expressed the insulin A
`
`and B chains in separate host cells, Patent Owners argue that the references
`
`lead the skilled artisan away from the claimed invention of the ’415 patent.
`
`Patent Owners also assert that there is “no explanation why one of skill in
`
`the art would rely upon Riggs & Itakura for some teachings (e.g., how to
`
`assemble a multimeric protein), but ignore the overarching strategy it
`
`advances for producing multimeric proteins.” Id.
`
`We determine that Petitioners have demonstrated a reasonable
`
`likelihood of prevailing with respect to this obviousness challenge.
`
`Although we do not consider Bujard’s teachings to be anticipatory for the
`
`reasons discussed above, we determine that Petitioners have made a
`
`sufficient showing of obviousness for purposes of our institution of inter
`
`partes review when those teachings are combined with the in vitro assembly
`
`technique taught by Riggs & Itakura and applied to produce an
`
`immunoglobulin molecule.
`
`We are unpersuaded by Patent Owners’ preliminary arguments
`
`regarding this challenge. Patent Owners do not appear to take into account
`
`that Bujard itself suggests the incorporation of a plurality of structural genes
`
`encoding for the subunits of a multimeric protein, such as immunoglobulin
`
`
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`18
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`IPR2015-01624
`Patent 6,331,415 B1
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`heavy and light chains, within a vector that would be placed in a single host
`
`cell. Ex. 1002, 3:46–48; see also Ex. 1006 ¶¶ 67–68 (Dr. Foote stating that
`
`the term “multimer” as used in Bujard would be understood by the skilled
`
`artisan as referring to genes encoding for proteins with more than one
`
`subunit). Moreover, Bujard teaches the desirability of inserting
`
`“translational stop codons e.g. oop or nonsense codons” in one or more
`
`reading frames of the vector, which would allow for the multiple structural
`
`genes to be translated into separate polypeptides.7 Ex. 1002, 2:8–13, 3:15–
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`21, 7:57–63. When these general teachings of Bujard are taken into
`
`consideration with the specific identification of immunoglobulins among
`
`“proteins of interest,” Petitioners have demonstrated a reasonable likelihood
`
`that the skilled artisan would have found it obvious to insert the genes
`
`encoding for the heavy and light chains, separated by a stop codon, between
`
`the promoter and terminator sequences of the vector, which would permit
`
`the independent expression of those genes as separate molecules in the
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