Trials@uspto.gov
`571.272.7822
`
`
`
`
`
`
` Paper No. 16
`
` Entered: June 23, 2016
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GENZYME CORPORATION,
`Petitioner,
`
`v.
`
`GENENTECH, INC. AND CITY OF HOPE,
`Patent Owner.
`____________
`
`Case IPR2016-00383
`Patent 6,331,415 B1
`____________
`
`
`
`Before LORA M. GREEN, ERICA A. FRANKLIN, and
`SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`GREEN, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
`
` Paper No. 16
`
` Entered: June 23, 2016
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GENZYME CORPORATION,
`Petitioner,
`
`v.
`
`GENENTECH, INC. AND CITY OF HOPE,
`Patent Owner.
`____________
`
`Case IPR2016-00383
`Patent 6,331,415 B1
`____________
`
`
`
`Before LORA M. GREEN, ERICA A. FRANKLIN, and
`SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`GREEN, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`IPR2016-00383
`Patent 6,331,415 B1
`
`
`INTRODUCTION
`
`Genzyme Corporation (“Petitioner”) filed a Petition requesting 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”). Paper 2 (“Pet.”).
`Genentech, Inc. and City of Hope (collectively “Patent Owner”) filed a
`Preliminary Response. Paper 10. In addition, after authorization from the
`Board (Paper 11), Petitioner filed a Reply to the Preliminary Response.
`Paper 12.
`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 considering the Petition and the
`Preliminary Response, we determine that Petitioner has failed to
`demonstrate a reasonable likelihood that it would prevail in showing the
`unpatentability of any of the challenged claims. Accordingly, we decline to
`institute an inter partes review.
`Related Proceedings
`A.
`Petitioner identifies IPR2015-01624, which was filed by Sanofi-
`Aventis U.S. LLC (“Sanofi”) and Regeneron Pharmaceuticals, as
`challenging claims in the ’415 patent. Pet. 58. Trial was instituted in
`IPR2015-01624 on February 5, 2016. IPR2015-01624, Paper 15.
`Patent Owner identifies also several district court and PTO
`proceedings related to the ’415 patent. Paper 6.
`The ’415 Patent (Ex. 1001)
`B.
`The ’415 patent issued on December 18, 2001, and claims priority to
`an application filed on April 8, 1983, now U.S. Patent No. 4,816,567. See
`
`2
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`IPR2016-00383
`Patent 6,331,415 B1
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`Ex. 1001, Title Page. Shmuel Cabilly, Herbert L. Heyneker, William E.
`Holmes, Arthur D. Riggs, and Ronald B. Wetzel are the listed co-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. Id., Abstract.
`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
`recognizes that “the use of recombinant DNA technology can express
`entirely heterologous polypeptides—so-called direct expression—or
`alternatively may express a heterologous polypeptide fused to a portion of
`the amino acid sequence of a homologous polypeptide.” Id. at 4:33–37.
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`
`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
`the opportunity to obtain unique and unprecedented assemblies of
`immunoglobulins, Fab regions, and univalent antibodies.” Id. at 12:52–62.
`Illustrative Claims
`C.
`Petitioner challenges claims 1–4, 9, 11, 12, 14–20, and 33 of the ’415
`patent. Claims 1, 15, 18, and 33 are independent. Independent claims 1 and
`18 are illustrative, and are 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.
`
`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.
`
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`IPR2016-00383
`Patent 6,331,415 B1
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`
`Salser and Ochi2
`
`Salser and Southern3
`
`D. The Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of claims 1–4, 9, 11, 12, 14–20,
`and 33 of the ’415 patent on the following grounds (Pet. 3):
`References
`Basis
`Claims Challenged
`Salser1
`§ 102(e)
`1–4, 9, 11, 12, 15–20, and
`33
`1–4, 9, 11, 12, 14–20, and
`33
`2, 18, and 20
`
`§ 103(a)
`
`§ 103(a)
`
`
`
`Petitioner relies also on the Declaration of Margaret H. Baron, M.D.,
`Ph.D. Ex. 1058.
`
`
`
`ANALYSIS
`Claim Construction
`A.
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable constructions in light of
`the Specification of the patent in which they appear. See 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, No. 15–446, 2016 WL
`3369425, at *12 (U.S. June 20, 2016) (upholding the use of the broadest
`reasonable interpretation standard). Under the broadest reasonable
`
`
`1 Salser et al., U.S. Patent No. 4,396,601, issued Aug. 2, 1983 (Ex. 1002)
`(“Salser”).
`2 Ochi et al., Transfer of a Cloned Immunoglobulin Light-Chain Gene to
`Mutant Hybridoma Cells Restores Specific Antibody Production, 302
`NATURE 340–42 (1983) (Ex. 1003) (“Ochi”).
`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, 1 J. MOLECULAR AND APPLIED GENETICS 327–341
`(1982) (Ex. 1004) (“Southern”).
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`construction standard, claim terms are presumed to have their ordinary and
`customary meaning, as would be understood by one of ordinary skill in the
`art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
`F.3d 1249, 1257 (Fed. Cir. 2007).
`We determine that, for purposes of this Decision, none of the terms in
`the challenged claims require express construction at this time. See, e.g.,
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
`1999) (noting that only claim terms that are in controversy need to be
`construed, and then only to the extent necessary to resolve the controversy).
`35 U.S.C. § 325(d)
`B.
`Patent Owner argues Sanofi is a real party-in-interest in both the
`
`instant proceeding, as well as IPR2015-01624. Prelim. Resp. 9. Patent
`Owner asserts that the prior art relied upon by Petitioner in this case were
`discussed in the Petition in IPR2015-01624, and were submitted also as
`exhibits to that Petition. Id. Patent Owner, therefore, contends that Sanofi
`cannot represent that those references were unknown to it at the time of
`filing of the Petition in IPR2015-01624. Id.
`Patent Owner additionally asserts that the grounds proffered by the
`instant Petition are substantially the same as the challenges raised in the
`petition in IPR2015-01624. Id. at 12–15. Patent Owner argues further that
`the Petition in the instant proceeding has the benefit of Patent Owner’s
`Preliminary Response in IPR2015-01624, and that we should not allow
`Petitioner in this proceeding “a second bite of the apple.” Id. at 15–20.
`Patent Owner, thus, requests that we exercise our discretion under 35 U.S.C.
`§ 325(d) and deny the Petition. Id. at 5.
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`35 U.S.C. § 325(d) states, in relevant part (emphasis added), that “[i]n
`determining whether to institute or a proceeding under this chapter . . . the
`Director may take into account whether, and reject the petition or request
`because, the same or substantially the same prior art or arguments previously
`were presented to the Office.” We have considered the Patent Owner’s
`arguments, along with the facts and circumstances of the instant proceeding,
`and we decline to exercise our discretion to deny the Petition under 35
`U.S.C. 325(d).
`
`Anticipation by Salser (Ex. 1002)
`C.
`Petitioner contends that claims 1–4, 9, 11, 12, 15–20, and 33 are
`anticipated by Salser. Pet. 26–47. Patent Owner disagrees. Prelim. Resp.
`37–52.
`
`Overview of Salser (Ex. 1002)
`i.
`Salser discloses “[m]ethods and compositions . . . for providing
`
`mammalian hosts with additional genetic capability, either a novel capability
`or enhancement of an existing one.” Ex. 1002, 1:46–49. Host cells that are
`capable of regeneration are removed from the host, and genetic material is
`introduced such that the genetic material “becomes capable of replication
`and expression.” Id. at 1:49–52. “The introduced genetic material includes
`at least one marker which allows for selective advantage for the host cells in
`which the introduced genetic material is capable of expression.” Id. at 1:52–
`56. In particular, the genetic material provides for the expression of an
`enzyme. Id. at 1:62–64. Salser teaches further that
`genetic functions can be provided for a variety of purposes
`including treatment of genetic deficiencies, which includes
`providing a genetic capability which the host lacks or production
`of a normal product where the host produces an abnormal one;
`production of enzymes which can protect the host from cytotoxic
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`agents; or for production of a wide variety of proteins e.g.
`hormones, globulins or the like.
`Id. at 2:29–36.
`
`As to the genetic material that may be introduced, Salser teaches:
`The genetic material which is employed for recombination
`with the host cells may be either naturally occurring, synthetic,
`or combinations thereof. Depending upon the mode employed
`for introduction, the size of the genetic material introduced will
`vary. Furthermore, when two or more genes are to be introduced
`they may be carried on a single chain, a plurality of chains, or
`combinations thereof. Restrictions as to the size of a DNA
`fragment will be as a result of limitations due to the technical
`aspects of the vector: if a recombinant DNA is to be used, by the
`packaging requirements of a viral vector; the probability of
`transfer into the recipient cells by the method employed; the
`manner of preparation and isolation of the DNA fragments; or
`the like.
`Id. at 3:46–59.
`
`As to the type of DNA, Salser teaches:
`[T]he types of DNA which will be employed for selective
`markers include genes which react with drugs which interfere
`with regeneration so as to destroy activity of the drug; genes
`which provide sites which are not susceptible to drug action, so
`as to prevent the drug’s action in the particular cell; genes which
`are repetitive for production of a desired protein e.g. an enzyme,
`which is inhibited by the drug; or genes which affect the
`regulatory function of
`the cell, so as
`to provide for
`overproduction of a particular enzyme by the natural processes
`of the cell, and which increase the normal replication of the cell
`genes to enable the cell to better compete for limited resources
`within the body.
`Id. at 4:54–66.
`
`Salser teaches also that the “DNA employed may provide for a single
`gene, a single set of genes, e.g. the beta-globin gene cluster, or a plurality of
`unrelated genes.” Id. at 5:27–29. Salser discloses that “[w]ith the
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`hemoglobinopathies, insertion of a normally regulated and structurally
`normal β-globin gene should be capable of correcting the defect in
`β-thalassemia and sickle cell disease.” Id. at 17:23–26.
`According to Salser:
`The transfer of genes for drug resistance to hematopoietic
`cells in vitro and their selection in intact animals in vivo provides
`for a variety of clinical applications. Such applications include
`the transfer of drug resistance genes with the objective of
`enabling patients with cancer to tolerate higher doses of anti-
`neoplastic drugs and insertion of genes which confer a
`proliferative advantage coupled to other genes to treat human
`genetic diseases such as the hemoglobinopathes.
`Id. at 17:6–33.
`
`Analysis
`ii.
`“Anticipation requires the presence in a single prior art disclosure of
`all elements of a claimed invention arranged as in the claim.” SynQor, Inc.
`v. Artesyn Techs., Inc., 709 F.3d 1365, 1375 (Fed. Cir. 2013) (quoting
`Connell v. Sears, Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983)).
`Nonetheless, “a reference can anticipate a claim even if it ‘d[oes] not
`expressly spell out’ all the limitations arranged or combined as in the claim,
`if a person of skill in the art, reading the reference, would ‘at once envisage’
`the claimed arrangement or combination.” Kennametal, Inc. v. Ingersoll
`Cutting Tool Co., 780 F.3d 1376, 1381 (Fed. Cir. 2015) (quoting In re
`Petering, 301 F.2d 676, 681 (CCPA 1962)); see also In re Preda, 401 F.2d
`825, 826 (CCPA 1968) (noting that “in considering the disclosure of a
`reference, it is proper to take into account not only specific teachings of the
`reference but also the inferences which one skilled in the art would
`reasonably be expected to draw therefrom”).
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`
`“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 might
`somehow combine to achieve the claimed invention.” Net MoneyIN, Inc. v.
`VeriSign, Inc., 545 F.3d 1359, 1371 (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 claims and that give the
`claims their meaning.’” Therasense, Inc. v. Becton, Dickinson & Co., 593
`F.3d 1325, 1332 (Fed. Cir. 2010) (quoting Lindemann Maschinenfabrik
`GMBH v. Am. Hoist & Derrick Co., 730 F.2d 1452, 1459 (Fed. Cir. 1984)).
`“It is well established that the disclosure of a genus in the prior art is
`not necessarily a disclosure of every species that is a member of that genus.”
`Atofina v. Great Lakes Chem. Corp., 441 F.3d 991, 999 (Fed. Cir. 2006).
`Rather, “whether a generic disclosure necessarily anticipates everything
`within the genus . . . depends on the factual aspects of the specific disclosure
`and the particular products at issue.” Sanofi–Synthelabo v. Apotex, Inc., 550
`F.3d 1075, 1083 (Fed. Cir. 2008). Of “critical importance” in conducting
`this analysis is “how one of ordinary skill in the art would understand the
`relative size of a genus or species in a particular technology.” OSRAM
`Sylvania, Inc. v. Am. Induction Techs., Inc., 701 F.3d 698, 706 (Fed. Cir.
`2012). One way that a genus may be narrowed is that the prior art discloses
`a “‘pattern of preferences’” that leads to the claimed species. Sanofi–
`Synthelabo v. Apotex, Inc., 470 F.3d 1368, 1377 (Fed. Cir. 2006).
`Moreover, the reference “must clearly and unequivocally disclose the
`claimed compound or direct those skilled in the art to the compound without
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`any need for picking, choosing, and combining various disclosures not
`directly related to each other by the teachings of the cited reference.” In re
`Arkley, 455 F.2d 586, 587 (CCPA 1972).
`a. Claim 1
`Independent claim 1 requires 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.” As to independent claim 1, Petitioner contends that Salser
`“discloses a process for producing an immunoglobulin molecule in a single
`host cell.” Pet. 33. Specifically, Petitioner asserts that Salser “provides a
`method for producing a ‘wide variety of proteins’ using rDNA technology . .
`. among which are ‘globulins.’” Id. (citing Ex. 1002, 2:29–36; Ex. 1058
`¶ 63).
`According to Petitioner, the ordinary artisan, upon considering the
`
`genus of “globulin proteins” as of April 1983, “would have immediately and
`primarily envisioned the species of immunoglobulins within the genus of
`globulins.” Id. Petitioner asserts that the family of mammalian globulins
`that would have been considered as targets for the gene replacement therapy
`of Salser is defined and limited, with no more than eight members. Id. at
`33–34 (citing Ex. 1058 ¶ 64). Petitioner asserts:
`The Medical Subject Headings index,4 the controlled vocabulary
`for indexing articles and cataloging books and other holdings in
`the National Library of Medicine, identifies three distinct sub-
`genus members of
`the globulin
`family:
`lactoglobulins
`
`4 Petitioner argues that the Medical Subject Headings index is extrinsic
`evidence as to how the ordinary artisan would have understood the term
`“globulin.” Pet. 34–35.
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`
`(lactoferrin), serum globulins, and thyroglobulin. Serum
`globulins are
`further broken down
`into six species:
`immunoglobulins (gamma globulins), alpha-globulins, beta-
`globulins, fibronectins, macroglobulins, and transcobalamins:
`
`
`
`Pet. 34 (citing Ex. 1012, 256–57; Ex. 1058 ¶ 64) (citations omitted)
`(footnote added).
`
`Petitioner asserts further that of the globulins identified in the Medical
`Subject Headings index, immunoglobulins would have been understood to
`be the most important from a medical and therapeutic standpoint, as they are
`necessary for a properly functioning immune system. Id. at 35 (citing Ex.
`1058 ¶ 65). According to Petitioner, the “sole conceptual difference”
`between Salser and the ’415 patent “is that Salser’s cell factory is returned to
`a host whereas the ’415 patent’s cell factory remains ex vivo.” Pet. 27.
`Petitioner asserts, however, that the function of both cells is to produce
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`recombinant proteins that are encoded by inserted foreign genes. Id. (citing
`Ex. 1058 ¶ 59).
`
`Patent Owner responds that Salser does not teach recombinant
`immunoglobulins, and in fact, does not disclose immunoglobulins at all.
`Prelim. Resp. 37. Petitioner, Patent Owner contends, “mischaracterizes the
`‘genus’ disclosed in Salser.” Id. at 38. Specifically, Patent Owner notes that
`the genus of Salser “consists of all hormones, all globulins, and all ‘like’
`proteins, not simply a genus of ‘globulins.’” Id. (citing Ex. 1002, 2:34–35).
`That genus, Patent Owner asserts, is vast. Id. And even if one were to
`consider only the genus of globulins, that genus includes 40 species of
`proteins, including “11 types of alpha globulins, 7 types of beta globulins,
`multiple different types of immunoglobulins and fragments, and several
`other subspecies of ‘globulin’ proteins.” Id. (citing Ex. 1012, 256–57).
`
`Moreover, Patent Owner contends that “Petitioner has not
`demonstrated that Salser would direct one of ordinary skill in the art to
`immunoglobulins specifically.” Id. Petitioner, Patent Owner asserts,
`ignores the fact that Salser focused specifically on treatments for
`hemoglobin-based genetic deficiencies, which were, at the time of Salser,
`important topics of investigation. Id. at 41 (citing Ex. 1002, 17:14; Ex.
`2010, 7).
`
`We agree with Patent Owner that Petitioner has not persuasively
`established that the ordinary artisan, when reading Salser’s genus of
`proteins, which could be a target of the disclosed methods, would “at once
`envisage” the species of “immunoglobulins” as required by challenged claim
`1, even with the specific mention of the subgenus of “globulins.” See
`Kennametal, Inc., 780 F.3d 1376 at 1381.
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`As noted by Patent Owner, the genus of Salser is not limited to
`
`globulins. Prelim. Resp. 38. Rather, Salser teaches:
`genetic functions can be provided for a variety of purposes
`including treatment of genetic deficiencies, which includes
`providing a genetic capability which the host lacks or production
`of a normal product where the host produces an abnormal one;
`production of enzymes which can protect the host from cytotoxic
`agents; or for production of a wide variety of proteins e.g.
`hormones, globulins or the like.
`Ex. 1002, 2:28–36 (emphasis added). And when Salser does focus on
`globulins, the focus is on the beta-globin gene for the treatment of
`hemoglobinopathies. Id. at 5:27–29, 17:6–33. Thus, Salser does not express
`a pattern of preferences such that the ordinary artisan would envision the use
`of DNAs encoding for immunoglobulin heavy and light chains in the gene
`therapy methods taught by that reference.
`
`We have considered the Declaration of Dr. Baron, as well as the
`Medical Subject Headings index, but they do not convince us otherwise.
`Petitioner relies on the Medical Subject Headings index to support its
`contention that the family of mammalian globulins that would have been
`considered as targets for the gene replacement therapy has no more than
`eight members. Pet. 33–34. Moreover, Dr. Baron opines:
`among the globulins identified in the Medical Subject Headings
`at the time, immunoglobulins were inarguably the most
`important of the globulins from a medical and therapeutic
`standpoint.
` Certainly
`immunoglobulins, and specifically
`antibodies, are an important and necessary component of a
`properly functioning immune system. And immunoglobulins
`were the subject of intense research and experimental focus
`before 1983 and remain so to this day. . . . This is reflected by
`their respective frequency of citation in the indexed literature in
`the U.S. National Library of Medicine’s “PubMed” database
`from the beginning of the 20th century until April 1983.
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`Ex. 1058 ¶ 65.
`
`As already discussed, the genus of Salser is not limited to globulins,
`but includes enzymes and hormones and the like. Ex. 1002, 2:28–36.
`Petitioner and its expert do not point us to any teaching in Salser upon
`consideration of the large genus of proteins, including enzymes, hormones,
`globulins and the like, that would have provided a pattern of preferences
`leading to the species of immunoglobulins.
`
`Petitioner contends further that Salser “discloses transforming a single
`host cell with two DNA sequences, encoding the immunoglobulin heavy and
`light chains.” Pet. 36. In particular, Petitioner notes that Salser teaches the
`transformation of mammalian cells with DNA that is capable of replication
`and expression in the host cell. Id. (citing Ex. 1002, 1:49–52; Ex. 1058
`¶¶ 67–68). As taught by Salser, the DNA includes a selectable marker, and
`may also contain other genetic material for the production of a wide variety
`of proteins. Id. at 37 (citing Ex. 1002, 2:15–18, 1:29–36; Ex. 1058 ¶ 68).
`According to Petitioner, Salser discloses that the “full complement of
`genetic material to be incorporated into the host cell by transformation can
`therefore include ‘two or more genes,’ ‘a single set of genes’ or a ‘plurality
`of unrelated genes’ in addition to the selectable marker, and they can be
`‘carried on a single chain, a plurality of chains, or combinations thereof.’”
`Id. at 37–38 (citing Ex. 1002 3:46–53, 5:26–29; Ex. 1058 ¶ 68). Petitioner
`asserts that “[t]hese are all unmistakable references to multiple different
`genes of interest.” Id. at 38 (footnote omitted).
`
`In particular, Petitioner points to Salser’s discussion that a single set
`of genes, such as the beta-globin gene cluster, may be transformed into a
`host cell. Id. at 29. Petitioner notes that as the beta-globin gene cluster is
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`
`five separate genes encoding five different polypeptides, wherein each gene
`is separated by non-coding DNA, expression of the cluster would result in
`five separate polypeptide molecules being expressed. Id. at 29–30.
`
`Therefore, Petitioner asserts that the disclosure of Salser “clearly
`accommodates the insertion into the cell of the two (heavy and light chain)
`DNA sequences that were known to [an ordinary artisan] in 1983 to be
`required to make an immunoglobulin.” Id. at 39 (citing Ex. 1058 ¶ 69).
`Petitioner contends “it takes no more than [an ordinary artisan’s] ordinary
`creativity to understand as a matter of simple logic that producing an
`immunoglobulin in a single host cell transformed with a vector having ‘two
`or more genes’ (or a ‘single set of genes’ or a ‘plurality of unrelated genes’)
`requires that both heavy and light chain DNA sequences be present in the
`single transformed host cell.” Id. at 40 (citing Ex. 1058 ¶ 70). According to
`Petitioner:
`[T]he Salser patent’s teaching to co-express heavy and light
`chains in a single host cell—from the disclosure of producing
`“globulins” by transforming a host cell with “two or more
`genes,” “a single set of genes” or a “plurality of unrelated
`genes”—is in line with the inventors’ goal of creating a gene-
`based treatment for subjects who cannot make, or make an
`incorrect version of, an immunoglobulin with therapeutic value;
`to produce the chains in separate cells and remove them from a
`common environment where they can assemble in vivo into a
`functional (antigen-binding) immunoglobulin would completely
`vitiate the intended goals of the Salser invention.
`Id. at 40–41 (citing Ex. 1058 ¶ 70).
`
`Patent Owner responds that Salser does not disclose the
`transformation of a single host cell with multiple DNA sequences that
`encode immunoglobulin heavy and light chains. Prelim. Resp. 43. Patent
`Owner characterizes Petitioner’s challenge as arguing that “Salser’s
`
`16
`
`
`
`IPR2016-00383
`Patent 6,331,415 B1
`
`disclosure of ‘genes’ (plural) ‘clearly accommodates’ the ‘insertion into the
`cell of the two (heavy and light chain) DNA sequences . . . required to make
`an immunoglobulin.’” Id. (quoting Pet. 39). “[A]ccommodating” such
`functionality as argued by Petitioner, Patent Owner asserts, does not meet
`the standard for anticipation. Id. Specifically, Patent Owner contends
`“Petitioner has only argued that the various disclosures could have been
`arranged by one of ordinary skill in the art in April 1983,” which is
`insufficient for anticipation. Id. at 43–44.
`
`According to Patent Owner, Petitioner has “cobbled together different
`passages from disparate parts of the disclosure” of Salser, by attempting to
`link the disclosure of introducing DNA of two or more genes to Salser’s
`disclosure of globulins. Id. at 44. Nothing in Salser, Patent Owner asserts,
`“discusses the transfection of a single host cell with multiple genes of
`interest with the goal of making a functional multimeric protein.” Id.
`
`Patent Owner argues that Salser’s reference to the beta-globin gene
`cluster does not help Petitioner’s anticipation challenge. Id. at 47. Patent
`Owner argues that the articles cited in the Petition teach that “the beta-globin
`gene cluster is made up of variants of the same gene that are expressed at
`different times during human development, i.e., all five genes are not
`expressed together in nature.” Id. (citing Ex. 1031, 853–854; Ex 1032, 855–
`856; Ex. 2012, 3930–3931; Ex. 2013, 1589). Petitioner, therefore, according
`to Patent owner, “has not shown that its citation to beta-globin discloses
`independent expression of multiple different proteins at the same time.” Id.
`
`Moreover, Patent Owner argues that Salser’s reference to beta-globin
`is not a reference to the transformation of a cell with two different
`exogenous genes of interest, with assembly of those genes into a multimeric
`
`17
`
`
`
`IPR2016-00383
`Patent 6,331,415 B1
`
`protein. Id. at 47–48. Rather, Salser’s reference to beta-globin in Salser is
`related to providing a structurally normal beta-globin gene for treating sickle
`cell anemia, which is caused by a mutation in hemoglobin beta chain. Id. at
`48. Hemoglobin, however, consists of two alpha and two beta chains. Id.
`(citing Ex. 2012, 3927). Thus, Patent Owner contends that, at best, Salser is
`suggesting exogenous introduction of only one of the components of
`hemoglobin, while the alpha chain is endogenous to the host organism. Id.
`
`We agree with Patent Owner that Petitioner has not also persuasively
`established that Salser teaches or suggests transforming a single host cell
`with two DNA sequences encoding the immunoglobulin heavy and light
`chains. Therefore, we agree that Petitioner has failed to persuasively
`establish that Salser anticipates challenged claim 1 because that limitation is
`missing from Salser’s teaching as well. Although Salser teaches that two or
`more genes may be introduced into a host cell, and that those genes may be
`carried on a single chain, a plurality of chains, or combinations thereof (Ex.
`1002, 3:46–59), that teaching, along with Salser’s teaching that the genes
`may be a single set of genes or unrelated genes (id. at 5:27–29), does not
`amount to a teaching that genes encoding for both the immunoglobulin
`heavy and light chains must be incorporated into the same vector or
`otherwise expressed within a single host cell. See Arkley, 455 F.2d at 587.
`
`Moreover, Petitioner’s reliance on Salser’s teaching that the DNA
`may encode the beta-globin cluster is equally unpersuasive. As noted by
`Patent Owner (Prelim. Resp. 47), the beta-globin gene cluster is made up of
`variants of the same gene, which are not expressed together at the same time.
`
`18
`
`
`
`IPR2016-00383
`Patent 6,331,415 B1
`
`Such understanding is supported, for example, by Levings,5 which teaches
`that the “five genes of the human β-globin locus are arranged in a linear
`array on chromosome 11 and are expressed in a developmental stage-
`specific manner in erythroid cells.” Ex. 2013, 1589; see also Ex. 1031, 853–
`854 (noting that the β-globin gene is expressed exclusively in red blood cells
`at specific times in their development). Neither Petitioner nor its expert
`explain how the ordinary artisan would envision the expression of an
`immunoglobulin heavy and light chain DNA sequences after reading Salser
`disclosure of the beta-globin gene cluster, which results in the expression of
`five separate polypeptides at different times. We, thus, determine that
`Petitioner has not sufficiently established that Salser teaches, either
`expressly or inherently, all of the limitations as arranged in challenged claim
`1.
`
`b. Remaining Claims
`In its challenge of the process of independent claim 33, and the
`composition of independent claims 15 and 18, Petitioner relies on the
`teaching of Salser as discussed above
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