Trials@uspto.gov
`571-272-7822
`
`Paper 40
`Date: April 14, 2020
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`GENOME & COMPANY,
`Petitioner,
`v.
`THE UNIVERSITY OF CHICAGO,
`Patent Owner.
`
`PGR2019-00002
`Patent 9,855,302 B2
`
`
`
`
`
`
`
`
`
`
`
`Before SHERIDAN K. SNEDDEN, SUSAN L.C. MITCHELL, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`SCHNEIDER, Administrative Patent Judge.
`
`
`
`
`
`JUDGMENT
`Final Written Decision
`Determining All Challenged Claims Unpatentable
`35 U.S.C. § 328(a)
`
`
`
`
`
`571-272-7822
`
`Paper 40
`Date: April 14, 2020
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`GENOME & COMPANY,
`Petitioner,
`v.
`THE UNIVERSITY OF CHICAGO,
`Patent Owner.
`
`PGR2019-00002
`Patent 9,855,302 B2
`
`
`
`
`
`
`
`
`
`
`
`Before SHERIDAN K. SNEDDEN, SUSAN L.C. MITCHELL, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`SCHNEIDER, Administrative Patent Judge.
`
`
`
`
`
`JUDGMENT
`Final Written Decision
`Determining All Challenged Claims Unpatentable
`35 U.S.C. § 328(a)
`
`
`
`
`
`
`PGR2019-00002
`Patent 9,855,302 B2
`
`
`INTRODUCTION
`I.
`This is a Final Written Decision in a post-grant review challenging the
`patentability of claims 1–29 (“the challenged claims”) of U.S. Patent
`9,855,302 B2 (“the ’302 patent,” Ex. 1001). We have jurisdiction under
`35 U.S.C. § 6, and enter this Decision pursuant to 35 U.S.C. § 328(a) and 37
`C.F.R. § 42.3. For the reasons set forth below, we determine that Genome &
`Company (“Petitioner”) has shown, by a preponderance of the evidence, that
`the challenged claims are unpatentable. See 35 U.S.C. § 326(e) (2012).
`A. Background
`Petitioner filed a Petition requesting post-grant review of claims 1–29
`of the ’302 patent. Paper 1 (“Pet.”). The University of Chicago (“Patent
`Owner”) filed a Preliminary Response. Paper 6 (“Prelim. Resp.”).
`On April 15, 2019, pursuant to 35 U.S.C. §324(a), we instituted trial
`to determine whether any of the challenged claims is unpatentable on the
`grounds raised in the petition. Paper 8 (“Inst. Dec.”).
`Patent Owner filed a Request for Rehearing of our Decision to
`Institute. Paper 11. On January 9, 2020, we denied Patent Owner’s request.
`Paper 34.
`Patent Owner filed a Patent Owner’s Response on August 1, 2019.
`Paper 17 (“PO Resp.”). Petitioner filed a Reply on November 11, 2019.
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`Patent 9,855,302 B2
`Paper 23 (“Pet. Reply”). Patent Owner filed a Sur-Reply on December 17,
`2019. Paper 29 (“PO Sur-Reply”).
`On oral hearing was held on January 15, 2020. A copy of the
`transcript has been made part of the record. Paper 37, 38 (Corrected)
`(“Tr.”).
`
`B. Real Parties in Interest
`Petitioner identifies itself, Genome & Company, as the real party in
`interest. Pet. 3. Patent Owner identifies itself, the University of Chicago, as
`the real part in interest and Evelo Biosciences, Inc. as an additional real
`party in interest. Paper 4, 5
`C. Related Matters
`The parties assert that there are no related matters involving the ’302
`patent. Pet. 3; Paper 4, 5
`
`D. The ’302 Patent
`The ’302 patent, titled “Treatment of Cancer by Manipulation of
`Commensal Microflora” issued on January 2, 2018, from U.S. Patent
`Application No. 15/170,284 filed on June 1, 2016. Ex. 1001, [54], [45],
`[21], [22]. The ’302 patent claims priority to U.S. Provisional Application
`No. 62/169,112 filed on June 1, 2015, and U.S. Provisional Application No.
`62/248,741 filed on October 30, 2015. Id. at [60].
`The ’302 patent teaches the treatment or prevention of cancer through
`the manipulation of commensal microflora either alone or in combination
`with one or more co-treatments. Ex. 1001, Abstr.
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`Patent 9,855,302 B2
`The ’302 patent discloses that aco-treatment can be the administration
`of an immune checkpoint inhibitor (“CPI”).1 Ex. 1001, col. 5, ll. 7–8. The
`CPI used in the practice of the invention disclosed in the ’302 patent can be
`a protein of a peptide, an antibody or fragment thereof, or an interfering
`nucleic acid molecule. Id. at col. 5, ll. 7–20.
`The ’302 patent discloses that one of the microflora that can be used
`in practice of the disclosed invention is bacteria of the genus
`Bifidobacterium. Id. at col. 3, ll. 10–29.
`E. Illustrative Claim
`Of the challenged claims, claims 1 is the sole independent claim and
`reads as follows:
`1. A method of treating cancer in a human subject comprising
`co-administering to the subject an immune checkpoint
`inhibitor and a bacterial formulation comprising bacteria of
`the genus Bifidobacterium.
`Ex. 1001, col. 41, ll. 61–64.
`
`F. Evidence
`Petitioner relies on the following references:
`Korman et al., US 2009/0217401 A1, published Aug. 27, 2009
`(“Korman”) (Ex. 1003).
`
`
`1Immune checkpoint inhibitors are described as follows: “We have learned
`over the last decade that powerful immunologic effector cells may be
`blocked by inhibitory regulatory pathways controlled by specific molecules
`often called ‘immune checkpoints.’ These checkpoints serve to control or
`turn off the immune response when it is no longer needed to prevent tissue
`injury and autoimmunity.” Ex. 1016, Abstr. Drugs that inhibit these
`pathways are called checkpoint inhibitors and their use is seen as a potential
`new strategy for treating cancer. Id.
`
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`Patent 9,855,302 B2
`Singh et al., Bifidobacterium longum, a lactic acid-producing
`intestinal bacterium inhibits colon cancer and modulates intermediate
`biomarkers of cancer carcinogenesis, 18 Carcinogenesis 833 (1997)
`(“Singh”) (Ex. 1004).
`Dong et al., The role of intestinal bifidobacteria on immune system
`development in young rats, 86 Early Human Devel. 51 (2010) (“Dong”)
`(Ex. 1005).
`van der Waaij et al., The influence of antibiotics on gut colonization,
`18 J. Antimicrobial Chemotherapy 155 (1986) (“van der Waaij”) (Ex. 1010).
`Topalian et al., Survival, Durable Tumor Remission, and Long-Term
`Safety in Patients with Advanced Melanoma Receiving Nivolumab, 32
`J. Clinical Oncol. 1020 (2014) (“Topalian”) (Ex. 1006).
`Kohwi et al., Anti-tumor Effects of Bifidobacterium infantis in Mice,
`69 Gann. 613 (1978) (“Kohwi”) (Ex. 1007).
`Mohania et al., Modulation of expression of Programmed Death-1 by
`administration of probiotic Dahi in DMH-induced colorectal carcinogenesis
`in rats, 84 Acta Biomed. 102 (2013) (“Mohania”) (Ex. 1008).
`Prakash et al., US 2010/028449 A1, published Feb. 4, 2010
`(“Prakash”) (Ex. 1009).
`Petitioner also relies on the Declarations of Jonathan Braun, M.D.,
`Ph.D. (Exs. 1002, 1043). Patent Owner relies on the Declaration of Sridhar
`Mani, M.D. (Ex. 2007).
`G. Prior Art and Asserted Grounds
`Petitioner asserts that claims 1–29 would have been unpatentable on
`the following grounds:
`Claim(s) Challenged
`1–29
`
`Reference(s)/Basis
`Enablement
`
`35 U.S.C. §
`112
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`5
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`Patent 9,855,302 B2
`Claim(s) Challenged
`1–9, 12–17, 19–25,
`27, 28
`10, 11, 26
`18, 19
`1–4, 7–9, 12–17, 19–
`25, 27, 28
`5, 6, 23, 24
`10, 11, 26
`18, 29
`1–9, 12–17, 19–25,
`27, 28
`10, 11, 26
`
`18, 29
`
`
`
`35 U.S.C. §
`103(a)2
`
`103(a)
`103(a)
`103(a)
`103(a)
`103(a)
`103(a)
`103(a)
`
`103(a)
`
`103(a)
`
`Reference(s)/Basis
`Korman, Singh, Dong
`Korman, Singh, Dong, van der
`Waaij
`Korman, Singh, Dong, Topalian
`Korman, Kohwi
`Korman, Kohwi, Singh
`Korman, Kohwi, van der Waaij
`Korman, Kohwi, Topalian
`Korman, Mohania, Prakash
`Korman, Mohania, Prakash, van
`der Waaij
`Korman, Mohania, Prakash,
`Topalian
`
`II. ANALYSIS
`A. Legal Standards
`1. Enablement
`“Section 112 requires that the patent specification enable those skilled
`in the art to make and use the full scope of the claimed invention without
`undue experimentation . . . . [S]ee also In re Goodman, 11 F.3d 1046, 1050
`(Fed. Cir. 1993) (‘[T]he specification must teach those of skill in the art how
`to make and how to use the invention as broadly as it is claimed.’).”
`
`
`2 The Leahy-Smith America Invents Act (“AIA”) Pub. Law. No. 112-29,
`125 Stat. 284, 287–288 (2001) amended 35 U.S.C. § 103(a). Because the
`application from which the ’302 patent issued was filed before March 16,
`2013, the effective date of the relevant amendment, the pre-AIA version of
`section 103 applies.
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`Invitrogen Corp. v. Clontech Labs. Inc., 429 F.3d 1052, 1070–71 (Fed. Cir.
`2005) (internal quotes omitted).
`Some experimentation, even a considerable amount, is not “undue” if,
`e.g., it is merely routine, or if the specification provides a reasonable amount
`of guidance as to the direction in which the experimentation should proceed.
`In re Wands, 858 F.2d 731, 736–37 (Fed. Cir. 1988). “Factors to be
`considered in determining whether a disclosure would require undue
`experimentation . . . include (1) the quantity of experimentation necessary,
`(2) the amount of direction or guidance presented, (3) the presence or
`absence of working examples, (4) the nature of the invention, (5) the state of
`the prior art, (6) the relative skill of those in the art, (7) the predictability or
`unpredictability of the art, and (8) the breadth of the claims.” Id. at 737.
`“Whether undue experimentation is needed is not a single, simple factual
`determination, but rather is a conclusion reached by weighing many factual
`considerations.” Id.
`
`2. Obviousness
`The question of obviousness is resolved on the basis of underlying
`factual determinations including (1) the scope and content of the prior art,
`(2) any differences between the claimed subject matter and the prior art, (3)
`the level of skill in the art, and (4) where in evidence, so-called secondary
`considerations. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). If
`the differences between the claimed subject matter and the prior art are such
`that the subject matter, as a whole, would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains, the claim is unpatentable under 35 U.S.C. § 103(a).
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007).
`An invention
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`composed of several elements is not proved obvious
`merely by demonstrating that each of its elements was,
`independently, known in the prior art. Although common sense
`directs one to look with care at a patent application that claims
`as innovation the combination of two known devices according
`to their established functions, it can be important to identify a
`reason that would have prompted a person of ordinary skill in
`the relevant field to combine the elements in the way the
`claimed new invention does.
`
`
`KSR, 550 U.S. at 418.
`
`
`B. Level of Ordinary Skill in the Art
`The level of ordinary skill in the art is a factual determination that
`provides a primary guarantee of objectivity in an obviousness analysis. Al-
`Site Corp. v. VSI Int’l Inc., 174 F.3d 1308, 1324 (Fed. Cir. 1999) (citing
`Graham, 383 U.S. at 17–18; Ryko Mfg. Co. v. Nu-Star, Inc., 950 F.2d 714,
`718 (Fed. Cir. 1991)).
`Dr. Braun, Petitioner’s proffered expert, defines a person of ordinary
`skill in the art as having an advanced degree or its substantial equivalent in
`the biological sciences, including specifically in the fields of immunology,
`microbiology and the microbiome, and oncology, coupled with research
`experience in those fields. Ex. 1002 ¶ 40. Patent Owner does not contest
`Petitioner’s definition of a person of ordinary skill in the art. See generally,
`PO Resp. We determine that Petitioner’s description of the level of ordinary
`skill in the art is supported by the current record. For purposes of this
`Decision, therefore, we adopt Petitioner’s description.
`We also note that the applied prior art reflects the appropriate level of
`skill at the time of the claimed invention. See Okajima v. Bourdeau,
`261 F.3d 1350, 1355 (Fed. Cir. 2001).
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`C. Claim Construction
`In a post-grant review filed before November 13, 2018, the Board
`interprets claim terms in an unexpired patent according to the broadest
`reasonable construction in light of the specification of the patent in which
`they appear. 37 C.F.R. § 100(b) (2018);3 Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131, 2142 (2016) (affirming applicability of broadest reasonable
`construction standard to trial proceeding before the USPTO.). Under that
`standard, and absent any special definitions, we generally give claim terms
`their ordinary and customary meaning, as would be understood by one of
`ordinary skill in the art at the time of the invention. See In re Translogic
`Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definitions
`for claim terms must be set forth with reasonable clarity, deliberateness, and
`precision. See In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`We determine that it is unnecessary to expressly construe any claim
`terms for purposes of this Decision. See 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)).
`
`
`3 The Office recently changed the claim construction standard to be
`employed in a post-grant review for petitions filed on or after November 13,
`2018. See Changes to the Claim Construction Standard for Interpreting
`Claims in Trial Proceedings Before the Patent Trial and Appeal Board, 83
`Fed. Reg. 51,340 (October 11, 2018) (amending 37 C.F.R. § 42.100(b)
`effective November 13, 2018) (now codified at 37 C.F.R. § 42.100(b)
`(2019)). Based on the filing date of the Petition in this proceeding, however,
`the applicable claim construction standard remains the broadest reasonable
`construction as set forth in 37 C.F.R. § 42.100(b) (2016).
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`D. Lack of Enablement
`Petitioner contends that the specification of the ’302 patent fails to
`adequately enable one skilled in the art to make and use the disclosed
`invention for the full scope of the claims. Pet. 36. Petitioner argues that
`when the Wands factors are properly considered, the factors lead to the
`conclusion that undue experimentation would be required to practice the full
`scope of the claims. Id.
`Patent Owner contends undue experimentation is not required to
`practice the invention as “all cancer types were known to be susceptible to
`immune system attack [and] the checkpoint inhibitors known at the time had
`been shown to work across a wide variety of cancer types and mutational
`loads.” PO Resp. 4. Patent Owner also contends that Petitioner has failed to
`present any credible evidence “of functional heterogeneity among
`Bifidobacterium strains or species.” Id.
`With respect to the Wands factors, Patent Owner contends that
`Petitioner’s arguments “boils down to a sheer numbers argument,” which is
`insufficient to show non-enablement. Id. at 37.
`As noted above, our reviewing court has outlined seven different
`factors which should be considered in determining if undue experimentation
`is needed to practice the claimed invention. No one factor is determinative,
`rather the determination should be made after weighing all the factors.
`Wands, 858 F2d at 736. Mindful of this guidance, we consider each of the
`factors in turn.
`
`1. Nature of the Invention
`One of the factors to be considered in the Wands analysis is the nature
`of the invention. Petitioner contends that the invention is directed to treating
`cancer in a human subject by administering both a CPI and a bacterial
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`Patent 9,855,302 B2
`formulation comprising Bifidobacterium. Pet. 36. Petitioner contends that
`the claims are not limited to a specific form of cancer nor to a specific
`species of Bifidobacterium. Id. Petitioner also points out that the broader
`challenged claims do not specify the CPI to be used. Id.
`Petitioner relies on the Declaration of Dr. Braun to support these
`contentions concerning the breadth of the challenged claims. Id. (citing Ex.
`1002 ¶¶ 129–31). In the paragraphs of Dr. Braun’s Declaration cited in the
`Petition, Dr. Braun cites to earlier portions of his Declaration where he
`discusses the teachings of theׄ ’302 patent. Ex. 1002 ¶ 131 (citing to ¶¶ 59–
`63). Dr. Braun discusses the examples in the ’302 patent and explains how
`the teachings of the examples are very limited. Ex. 1002 ¶¶ 59–63.
`Patent Owner does not address this factor other than to contend that
`Petitioner’s analysis presents this factor as a subsidiary point to support
`Petitioner’s argument with regards to the quantity of experimentation
`required. PO Resp. 37–38.
`We have considered the positions of the parties and the evidence of
`record and conclude that Petitioner’s analysis of the nature of the invention
`is correct. The invention is directed to a method for treating any cancer
`using a combination of a CPI and a bacteria from the species
`Bifidobacterium. See, e.g., Ex. 1001, col. 41, ll. 61–64 (Claim 1).
`2. Level of Ordinary Skill in the Art
`Another factor to be considered is the level of ordinary skill in the art.
`Petitioner argues that the level of skill in the art is high, an assessment with
`which we agree on this record. Pet. 37; see supra Section II B. Petitioner
`contends that the ordinarily skilled artisan would have a specialized
`knowledge of cancer, immunology, and microbiota. Petitioner contends that
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`Patent 9,855,302 B2
`this specialized training is necessary as developing a cancer therapeutic is
`difficult, complicated, and highly unpredictable. Id.
`In support of these contentions, Petitioner points to the Declaration of
`Dr. Braun. Id.; Ex. 1002 ¶¶ 132–134 In these paragraphs of his Declaration,
`Dr. Braun cites to earlier paragraphs in his Declaration where he discusses in
`detail the support for his opinion as to the level of skill required to develop a
`cancer therapeutic. Id. at ¶ 133 (citing ¶¶ 93–109).
`Patent Owner has not contested the definition of a person of ordinary
`skill in the art advanced by Petitioner and has not contested Petitioner’s
`contentions as to this factor. See generally, PO Resp.
`For purposes of this decision, we agree with Petitioner that the level
`of ordinary skill is high in developing a cancer therapeutic as evidenced by
`the prior art of record here and that such a skilled artisan would have a
`specialized knowledge of cancer, immunology, and microbiota. See
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (the prior art
`itself can reflect the appropriate level of ordinary skill in the art).
`3. The Breadth of the Claims
`Petitioner contends that the claims are very broad in that they cover
`“thousands of different combinations of cancers, immune checkpoint
`inhibitors and genera of Bifidobacterium.” Pet. 38. Petitioner contends that
`the claims are directed to any type of cancer and that the Specification of the
`’302 patent lists more than 165 types of cancer that can be treated. Id.
`Petitioner also contends that the broader claims do not specify which CPI is
`to be used and that CPIs include a broad class of agents, such as proteins,
`including antibodies and fragments thereof, and nucleic acids. Id.
`In support of these contentions, Petitioner cites to the Declaration of
`Dr. Braun. Id. at 38–41 (citing Ex. 1002 ¶¶ 136, 138–141, 143–146). In the
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`cited paragraphs, Dr. Braun cites to an earlier discussion in his Declaration
`where he describes in detail different types of cancer and explains how each
`is treated by different methods. Ex. 1002 ¶ 138 (citing ¶¶ 95–96). In this
`earlier discussion, Dr. Braun cites to additional references that support his
`opinions. See, e.g. Ex. 1002 ¶ 95 (citing to Kandoth4); Ex. 1021.
`Dr. Braun also discusses the different types of CPIs in general and
`how they have been effective in treating a limited number of cancers and
`only for a limited subset of patients affected by those cancers. Ex. 1002
`¶¶ 100–103. In support of his opinions, Dr. Braun cites to Pardoll,5 which
`discusses CPIs and their use in treating cancer. Id.
`Patent Owner does not dispute the issue of the breath of the claims,
`but appears to agree that the claimed method encompasses any CPI
`combined with any Bifidobacterium to treat any cancer. See PO Resp. 6–9.
`The Specification of the ’302 patent teaches that a CPI may comprise
`a protein or peptide, an antibody or antigen binding fragment thereof, or an
`interfering nucleic acid molecule. Ex. 1001, col. 5, ll. 7–20. Additionally,
`the Specification lists over 165 different cancers that can be treated and lists
`dozens of species of Bifidobacterium that can be used. Id. at col. 2, l. 61–
`col. 4, l. 55. We conclude from the language of the claims when read in
`light of the Specification of the ’302 patent that the scope of the claims is
`broad encompassing a broad range of CPIs and any genus or strain of
`Bifidobacterium to treat a broad range of cancers.
`
`
`4 Kandoth, et al., Mutational landscape and significance across 12 major
`cancer types, 502 NATURE 333 (2013) (“Kandoth”) (Ex. 1021).
`5 D. Pardoll, The blockade of immune checkpoints in cancer immunotherapy,
`12 NAT. REV. CANCER 252 (2012) (“Pardoll”) (Ex. 1026).
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`4. Presence of Working Examples
`Petitioner contends that the examples in the ’302 patent are limited to
`two specific types of cancer, melanoma and bladder, and one CPI. Pet. 41.
`With respect to the Bifidobacterium used in the examples, Petitioner
`contends that the ’302 patent only used mouse feces, which contains one
`unidentified species of Bifidobacterium and other gut bacteria and another
`composition comprising a mixture of four different species of
`Bifidobacterium. Id. at 41–42. Petitioner also notes that the data presented
`in the ’302 patent are limited to mouse data and that no human data are
`discussed. Id. at 42.
`In support of these contentions, Petitioner relies on the Declaration of
`Dr. Braun. Id. As noted above, Dr. Braun discusses the limited nature of
`the experiments reported in the examples citing various passages in the ’302
`patent. Ex. 1002 ¶¶ 59–63, 147–149.
`Again, Patent Owner does not offer any specific argument regarding
`this factor except to argue that, as presented by Petitioner, this factor is
`subsidiary to the factor addressing the amount of testing required. PO Resp.
`37–39.
`After considering the arguments presented by the parties and the
`evidence of record, we conclude that while there are working examples in
`the Specification, the examples give little guidance to one skilled in the art
`about how to practice the broad scope of the claimed invention. The
`examples are based on a single CPI, an antibody against PD-L1. Ex. 1001,
`col. 34, ll. 23–25; col. 36, l. 56–col. 37, l. 9. The Bifidobacterium use was
`limited to an unspecified species of Bifidobacterium present in mouse feces
`and a mixture of four different species of Bifidobacterium. Id. at col. 34, ll.
`13–25, 57–61. The CPI and Bifidobacterium were used against only two
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`types of cancer, melanoma and bladder cancer. Ex. 1001, col. 33, ll. 44–58.
`Thus, we agree with Dr. Braun that the working examples are limited when
`compared to the broad scope of most of the claims, which are directed to
`treatment of any cancer with any species of Bifidobacterium using any CPI.
`5. Amount of Guidance in the Specification
`Petitioner contends that the ’302 patent provides no guidance as to
`which CPI to select to treat a specific cancer. Pet. 42. Petitioner contends
`that the only guidance in the examples is limited to two types of cancer and
`one CPI. Id. Petitioner contends that given the scope of the claims and the
`unpredictable nature of the technology, the guidance given in the ’302 patent
`is inadequate. Id. at 43.
`Petitioner relies on the Declaration of Dr. Braun to support these
`contentions. Id. As described above, Dr. Braun discusses the examples
`provided in the ’302 patent and the guidance given in the rest of the
`Specification. Ex. 1002 ¶¶ 41–63, 150–151.
`Once again, Patent Owner does not address this factor except to
`contend that this factor is subsidiary to the amount of testing required. See
`PO Resp. 37–38.
`We have considered the arguments of the parties and the evidence of
`record and conclude that the guidance in the Specification of the ’302 patent
`as to how to practice the broad claims is limited. While the Specification
`defines CPI broadly as including a protein or polypeptide that binds an
`immune checkpoint as well as an interfering nucleic acid molecule, the CPIs
`listed in the Specification are almost exclusively antibodies, with the
`exception of AMP-224, which is a fusion protein containing a fragment of
`an antibody. Ex. 1001, col. 5, ll. 8–26; Exs. 2034, 1195, 2006. Although
`encompassed within the broad claims as evidenced by their express
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`inclusion as a CPI in the Specification of the ’302 patent, no discussion of
`other CPIs such as interfering nucleic acid molecules can be found in the
`Specification.
`With respect to selection of Bifidobacterium, while the Specification
`only contains the limited examples discussed above, the Specification does
`teach how to identify bifidobacteria that can be used to practice the
`invention. See Ex. 1001, col. 36, l. 43–col. 37, l. 37. Although the
`Specification appears to provide sufficient guidance to determine which
`Bifidobacterium to use, we find that there is insufficient guidance with
`respect to the CPI to use or which cancers to treat.
`6. Predictability of the Art.
`Petitioner contends that the art relating to the claimed invention is
`highly unpredictable. Pet. 43. Petitioner lists several different factors in
`support of this contention, including:
`- Cancer is a term that embraces a variety of specific diseases with
`different etiologies, outcomes, and therapies;
`- There are a limited number of CPIs that have been shown to work
`for a limited number of cancers, and for only a limited subset of
`patients with those cancers;
`- The properties of Bifidobacterium are species and sometimes strain
`specific; and
`- Only certain species of Bifidobacterium have been shown to be
`effective against cancer.
`Pet. 43.
`Petitioner contends that cancer therapy is an unpredictable art.
`Pet. 44. Petitioner contends that cancers develop in different ways and can
`require different methods of treatment. Id.
`
`16
`
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`PGR2019-00002
`Patent 9,855,302 B2
`In support of these contentions, Petitioner cites to the Declaration of
`Dr. Braun. Id. Dr. Braun provides a detailed analysis supporting his
`conclusion that the art of treating cancer is unpredictable. Ex. 1002 ¶¶ 93–
`109, 152–155. In support of his conclusions, Dr. Braun cites to Kandoth and
`Kumar6 for the proposition that there are a variety of different cancer types
`and different methods for treating cancers. Ex. 1002 ¶¶ 95–97. Dr. Braun
`cites to Pardoll to support his conclusions regarding the limited effectiveness
`of CPIs, and cites to DiMasi7 for the proposition that development of a
`cancer therapy is difficult and complicated. Id. at ¶¶ 100–104.
`With respect to the action of Bifidobacterium, Petitioner contends that
`the art demonstrates that different species and strains of the genus affect the
`immune system in different and unpredictable ways. Pet. 32, 44. Petitioner
`contends that this unpredictability makes the use of the bacteria
`unpredictable. Id. at 44–45.
`Petitioner supports its contentions with respect to the unpredictability
`of Bifidobacterium with the declaration of Dr. Braun, the O’Mahony
`published patent application, and articles by Lopez8 and Dong, which
`describe the variability between species and strains of Bifidobacterium. Pet.
`29–31, 44–45; Ex. 1002 ¶ 155; Ex. 1005; Ex. 1017; Ex. 1038.
`Patent Owner responds by contending that CPIs are known to be
`effective against cancer. PO Resp. 4. Patent Owner contends that “Cancers
`
`
`6 Kumar et al., Drug Targets for Cancer Treatment: An Overview, 5 MED.
`CHEM. 115 (2015) (“Kumar”) (Ex. 1022).
`7 DiMasi and Grabowski, Economic of New Oncology Drug Development,
`25 J. CLINICAL ONCOL. 209 (2007) (“DiMasi”) (Ex. 1027).
`8 Lopez et al., Distinct Bifidobacterium strains drive different immune
`responses in vitro, 138 INTERN. J. FOOD. MICROBIO. 157 (2010)
`(“Lopez”) (Ex. 1038)
`
`17
`
`
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`PGR2019-00002
`Patent 9,855,302 B2
`from all manners of tissue types and of all degrees of mutational burden
`have been shown to respond to CPI therapy.” Id. at 6. In support of this
`contention, Patent Owner cites the testimony of Dr. Mani wherein he
`describes the current understanding as to how CPIs promote an
`immunological response to treat cancer. PO Resp. 6–9 (citing Ex. 2007
`¶¶ 23–28; Exs. 2023–2028, 2033).
`Patent Owner also contends that the evidence of record shows that
`that cancer representative of all cancer types respond to CPIs. PO Resp. 9–
`13. Patent Owner again relies on the testimony of Dr. Mani as well as
`several articles which report various clinical trials using CPIs. Id. (citing
`Exs. 2007 ¶¶ 39, 40, 42–45; Exs. 1021, 2029, 2030, 2055, 2056).
`Patent Owner offers the following chart to summarize the results of
`the clinical trials reported at the time the ’302 patent was filed. PO Resp.
`10.
`
`18
`
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`PGR2019-00002
`Patent 9,855,302 B2
`
`
`
`PO Resp. 10 (chart showing summary of clinical trials of CPIs).
`Patent Owner contends that CPIs are considered effective even though
`they may have a low response rate in treating a cancer. PO Resp. 13–16.
`Patent Owner contends that in the area of treating cancer, a 100% response
`rate is not required and that low response rates are often considered
`acceptable given the dire need for cancer treatments. Patent Owner supports
`these contentions with the testimony of Dr. Mani and the exhibits cited by
`Dr. Mani. Id. (citing Ex. 2007 ¶¶ 46–53; Ex. 1006; Ex. 1029; Ex. 1030; Ex.
`2037; Ex. 2058–2061, 2064).
`
`19
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`PGR2019-00002
`Patent 9,855,302 B2
`Patent Owner contends that the use of several different cancer
`treatments before settling in on one that provides a satisfactory result is not
`an indication that such treatments are unpredictable requiring extensive
`testing. PO Resp. 16–18. Patent Owner contends that at the time the present
`application was filed, clinical trials on various CPIs had shown efficacy
`across a wide range of cancers at all levels of mutational load9, and with
`response rates sufficient to persuade the FDA to begin approving them. Id.
`at 18 (citing Ex. 2007 ¶¶ 42–47). This fact, coupled with the oncologist’s
`normal practice of trying several drugs, meant that, for one of ordinary skill
`at the time, testing multiple CPIs to find the best fit for a patient’s cancer
`was simply routine. Id. (citing Ex. 2007 ¶¶ 52–54).
`With respect to the immunological effects of Bifidobacterium, Patent
`Owner contends that the references cited by Petitioner, namely O’Mahony
`and Lopez are not credible and do not support Petitioner’s contentions. See
`PO Resp. 19–30. Patent Owner argues that, “[a]mong other problems,
`neither reference provides sufficient data or statistical analysis to have
`justified one of ordinary skill in the art to reach the conclusions Petitioner
`ascribes to it.” PO Resp. 20 (citing Ex. 2007 ¶¶ 55–56).
`In reply, Petitioner argues that Patent Owner improperly relies on
`third party publications to address deficiencies in the present Specification.
`Pet. Reply 7–8. Petitioner contends that the knowledge of a person of
`
`
`9 Mutational load when used in conjunction with cancer cells is a measure of
`the number of mutations within a tumor genome. It can be used to predict
`responses to certain cancer immunotherapies. Normanno, Tumor Mutational
`Load: ESMO Biomarker Factsheet, https://oncologypro.esmo.org/education-
`library/factsheets-on-biomarkers/tumour-mutational-load, last accessed
`April 7, 2020.
`
`20
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`PGR2019-00002
`Patent 9,855,302 B2
`ordinary skill in the art cannot serve as a substitute for enabling information
`missing in a specification. Id. Petitioner contends
`Here, the ‘302 specification is missing key information,
`not the least of which is its failure to provide a POSITA
`guidance concerning the selection of which of the multiple CPIs
`(which includes countless numbers of proteins, antibodies,
`antibody fragments or interfering nucleic acids) to co-
`administer with which of the 36 Bifidobacterium species or
`strains t
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