By:
`
`John A. Bauer
`Nelson Mullins Riley & Scarborough LLP
`280 Park Avenue, 15th Floor West
`New York, NY 10017
`(646) 428-2615 (telephone)
`(646) 428-2610 (facsimile)
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`GENOME & COMPANY,
`Petitioner
`
`v.
`
`THE UNIVERSITY OF CHICAGO,
`Patent Owner
`___________________
`
`Case No. PGR2019-00002
`U.S. Patent 9,855,302 B2
`___________________
`
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`i
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES ................................................................................ iv
`
`TABLE OF EXHIBITS ......................................................................................... v
`
`TABLE OF ABBREVIATIONS ............................................................................ x
`
`I.
`
`II.
`
`SUMMARY OF ARGUMENT .................................................................... 1
`
`THE CLAIMS OF THE ‘302 PATENT ARE INVALID .............................. 3
`
`A.
`
`PO’s Failure to Cite to the ‘302 Specification to Rebut
`Petitioner’s Lack of Enablement Assertions Confirms the ‘302
`Specification Does Not Enable the ‘302 Claims .................................. 3
`
`1.
`
`2.
`
`3.
`
`PO Fails to Address the Broad Scope of the Functionally
`Claimed CPIs, Broad Genus of Bifodobacterium Species,
`and Inoperable Routes of CPI and Bifodobacterium
`Administration .......................................................................... 3
`
`PO Fails to Deny the ‘302 Specification Does Not
`Provide Meaningful Guidance to Practice the Claimed
`Invention ................................................................................... 6
`
`The Undisputed Lack Of Guidance Provided By the ‘302
`Specification Combined with The Highly Unpredictable
`Nature of CPIs and Bifidobacterium to Treat Cancer in
`Humans Confirms That Extensive and Undue
`Experimentation Is Required To Practice The Claimed
`Invention ................................................................................... 6
`
`B.
`
`PO’s Reliance Exclusively on Third Party CPI Publications to
`Rebut Petitioner’s Lack of Enablement Charge Fails to Rescue
`the Deficient ‘302 Disclosure .............................................................. 7
`
`1.
`
`PO’s Reliance Exclusively on Third Party Publications
`To Supply Necessary Information Missing From the ‘302
`Specification Is Not Only Legally Impermissible But
`Also Substantively Deficient ..................................................... 7
`
`ii
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`2.
`
`3.
`
`4.
`
`Cancer Immunotherapy Is Vastly More Complex and
`Uncertain Than Simply Targeting Immune Checkpoints ......... 12
`
`CPIs Show Low Response Rates In A Limited Number
`Of Cancers And For Only A Subset Of Cancer Patients
`Having Those Cancers ............................................................ 13
`
`PO Fails to Rebut Petitioner’s Evidence that Extensive
`and Undue Experimentation Is Required To Practice the
`Claims of the ‘302 Patent ........................................................ 15
`
`III. The ‘302 Claims are Obvious (3841 Words Up to Here) ............................. 18
`
`A.
`
`B.
`
`C.
`
`(Ground 2) Korman ‘401 in View of Singh and Dong Render
`Obvious Claims 1-9, 12-17, and 19-25, and 27-28 ............................ 18
`
`(Ground 5) Korman ‘401 in View of Kohwi Renders Obvious
`Claims 1-4, 7-9, 12-17, 19-25, and 27-28 .......................................... 21
`
`1.
`
`Claims 5, 6, 9, 10, 11, 23, 24 and 26 Are Obvious .................. 24
`
`Ground (9) Korman ‘401 in View of Mohania and Prakash ‘449
`Renders Obvious Claims 1-9, 12-17, and 19-25, and 27-28 .............. 25
`
`IV. CONCLUSION .......................................................................................... 28
`
`
`
`
`
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`
`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
` Page(s)
`
`Cases
`
`ALZA Corp. v. Andrx Pharm. LLC, 603 F.3d 935 (Fed. Cir. 2010) ......................... 8
`
`Enzo Life Sciences, Inc. v. Roche Molecular Systems et al,
`928 F.3d 1340 (Fed. Cir. 2019) .......................................................................... 8
`
`Genentech Inc. v. Novo Nordisk A/S, 108 F.3d 1361 (Fed. Cir. 1997) ................. 3, 7
`
`
`
`
`
`iv
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`TABLE OF EXHIBITS
`
`
`Previously Filed Exhibits
`
`
`Exhibit Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`U.S. Patent No. 9,855,302
`
`First Declaration of Jonathan Braun, M.D., Ph.D.
`
`U.S. Publication No. 2009/027401 to Korman et al.
`
`Jagveer Singh et al., Bifidobacterium longum, a lactic acid-producing
`intestinal bacterium inhibits colon cancer and modulated the
`intermediate biomarkers of colon carcinogenesis, Carcinogenesis
`(1997)
`
`Ping Dong et al., The role of intestinal Bifidobacteria on immune
`system development in young rats, Early Human Development (2010)
`
`Suzanne L. Topalian et al., Survival, Durable Tumor Remission, and
`Long-Term Safety in Patients With Advanced Melanoma Receiving
`Nivolumab, Journal of Clinical Oncology (Apr. 1, 2014)
`
`Yoshinori Kohwi et al., Antitumor effect of Bifidobacterium Infantis in
`Mice, Gann (Oct. 1978)
`
`Dheeraj Mohania et al., Modulation of expression of Programmed
`Death-1 by administration of probiotic Dahi in DMH-induced
`colorectal carcinogenesis in rats, Acta Biomed (2013)
`
`U.S. Publication No. 2010/0028449 to Prakash et al.
`
`D. van der waaij et al., The Influence of antibiotics on gut
`colonizastion, Journal of Antimicrobial Chemotherapy (1986)
`
`Do Kyung Lee et al., Anti-proliferative effects of Bifidobacterium
`adolescentis SPM0212 extract on human colon cancer cell lines, BMC
`Cancer, (Oct. 2008)
`
`U.S. Provisional Patent Application No. 62/169,112
`
`U.S. Provisional Patent Application No. 62/248,741
`
`File History of U.S. Patent No. 9,855,302
`
`File History of U.S. Patent Application No. 15/718,735
`
`Elad Sharon et al, Immune checkpoints in cancer clinical trials,
`Chinese Journal of Cancer (2014)
`
`1017
`
`U.S. Publication No. 2012/0276143 to O’Mahony et al.
`
`v
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`Exhibit Description
`
`U.S. Publication No. 2007/0258953 to Duncan et al.
`1018
`1019 Mosby’s Medical dictionary 8th ed. (2009)
`Dorland’s Illustrated Med Diction 31st ed. (2007)
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`Cyriac Kandoth et al., Mutational landscape and significance across
`12 major cancer types, Nature (Oct. 17, 2013)
`
`Shashank Kumar et al., Drug Targets for Cancer Treatment: An
`Overview, Medicinal Chemistry (2015)
`
`Targeted Cancer Therapies, National Cancer Institute,
`https://www.cancer.gov/about-cancer/treatment/types/targeted-
`therapies/targeted-therapies-factsheet
`
`Andrew M. Scott et al., Monoclonal antibodies in cancer therapy,
`Cancer Immunity Commentary (May 1, 2012)
`
`Henrique Neves et al., Recent advances in the field of anti-cancer
`immunotherapy, BBA Clinical (2015)
`
`Drew M. Pardoll, The blockade of immune checkpoints in cancer
`immunotherapy, Nature Reviews Cancer (Apr. 2012)
`
`Joseph A. DiMasi et al., Economics of New Oncology Drug
`Development, Journal of Clinical Oncology (Jan. 10, 2007)
`
`Satheesh Thungappa et al., Immune checkpoint inhibitors in lung
`cancer: the holy grail has not yet been found…, ESMO Open (2017)
`
`Naiyer A. Rizvi et al., Mutational landscape determines sensitivity to
`PD-1 blockade in non-small cell lung cancer, Science (2015)
`
`Julie R. Brahmer et al., Phase I Study-Agent Anti-Programmed Death-
`1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity,
`Pharmacodynamics, and Immunologic Correlates, Journal of Clinical
`Oncology (July 1, 2010)
`
`D. T. Le et al., PD-1 Blockade in Tumors with Mismatch-Repair
`Deficiency, The New England Journal of Medicine (2015)
`
`Jocelyn Kaiser, Why a powerful cancer drug only helps some patients,
`Science(Mar. 12, 2015)
`
`Alexandra Snyder et al., Genetic basis for clinical response to CTLA-4
`blockade in melanoma, The New England Journal of Medicine (2014)
`
`Ivaylo I. Ivanov et al. Intestinal commensal microbes as immune
`modulators,” Cell Host & Microbe (2012)
`
`vi
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`Exhibit Description
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`Lora V. Hooper et al., Interactions between the microbiota and the
`immune system” Science (June 8, 2012)
`
`Kenya Honda et al., The Microbiome in Infection Disease and
`Inflammation, Annual Review of Immunology (2012)
`
`Paul B. Eckburg et al., Diversity of the human intestinal microbial
`flora, Science (June 10, 2005)
`
`Patricia Lopez et al., Distinct Bifidobacterium strains drive different
`immune responses in vitro, International Journal of Food Microbiology
`(2010)
`
`U.S. Publication No. 2008/0193373 to Stritzker et al.
`
`Bandaru S. Reddy et al., Inhibitory effect of Bifidobacterium longum
`on Colon, Mammary, and Liver Carcinogenesis Induced by 2-Amino-
`3-methylimidazo[4,5-f]quinolone, a Food Mutagen,” Cancer Research
`(Sept. 1, 1993)
`
`
`New Exhibits
`
`
`Exhibit Description
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`Charlene M. Fares et al., Mechanisms of Resistance to Immune
`Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunity Not
`Work for All Patients?, American Society of Clinical Oncology
`Educational Book, 39:147-164 (May 17, 2019)
`
`Transcript of Deposition of Sridhar Mani, M.D., on September 26,
`2019 (141 pages)
`
`Second Declaration of Jonathan Braun, M.D., Ph.D.
`
`Borja Sánchez et al., The Effects of Bifidobacterium breve on Immune
`Mediators and Proteome of HT29 Cells Monolayers, BioMed
`Research International, 2015 (Article ID 479140):1-6 (2015)
`
`Vanessa K. Ridaura et al., Gut Microbiota from Twins Discordant for
`Obesity Modulate Metabolism in Mice, Science, 341:1079, 1241214
`(2013)
`
`1046
`
`Gavin P. Dunn et al., The Three Es of Cancer Immunoediting, Annu.
`Rev. Immunol., 22:329-360 (2004)
`
`vii
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`Exhibit Description
`
`1047
`
`1048
`
`1049
`
`Patrick Blanco et al., Dendritic cells and cytokines in human
`inflammatory and autoimmune diseases, Cytokine & Growth Factor
`Reviews, 19 (Issue 1):41-52 (2008)
`
`Reza Aghebati Maleki et al., Effects of some natural
`immunomodulatory compounds in combination with thalidomide on
`survival rate and tumor size in fibrosarcoma-bearing mice, Advanced
`Pharmaceutical Bulletin, 4, Suppl 1:465-470 (2014)
`
`Blanda Di Luccia et al., Lactobacillus gasseri SF1183 Affects
`Intestinal Epithelial Cell Survival and Growth, PLoS ONE,
`8(7):e69102 (2013)
`
`1050 Mario Uccello et al., Potential role of probiotics on colorectal cancer
`prevention, BMC Surgery, 12 (Suppl 1):S35(1-8) (2012)
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`Yu-Jie Zhang et al., Impacts of Gut Bacteria on Human Health and
`Diseases, Int. J. Mol. Sci., 16:7493-7519 (2015)
`
`Natarajan Sithranga Boopathy et al., Effect of Mangrove Tea Extract
`from Ceriops decandra (Griff.) Ding Hou. on Salivary Bacterial Flora
`of DMBA Induced Hamster Buccal Pouch Carcinoma, Indian Journal
`of Microbiology, 51(3):338-344 (2011)
`
`Yoram Bouhnik et al., Four-week short chain fructo-oligosaccharides
`ingestion leads to increasing fecal bifidobacteria and cholesterol
`excretion in healthy elderly volunteers, Nutrition Journal, 6(42):1-7
`pages (2007)
`
`Yan Yin et al., Therapeutic efficacy of Bifidobacterium longum-
`mediated human interleukin-2 with endostatin or TRAIL in
`transplanted tumors in mice, Experimental and Therapeutic Medicine,
`3:481-486 (2012)
`
`Rakesh K. Jain et al., Can engineered bacteria help control cancer?,
`PNAS, 98(26):14748-14750 (2001)
`
`I. Brook, Isolation of non-sporing anaerobic rods from infections in
`children, J Med Microbiol., 45(1):21-26 (1996)
`
`Emmanuelle Weber et al., Bifidobacterium Species Bacteremia: Risk
`Factors in Adults and Infants, Clin Infect Dis., 61(3):482-484 (2015)
`
`Hilde Cheroutre et al., The light and dark sides of intestinal
`intraepithelial lymphocytes, Nature Reviews Immunology, 11(7):445-
`456 (2011)
`
`viii
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`Exhibit Description
`
`1059
`
`Declaration of Andrew Schultz
`
`
`
`
`
`
`ix
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`TABLE OF ABBREVIATIONS
`
`
`Abbreviation
`Description
`U.S. Patent 9,855,302
`“302 Patent”
`“PO”
`Patent Owner
`“POR”
`Patent Owner’s Response (Paper 17)
`“CPI”
`Checkpoint Inhibitor
`Petition for Post Grant Review (Paper 1) “Pet.”
`Institution Decision (Paper 8)
`“I.D.”
`
`
`
`
`
`
`
`x
`
`

`

`I.
`
`SUMMARY OF ARGUMENT
`
`The ‘302 Patent fails to provide sufficient disclosure to enable a POSITA to
`
`practice the full scope of the claimed invention, viz, methods of treating any type of
`
`cancer in a human subject by co-administering the combination of any CPI with any
`
`species of Bifidobacterium.
`
`PO does not rely on a single citation from the ‘302 Patent to rebut Petitioner’s
`
`lack of enablement assertions.1 In lieu thereof, PO impermissibly relies exclusively
`
`on third party publications, nearly all of which were not incorporated by reference,
`
`allegedly (a) showing low CPI response rates for a few CPIs against a small number
`
`of cancers, and (b) supporting the assertion a POSITA would have held a reasonable
`
`belief that CPIs could, in theory, treat all cancers. Further, according to PO, although
`
`treating cancer with CPIs is unpredictable and requires trial and error testing, such
`
`testing is routine precisely because a POSITA would have expected to engage in
`
`such testing.
`
`Enablement is not established in an unpredictable field such as cancer therapy
`
`by proffering low CPI response rates for a few CPIs in a small number of cancers in
`
`which most treatments fail. Moreover, PO omits the fact that there are many immune
`
`mechanisms of tumor cell evasion not attributable to immune checkpoints.
`
`
`1
`PO’s expert spent less than an hour reviewing the ‘302 Patent and its file
`history. Ex. 1042, 12:11-13:7.
`
`
`1
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`Nor is enablement established by asserting theoretical possibilities of CPIs
`
`and that trial and error testing is routine, while concurrently not disputing that the
`
`‘302 specification does not provide guidance for practicing the invention.
`
`Furthermore, PO’s reliance exclusively on third party publications showing
`
`low CPI response rates for a few CPI’s in a small number of cancers fails to address
`
`enablement of what is actually claimed, i.e., methods of co-administering the
`
`combination of any CPI, which includes a nearly limitless number of proteins,
`
`antibodies, antibody fragments, and interfering nucleic acids, with any of the 36
`
`species of Bifidobacterium to treat any cancer in a human subject.
`
`In short, PO’s Response falls far short of rebutting Petitioner’s lack of
`
`enablement evidence.
`
`PO’s obviousness rebuttal fares no better. Faced with unequivocal statements
`
`in the cited prior art that the Bifidobacterium organisms described therein exert
`
`antitumor activity, PO attempts to whitewash them by alleging those references
`
`lacked the experimental scientific rigor to support those statements.
`
`PO’s argument is groundless. First, the statements in those prior art references
`
`stand on their own. Second, Petitioner’s prior art references were referenced in
`
`subsequently published, peer reviewed articles for the proposition that the
`
`Bifidobacterium organisms described therein exhibited antitumor properties.
`
`2
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`PO also attacks Petitioner’s alleged motivation combine the CPI reference
`
`with the various Bifidobacterium references, asserting Petitioner’s Bifiodobacterium
`
`references do not describe an immunostimulatory Bifiodobacterium organism. That
`
`assertion is also incorrect and contradicted by subsequently published peer reviewed
`
`articles. Furthermore, the combination of references was also proper because both
`
`the CPI reference and Bifidobacterium references each describe the CPI and
`
`Bifidobacterium organisms as having anti-cancer properties. Accordingly, the cited
`
`prior art references, when interpreted correctly, were properly combined and
`
`provided a reasonable expectation of success, thereby rendering the claimed
`
`invention obvious.
`
`II. THE CLAIMS OF THE ‘302 PATENT ARE INVALID
`
`A.
`
`PO’s Failure to Cite to the ‘302 Specification to Rebut Petitioner’s
`Lack of Enablement Assertions Confirms the ‘302 Specification
`Does Not Enable the ‘302 Claims
`
`1.
`
`PO Fails to Address the Broad Scope of the Functionally
`Claimed CPIs, Broad Genus of Bifodobacterium Species,
`and Inoperable Routes of CPI and Bifodobacterium
`Administration
`
`§112(a) requires that “the specification of a patent must teach those skilled in
`
`the art how to make and use the full scope of the claimed invention without “undue
`
`experimentation.” Genentech Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1365 (Fed.
`
`Cir. 1997). Claim 1 recites:
`
`3
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`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 at 41:62-64.
`
`The claimed “immune checkpoint inhibitor” is a functional limitation
`
`covering a nearly limitless number of molecular entities. It includes any “protein or
`
`polypeptide that binds an immune checkpoint” (Pet., 8; I.D., 4), including
`
`“antibodies or antigen binding fragments that bind to and inhibit an immune
`
`checkpoint protein.” Id. It also includes “an interfering nucleic acid molecule”
`
`including “an shRNA molecule or an antisense RNA molecule.” Id. See also
`
`dependent claims 12 and 15, respectively, claiming the CPI “is a protein or
`
`polypeptide that binds to an immune checkpoint protein” or “antibody or antigen
`
`binding fragment thereof that binds to an immune checkpoint protein.” Pet. 39.2
`
`Significantly, PO’s expert admitted his analysis did not include enablement of
`
`any antigen binding fragments or interfering nucleic acid molecules. Ex. 1042, 19:7
`
`- 29:6.3 And the ‘302 specification does not provide any guidance for making
`
`
`2
`The opinions are of Dr. Braun. Ex. 1033, 90:20-92:10.
`
`None of Exhibits 2009, 2011-2014, or 2016 describe the use of antibody
`
`
`
` 3
`
`fragment as a CPI. Ex. 1043, ¶16-18.
`
`4
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`fragments or interfering nucleic acid molecules that successfully function as CPIs.4
`
`Pet.8; Ex 1043, ¶15. Thus, on those grounds alone, the claims of the ‘302 patent are
`
`not enabled. Pet., 1, 8, 38-40.5
`
`PO’s expert also admitted he did not consider the claim term “co-
`
`administering,” which the ’302 specification defines to include administering the
`
`check point inhibitor orally, topically or via an aerosol, or administering the
`
`Bifidobacterium topically or by inhalation, and further admitted those routes of
`
`administration were likely inoperable. Ex. 1042, 29:17 – 30:3; see also Pet., 46-47.
`
`That testimony provides additional evidence that the claims are not enabled.
`
`
`
`Peititioner’s expert is not aware of any antibody fragments or interfering
`
` 4
`
`
`
`nucleic acids showing efficacy as a CPI in treating cancer. Ex. 1043, ¶19.
`
`PO alleges Petitioner did not address enablement of the dependent claims –
`
`
`
` 5
`
`claims 14, 17, and 28 in particular. POR, 36, 37. PO is wrong. See Pet, 40.
`
`Petitioner also addressed these dependent claims, sometimes in groups: 1-
`
`29; 1-11, 19-26; 12-18, 27-29; 12, 15, 13, 16, 14, 17, 18, 29; and 1-3, 5-21, and 23-
`
`29. Pet, 38-41; 45-48.
`
`
`
`
`
`
`
`5
`
`

`

`2.
`
`PO Fails to Deny the ‘302 Specification Does Not Provide
`Meaningful Guidance to Practice the Claimed Invention
`
`There is no meaningful guidance provided by the ‘302 specification
`
`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`instructing (a) which of the limitless number of CPIs should be co-administered with
`
`(b) which of the 36 species of Bifidobacterium or strain thereof to (c) treat which of
`
`the over 165 types of cancers of listed in the ‘302 specification. I.D., 14-15; Pet.,
`
`42-43. In fact, other than a few mouse experiments involving two types of cancer
`
`(melanoma and bladder), one immune checkpoint inhibitor (αPD-L1 antibody), and
`
`a cocktail of four different Bifidobacterium species (Bifidobacterium: B. breve, B.
`
`longum, B. lactis, and B.bifidum.) a POSITA would not find any direction or
`
`guidance from the specification. I.D., 14-15, Pet., 41-43.
`
`Significantly, PO does not dispute that the ‘302 patent does not provide
`
`guidance for practicing the claimed invention. Its failure to do so speaks volumes
`
`to the lack of enablement of the claimed invention.
`
`3.
`
`The Undisputed Lack Of Guidance Provided By the ‘302
`Specification Combined with The Highly Unpredictable
`Nature of CPIs and Bifidobacterium to Treat Cancer in
`Humans Confirms That Extensive and Undue
`Experimentation Is Required To Practice The Claimed
`Invention
`
`In light of the unpredictable nature of cancer therapy, combined with the
`
`unpredictable nature of CPIs and different species of Bifidobacterium, the failure of
`
`the ‘302 specification to provide guidance concerning which CPI should be co-
`
`6
`
`

`

`PGR2019-00002
`U.S. Patent 9,855,302 B2
`
`administered with which Bifidobacterium species, or even strain of Bifidobacterium
`
`species, to treat which of the over 165 types of cancers of listed in the ‘302
`
`specification confirms that a POSITA would have to engage extensive and unduly
`
`burdensome testing that would take years to complete. See section §II.B, infra.
`
`B.
`
`PO’s Reliance Exclusively on Third Party CPI Publications to
`Rebut Petitioner’s Lack of Enablement Charge Fails to Rescue
`the Deficient ‘302 Disclosure
`
`1.
`
`PO’s Reliance Exclusively on Third Party Publications To
`Supply Necessary Information Missing From the ‘302
`Specification Is Not Only Legally Impermissible But Also
`Substantively Deficient
`
`PO attempts to rebut Petitioner’s lack of enablement evidence by relying
`
`exclusively on third party publications, nearly all of which are not incorporated by
`
`reference, that report low CPI response rates for a few CPIs in a limited number of
`
`cancers and for only a subset of cancer patients having those cancers. PO also relies
`
`on such third party publications as providing support for its assertion that a POSITA
`
`would have held a reasonable belief that CPI’s could, in theory, treat all cancers
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`because CPIs unblock the immune system, thereby preventing the tumor cells from
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`continuing to evade the immune system. POR, 4-16.
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`PO’s reliance entirely on such third party publications is impermissible as a
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`matter of law. Although a patent specification need not disclose what is well known
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`in the art, “that general, oft-repeated statement is merely a rule of supplementation,
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`not a substitute for a basic enabling disclosure.” Genentech, 108 F.3d at 1366
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`7
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`U.S. Patent 9,855,302 B2
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`(emphasis added). “[A] patentee ‘cannot simply rely on the knowledge of a person
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`of ordinary skill to serve as a substitute for the missing information in the
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`specification.” Enzo Life Sciences, Inc. v. Roche Molecular Systems et al, 928 F.3d
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`1340,1347 (Fed. Cir. 2019), citing ALZA Corp. v. Andrx Pharm. LLC, 603 F.3d 935,
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`941 (Fed. Cir. 2010).
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`Here, the ‘302 specification is missing key information, not the least of which
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`is its failure to provide a POSITA guidance concerning the selection of which of the
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`multiple CPIs (which includes countless numbers of proteins, antibodies, antibody
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`fragments or interfering nucleic acids) to co-administer with which of the 36
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`Bifidobacterium species or strains thereof, to treat which of the 165 cancers listed in
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`the ‘302 patent.
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`Furthermore, PO’s reliance on third party publications showing low CPI
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`response rates of a few CPIs in a small number of cancers fails to address enablement
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`of what is actually claimed, viz, methods of co-administering the combination of a
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`CPI and Bifidobacterium to treat cancer in a human subject. (Significantly, if proof
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`of enablement in this case could be satisfied by simply showing the anti-cancer
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`properties of CPIs, then the ‘302 claims are not inventive.)
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`Noticeably absent from PO’s Response is the citation to any evidence showing
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`the combination of a CPI and Bifidobacterium to treat cancer. The failure of PO to
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`do so is critical given the limited disclosure of the ‘302 patent and the fact that the
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`8
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`properties of Bifidobacterium are not only unpredictable, but also species and
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`U.S. Patent 9,855,302 B2
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`sometimes strain specific.
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`Indeed, to secure allowance of the ‘302 Patent, PO represented that
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`Bifidobacterium longum strain 1714 described in O’Mahoney (Ex. 1017) was
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`immunosuppressive. PO stated:
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`O'Mahoney et al. teach that the disclosed Bifidobacterium
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`strain suppresses such immune responses.
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`Ex. 1014, 123-132, 132. And in a subsequent response, PO reiterated that
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`“O’Mahoney describes suppression of immune response.” Ex. 1014, 57-65, 64. 6
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`The ‘302 patent,
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`in contrast, describes Bifidobacterium
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`longum as
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`immunostimulatory. Pet, 11-12; Ex. 1001, 38:36-58; 39:12-40:54. Similarly, Dong
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`(Ex. 1005) also describes Bifidobacterium longum as immunostimulatory. Pet., 50-
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`51. Notably, Drs. Gajewski, Sivan, and Corrales, inventors of the ‘302 patent,
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`expressly referenced Dong as describing “[s]timulatory interactions between
`
`
`6
`PO’s assertions that O’Mahoney’s data are not trustworthy or otherwise
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`insufficient to draw any conclusion regarding its immune effects are thus directly
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`contradicted by PO’s express representations made to the USPTO to secure
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`allowance. See POR, 20-24; see also Ex. 1043, ¶23-30 (explaining that
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`O’Mahoney’s data are sufficient to draw conclusions regarding the
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`Bifidobacterium’s immune effects.)
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`
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`bifidobacteria [longum] and the host immune system, including those associated
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`with interferon-(cid:1) (IFN(cid:1)).7 Ex. 2005, 1085.
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`Significantly, the ‘302 patent also pointed to elevated levels of T-cell induced
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`IFN-γ as evidence of bifidobacterium’s immunostimulatory function to activate
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`dendritc cells. Ex. 1001, 39:43-40:54. Ex. 1043, ¶41.
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`In addition, Lopez reported testing twelve different strains belonging to four
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`different species of Bifidobacterium and concluded that “this work shows species
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`and strain specific effects of Bifidobacterium.” Pet. 30-31, Ex. 1038, 164.
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`PO attacks Lopez, asserting that its methodology is unreliable. POR, 19, 24-
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`36. However, a subsequently published, peer reviewed journal cited Lopez as
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`describing strain specific effects of Bifidobacterium that correlate to different in vivo
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`effects, i.e., Th1 and Th2 responses:
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`It is known that different probiotic bacteria present
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`different effects upon the immune system [7, [Lopez]],..
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`Some strains promote Th1 responses, characterized by the
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`
`PO’s assertion that a POSITA would not have concluded Dong shows
`7
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`Bifidobacterium Longum is immunostimulatory is thus expressly contradicted by
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`the inventors of the ‘302 Patent. See POR, 53; see also Ex. 1043, ¶31-42
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`(explaining Dong’s methodology is sound and confirming its description of an
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`immunostimulatory B. Longum characterized by induction of IFN- γ. (¶40 citing to
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`Ex. 1046).
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`production of IFN(cid:1) and TNF(cid:2), whereas other strains
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`induce anti-inflammatory cytokines generating a Th2
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`profile [7, [Lopez]]
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`Ex. 1044.8 The above quote also shows, contrary to PO’s assertions, that the data in
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`Lopez does show how the immune system would be effected, in vivo, i.e, by
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`generating a Th1 or Th2 response. POR, 32; Ex. 1043, ¶¶43-44, see also ¶¶ 45-51
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`explaining that Lopez’s conclusions are well substantiated, including the critical role
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`of IFN(cid:1) and IL-12 being immunostimulatory, citing to Ex. 1046, 1047.)
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`Furthermore, PO’s expert admitted that the properties of each species and
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`strain of each species of bifidobacterium must be tested; its properties cannot be
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`predicted. Ex. 1042 at 138:5-25.
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`In sum, given the overwhelming evidence showing the properties of
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`bifidobacterium are unpredictable and species and strain specific, PO’s failure to cite
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`to any evidence showing co-administration of the combination of a CPI and a species
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`of bifidobacterium to treat even a limited number of cancers in a human, let alone a
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`significant portion of all cancers encompassed by the claims, is fatal to rebutting
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`Petitioner’s lack of enablement case.
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`8
`Sanchez et al., Ex. 1044.
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`11
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`2.
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`Cancer Immunotherapy Is Vastly More Complex and
`Uncertain Than Simply Targeting Immune Checkpoints
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`PO asserts that all cancer cells express and present foreign antigens on their
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`surfaces, and therefore, all cancer cells are recognizable, at least in theory, by the
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`immune system. POR, 4-9.
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`Immune checkpoints, however, suppress the functioning of the immune
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`system, thereby allowing the tumor cells to evade the immune system. Thus,
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`according to PO, by administering a checkpoint inhibitor to inhibit the function of
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`the immune checkpoint, the functioning of the immune system will be restored and,
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`in theory, all cancer cells, regardless of cancer type, will be recognized by the
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`immune system and destroyed. POR, 8-9.
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`PO’s theory ignores that fact that there are many immune mechanisms by
`
`which tumor cells evade the immune system.. Immune checkpoints are merely one
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`those immune mechanisms. Ex. 1043, ¶59.
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`For example, tumor cells can secrete immunosuppressive factors such as
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`TGF-ß, indoleamine-pyrrole-2,3-dioxygenase (1DO), tryptophan-2,3-dioxygenase
`
`(TDO), galectin 3, or natural killer cell decoys. Ex. 1043, ¶60, citing to Ex. 2028,
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`308, 309. Tumor cells can also produce immunosuppressive metabolites such as
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`lactic acid, adenosine, and prostaglandins. Id. They can also decrease their
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`antigenicity by downregulating or extinguishing HLA class I molecules. Id.
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`Non-tumor cells can also contribute to immunosuppressive mechanisms.
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`These include “regulatory T [Treg] cells that could be attracted to some tumors by
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`chemokines, and myeloid-derived suppressor cells and their contact-dependent
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`immunosuppression, which involves nitrogen oxide (NO) and reactive oxygen
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`species (ROS).” Ex. 1043, ¶61, citing to Ex. 2028, 309.
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`Another mechanism by which the tumor cells evade the immune system is the
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`inability of the immune cells to penetrate the tumor. Ex. 1043, ¶62, citing to Ex.
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`2028, 310.
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`PO’s expert admitted he did not account for any of these possibilities when
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`rendering his enablement analysis. Ex. 1042: 47:21-59:3.
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`3.
`
`CPIs Show Low Response Rates In A Limited Number Of
`Cancers And For Only A Subset Of Cancer Patients Having
`Those Cancers
`
` PO asserts that “cancers from all manner of tissue types and all degrees of
`
`mutational burden have been shown to respond to CPI therapy,” and therefore, it
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`“would not have been necessary to test all cancers for CPI efficacy.” See POR, 9-
`
`13, 6. PO alleges that a sample of clinical trial reports, whose results are tabulated
`
`in a demonstrative Table at page 10 of the POR, showed responses in cancers arising
`
`in a wide variety of tissue types that are collectively representative of all cancers.
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`POR, 11. Further, those reports showed responses in cancers throughout the
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`13
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`mutational landscape, as shown in demonstrative annotated Figures at p. 11 and 12
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`of the POR. Id.
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`Patent Owner grossly overstates its case. Those clinical trial reports provide
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`data for a total of 3 different checkpoint inhibitors: CTLA-4, PD-1, and PD-L1; and
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`for 16 types of cancer. None of the CPI’s are antibody fragments or interfering
`
`nucleic aci