UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`JENNEWEIN BIOTECHNOLOGIE GmbH
`Petitioner
`
`v.
`
`GLYCOSYN LLC
`Patent Owner
`____________
`
`Case No.: PGR2019-00023
`Patent 9,970,018
`____________
`
`PETITION FOR POST-GRANT REVIEW
`OF U.S. PATENT NO. 9,970,018
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`III.
`
`MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8 .................... 3
`A.
`Real Parties-In-Interest ........................................................................ 3
`B.
`Related Matters .................................................................................... 3
`C.
`Lead and Backup Counsel ................................................................... 3
`D.
`Service Information ............................................................................. 4
`E.
`Payment of Fees .................................................................................. 5
`BACKGROUND OF THE TECHNOLOGY AT ISSUE ............................. 5
`THE ’018 PATENT ....................................................................................... 8
`A.
`General Overview of Claimed Subject Matter .................................. 10
`B.
`The Challenged Claims ..................................................................... 12
`C.
`Prosecution History of the ’018 Patent’s Great-Grandparent: the
`’230 Patent ......................................................................................... 13
`1.
`The Examiner’s First Enablement Rejection .......................... 13
`2.
`The Examiner’s Second Enablement Rejection ..................... 15
`3.
`The Examiner’s Third Enablement Rejection ........................ 17
`4.
`The Examiner’s Fourth Enablement Rejection ....................... 18
`5.
`The Second RCE ..................................................................... 18
`Prosecution History of the ’018 Patent ............................................. 19
`D.
`IV. CLAIM CONSTRUCTION ........................................................................ 20
`V.
`STANDING ................................................................................................. 20
`A.
`Eligibility for PGR Turns on Whether a pre-March 16, 2013
`Application Satisfies the Written Description and Enablement
`Requirements for Each Claim of the Challenged Patent.................... 22
`The Earlier-Filed Applications Fail to Enable the Full Scope of
`at Least Claim 1 of the ’018 Patent. .................................................. 25
`1.
`Enablement Case Law ............................................................. 26
`
`B.
`
`-i-
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`2.
`
`Failure of the ’230/’018 Patent Specification to Enable
`the Range of “0.05 and 200 Units” Recited by Claim 1 of
`the ’018 Patent ........................................................................ 27
`VI. ARGUMENTS FOR UNPATENTABILITY ............................................. 37
`A.
`Ground 1: Claims 1-28 Are Indefinite for Failing to Specify
`Precisely How to Measure β-Galactosidase Activity. ....................... 39
`1.
`Different Miller Methods Lead to Different Miller Units. ...... 41
`2.
`Imprecise Amounts of Permeabilizing Solvent in the
`Miller Assay Lead to Varied Miller Units. ............................. 44
`Miller Units Results Depend on Unspecified Assay
`Conditions such as Length of Incubation Period, Culture
`Volume and Stage, and Others................................................ 46
`The Patent Fails to Teach When to Measure β-
`Galactosidase Activity. ........................................................... 51
`Ground 2: Claim 1-28 Are Indefinite For Reciting That the
`Activity Level “Comprises” a Range. ............................................... 53
`Ground 3: Claims 1-17 and 19-24 Are Not Enabled by the ’018
`Patent’s Specification. ....................................................................... 56
`VII. CONCLUSION ............................................................................................ 57
`
`3.
`
`4.
`
`B.
`
`C.
`
`-ii-
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`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`PETITIONER’S EXHIBIT LIST
`
`Exhibit # Description
`1001
`U.S. Patent 9,970,018 (the “’018 patent”)
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`Prosecution History of the ’018 Patent
`
`U.S. Patent No. 9,453,230 (the “’230 patent”)
`
`Prosecution History of the ’230 Patent
`
`U.S. Patent No. 9,587,241
`
`U.S. Patent Application No. 15/442,131
`
`U.S. Provisional Patent Application No. 61/443,470
`
`April 7, 2016 Declaration of Co-Inventor John McCoy (the “Second
`McCoy Declaration”)
`
`1009 Miller, J.H., Experiments in Molecular Genetics (Cold Spring Harbor
`Lab. 1972), pp. 352-55 (“Miller”)
`
`1010
`
`1011
`
`1012
`
`Giacomini, et al., “Experimental conditions may affect reproducibility
`of the β-galactosidase assay,” FEMS Microbiology Letters, 100
`(1992), pp. 87-90
`
`Glycosyn LLC GRAS Notice, GRN 735
`
`Goehring et al., Similar to Those who are Breastfed, Infants Fed a
`Formula Containing 2’- Fucosyllactose Have Lower Inflammatory
`Cytokines in a Randomized Controlled Trial, J. Nutr. 146 (12) 2559-
`2566 (2016)
`
`1013 Marriage et al., Infants Fed a Lower Calorie Formula With 2’-FL
`Show Growth and 2’-FL Uptake Like Breast-Fed Infants, JPGN 61:
`649-658 (Marriage et al. (2015)
`
`-i-
`
`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`Exhibit # Description
`Puccio et al., Effects of Infant Formula With Human Milk
`1014
`Oligosaccharides on Growth and Morbidity: A Randomized
`Multicenter Trial, JPGN 64 (4) 624- 631 (2017)
`
`1015
`
`1016
`
`Curriculum Vitae of Dr. Stephanopoulos
`
`Halford, Bethany, “How is directed evolution changing the world?
`Newly minted Nobelist Frances Arnold talks about the past and future
`of evolved enzymes,” Chemical & Engineering News, Vol. 96, Iss. 44,
`Oct. 30, 2018.
`
`1017
`
`Declaration of Dr. Stephanopoulos
`
`-ii-
`
`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`Three defects in the sole independent claim of U.S. Patent No. 9,970,018
`
`(the “’018 patent”) (“Ex. 1001”) render every claim of this patent invalid as
`
`indefinite under 35 U.S.C. § 112(b) and most every claim invalid for want of
`
`enablement under 35 U.S.C. § 112(a).
`
`First, the claim recites a “level of β-galactosidase activity [that] comprises
`
`between 0.05 and 200 units,” but neither the specification nor the publication the
`
`specification relies on to define that measurement adequately identify the
`
`parameters necessary to determine whether a given bacteria will or won’t produce
`
`activity falling within that range. This lack of reasonable certainty as to what the
`
`claims capture renders them indefinite.
`
`Second, the claims’ recitation of an activity level that “comprises between
`
`0.05 and 200 units” injects unreasonable uncertainty by modifying a specified
`
`range with an open-ended term. This inartful claim drafting raises a question
`
`unanswered by any intrinsic evidence: if the claims are limited to the recited range
`
`of activity between 0.05 and 200 units, then what meaning does the open-ended
`
`term comprising have in this claim?
`
`Third, each claim that relies on the broad range of 0.05 to 200 units fails the
`
`enablement requirement of § 112(a). The specification of the ’018 patent—as well
`
`as those of the other applications in this priority chain—fails to show how to
`
`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`genetically modify bacteria capable of producing β-galactosidase activity within
`
`the full scope of the claimed range, or that bacteria producing β-galactosidase
`
`activity at the higher end of the range would still be capable of producing a
`
`fucosyllactose as claimed. The sole example in the patent’s specification claims
`
`activity in a range of only 1-2 units, and even one of the co-inventors was at best
`
`able to provide data of additional activity only up to 5.8 units—a far cry from the
`
`200-unit ceiling recited by the claims.
`
`This enablement issue pervades throughout the only applications that would
`
`entitle the ’018 patent to a pre-March 16, 2013 effective filing date. This failure of
`
`the prior applications to satisfy § 112(a)’s requirement for an enabling disclosure
`
`strips the ’018 patent of its earlier effective filing date, leaving it with its
`
`September 21, 2017 filing date and making it eligible for post-grant review.
`
`Therefore, pursuant to 35 U.S.C. §§ 321-29 and 37 C.F.R. §§ 42.1-.80 &
`
`42.200-.224 et seq., Petitioner Jennewein Biotechnologie GmbH respectfully
`
`requests post-grant review of claims 1-28 of the ’018 patent, which issued on May
`
`15, 2018.
`
`- 2 -
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`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`I.
`
`MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8
`A.
`Real Parties-In-Interest
`Petitioner Jennewein Biotechnologie GmbH is the real party-in-interest in
`
`this proceeding.
`
`Related Matters
`B.
`The following actions brought by Patent Owner against Petitioner may affect
`
`or be affected by a decision in this proceeding:
`• Certain Human Milk Oligosaccharides and Methods of Producing the
`
`Same, Inv. No. 337-TA-1120 (U.S.I.T.C.); and
`• Glycosyn LLC v. Jennewein Biotechnologie GmbH, Case 1:18-cv-
`
`10423 (D. Mass.).1
`
`Lead and Backup Counsel
`C.
`Petitioner designates the following lead and backup counsel:
`
`1 Although the ’018 patent is not presently asserted in this district court case, a
`
`parent to the ’018 patent (U.S. Patent No. 9,453,230) is asserted there. Although
`
`that case is presently stayed pending the ITC investigation, Petitioner anticipates
`
`that, should the stay be lifted, Patent Owner will amend its complaint to include the
`
`’018 patent, as it did for the ITC investigation once the ’018 patent issued. Thus,
`
`Petitioner has identified this case here as potentially affected by this PGR.
`
`- 3 -
`
`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`Lead Counsel
`Bryan Nese (Reg. No. 66,023)
`MAYER BROWN LLP
`1999 K Street, N.W.
`Washington, DC 20006-1101
`Telephone: (202) 263-3266
`Fax: (202) 263-3300
`bnese@mayerbrown.com
`
`Backup Counsel
`Gary M. Hnath
`(permission to file motion for pro hac
`vice admission to be sought)
`MAYER BROWN LLP
`1999 K Street, N.W.
`Washington, DC 20006-1101
`Telephone: (202) 263-3040
`Fax: (202) 263-3300
`ghnath@mayerbrown.com
`
`Scott A. McMurry (Reg. No. 61,152)
`Ying-Zi Yang (Reg. No. 52,381)
`file
`(permission
`to
`Lana Khoury
`motion for pro hac vice admission to
`be sought)
`MAYER BROWN LLP
`1221 Avenue of the Americas
`New York, NY 10020
`Telephone: (212) 506-2500
`Fax: (212) 849-5656
`smcmurry@mayerbrown.com
`yyang@mayerbrown.com
`lkhoury@mayerbrown.com
`
`Service Information
`D.
`Please direct all correspondence regarding this proceeding to counsel at the
`
`address identified above. Petitioner consents to electronic service by email:
`
`ghnath@mayerbrown.com, bnese@mayerbrown.com,
`
`smcmurry@mayerbrown.com, lkhoury@mayerbrown.com, and
`
`- 4 -
`
`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`yyang@mayerbrown.com, with a courtesy copy to US-CLIENT-Jennewein-
`
`ITC@mayerbrown.com.
`
`Payment of Fees
`E.
`Pursuant to 37 C.F.R. § 42.203(a) and 42.15(b), $51,725 is being paid at the
`
`time of filing this Petition, charged to Deposit Account 130019. Should any further
`
`fees be required, the Board is hereby authorized to charge the above referenced
`
`Deposit Account.
`
`II.
`
`BACKGROUND OF THE TECHNOLOGY AT ISSUE
`The challenged claims recite a method for producing fucosylated
`
`oligosaccharides using genetically engineered Escherichia coli (E. coli) bacteria.
`
`An oligosaccharide is a molecule composed of various sugar units
`
`chemically bonded together. For example, the molecule 2’-fucosyllactose
`
`(“2’-FL”), shown in the following image, is composed of three single sugar units
`
`(or “monosaccharides”) chemically bonded together to form a three-membered
`
`oligosaccharide. Ex. 1011 at 1610-11.
`
`- 5 -
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`

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`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`One of these monosaccharides is fucose, which is chemically bonded to the
`
`disaccharide lactose (made of the monosaccharides galactose and glucose) at the 2’
`
`position (shown by the numbering in the prior figure), hence the name 2’-
`
`fucosyllactose or “2’-FL.” Id.
`
`2’-FL is a type of human milk oligosaccharide (“HMO”)—a type of
`
`oligosaccharide naturally found in human breast milk. Ex. 1001 at 1:34-39; Ex.
`
`1004 at 1058. HMOs are thought to be useful in preventing or treating certain
`
`diseases in infants and children. Id.
`
`Recently, interest has grown for using cells to produce oligosaccharides such
`
`as HMOs. Ex. 1017 at ¶¶ 57-58. Producing HMOs by cells requires growing (or
`
`“culturing”) enough cells to produce a measurable amount of product. Id. Culturing
`
`a cell entails placing it in an environment where it will grow, for which the cell
`
`needs nutrients. Id. at ¶ 50. These nutrients are normally supplied by a solution that
`
`bathes the cell in the necessary nutrients, which is called a “medium.” Id.; see also
`
`SkinMedica, Inc. v. Histogen Inc., 830 F. Supp. 2d 986, 988 (S.D. Cal. 2011), aff’d,
`
`- 6 -
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`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
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`727 F.3d 1187 (Fed. Cir. 2013) (“Cell culture medium is the liquid solution used to
`
`‘culture,’ or, ‘grow’ cells in vitro, and typically includes various raw materials—
`
`e.g., amino acids, vitamins, sugars, etc.—that the cells need to grow and expand in
`
`number.”).
`
`Synthesizing 2’-FL requires attaching fucose to the 2’ position of lactose.
`
`Ex. 1017 at ¶35. As shown in the following figure, in a cell, this can be
`
`accomplished by an enzyme called α1,2-fucosyltransferase (“α(1,2)FT”):
`
`Ex. 1001, FIG. 3
`Lactose is critical for making HMOs like 2’-FL. Ex. 1017 at ¶35. One
`
`complicating factor in making 2’-FL is that the lactose feedstock can be cleaved by
`
`- 7 -
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`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`a native E. coli enzyme, LacZ. LacZ is a “b -galactosidase” enzyme that is present
`
`naturally in E. coli. Id. at ¶53. β-galactosidase refers generally to a family of
`
`enzymes that cleave the β-glycosidic bond in lactose, forming its constituent
`
`monosaccharides: galactose and glucose. Id. at ¶54. Because lactose is such an
`
`important feedstock for 2’-FL production, manufacturers must reduce or eliminate
`b -galactosidase activity while 2’-FL is forming. Id. at ¶56.
`
`Once 2’-FL is made, however, purifying 2’-FL from the residual lactose in
`
`the culture medium can be difficult and costly, particularly on a commercial scale.
`Id. at ¶¶12-16. According to the '018 patent, a low or controllable level of b -
`
`galactosidase activity therefore helps purify 2’-FL from the lactose-containing
`
`culture medium when production ends, yet avoids destroying the lactose feedstock
`
`during production. Id.
`
`It is against this backdrop that the inventors of the ’018 patent attempted to
`
`optimize the level of β-galactosidase activity during production of fucosylated
`
`oligosaccharides using genetically engineered bacteria. See Ex. 1001 at 15:62-16:4;
`
`Ex. 1004 at 1058.
`
`III. THE ’018 PATENT
`The ’018 patent is entitled “Biosynthesis of Human Milk Oligosaccharides
`
`in Engineered Bacteria” and issued to inventors Massimo Merighi, John M.
`
`- 8 -
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`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`McCoy, and Matthew Ian Heidtman on May 15, 2018, from an application filed on
`
`September 21, 2017.
`
`The ’018 patent claims priority to February 16, 2011, through a series of
`
`continuation and divisional applications, and one provisional application. Ex. 1001
`
`at (60). Specifically, the ’018 patent is a continuation of Application No.
`
`15/442,131 (Ex. 1006), filed on February 24, 2017, which is a continuation of
`
`Application No. 14/033,664, filed on September 23, 2013, now U.S. Patent No.
`
`9,587,241 (Ex. 1005), which is a divisional of Application No. 13/398,526, filed on
`
`February 16, 2012, now the ’230 patent (Ex. 1003). Id. The ’018 patent also claims
`
`the benefit of Provisional Application No. 61/443,470 (Ex. 1007), filed on
`
`February 16, 2011.
`
`The intervening non-provisional applications have substantially the same
`
`specification and figures as the '018 patent. Compare Ex. 1001 with Ex. 1003 (’230
`
`patent); Ex. 1005 (’241 patent); Ex. 1006 (’131 Application). The ’470 Provisional
`
`Application has a more bare-bones disclosure: it lacks some disclosures that are
`
`present in the non-provisional applications, including some examples. Compare
`
`Ex. 1001 at 16:6-26:50 (Examples 1-8 in ’018 patent); Ex. 1003 at 16:6-26:50
`
`(same in ’230 patent) with Ex. 1007 at 1545-72 (Examples 1-4).
`
`- 9 -
`
`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`Accordingly, the ’018 patent’s specification is representative of the
`
`disclosures of each of its parent non-provisional applications (including the ’230
`
`patent), and the ’470 Provisional Application contains no additional (and, in fact,
`
`less) support. Ex. 1017 at ¶¶ 62-65. For this reason, because the parent non-
`
`provisional applications do not enable the claims of the '018 patent, the ’470
`
`Provisional Application also does not enable the claims of the ’018 patent. See
`
`Dynamic Drinkware LLC v. National Graphics Inc., 800 F.3d 1375, 1381 (2015)
`
`(“A reference patent is only entitled to claim the benefit of the filing date of its
`
`provisional application if the disclosure of the provisional application provides
`
`support for the claims in the reference patent in compliance with Section 112…”).
`
`General Overview of Claimed Subject Matter
`A.
`The ’018 patent describes methods for engineering E. coli bacteria to
`
`produce fucosylated oligosaccharides, such as 2’-FL. See, e.g., Ex. 1001 at claim 1.
`
`For example, the ’018 patent purports to describe strategies for manufacturing
`
`HMOs “inexpensively” using engineered E. coli strains “for low-cost, large-scale
`
`production of fucosylated oligosaccharides.” Id. at 15:62-16:4; Ex. 1004 at 1058.
`
`According to statements made in the prosecution history of the ’018 patent’s
`
`parent, “[a] prototype production host strain was developed that is useful in
`
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`

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`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`bioreactor production of the oligosaccharides while facilitating purification of the
`
`desired oligosaccharide products.” Ex. 1004 at 1058.
`
`Specifically, the ’018 patent purports to describe engineered E. coli strains
`
`with reduced levels of β-galactosidase (LacZ) activity as compared to wild type
`
`(naturally occurring) strains. Id. For example, the ’018 patent claims an E. coli
`
`bacterium with β-galactosidase activity of 0.05-200 units. See id.; Ex. 1001 at
`
`claim 1.
`
`Because β-galactosidase cleaves lactose, high levels of β-galactosidase will
`
`interfere with production of 2’-FL. Ex. 1017 at ¶56. According to the Patent
`
`Owner, when using strains that produce reduced levels of β-galactosidase activity,
`
`“[t]he system strikes a balance between production of desired fucosylated
`
`oligosaccharides and the level of β-galactosidase produced. The 0.5-200 [sic] unit
`
`level chosen maximizes oligosaccharide end product production while preserving
`
`the advantage of depleting a bacterial culture of residual lactose at the end of
`
`production runs.” Ex. 1004 at 1058.
`
`Put more simply, according to the ’018 patent, relatively low levels of β-
`
`galactosidase may allow for producing HMOs without degrading the lactose
`
`feedstock, while higher levels of β-galactosidase (as in the wild type) will deplete
`
`lactose, interfering in 2’-FL production. See id.; Ex. 1017 at ¶56.
`
`- 11 -
`
`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`The claimed range of β-galactosidase activity (“between 0.05 and 200
`
`units”) is at the center of both the enablement and indefiniteness issues in this
`
`Petition.
`
`The Challenged Claims
`B.
`The patent includes 28 claims, all of which are challenged here. Claim 1 is
`
`the ’018 patent’s sole independent claim. It reads as follows:
`
`1.
`
`A method for producing a fucosylated oligosaccharide in a
`bacterium, comprising
`providing an isolated E. coli bacterium comprising,
`(i)
`a deletion or functional inactivation of an
`endogenous β-galactosidase gene;
`(ii) an exogenous functional β-galactosidase gene
`comprising a detectable level of β-galactosidase
`activity that is reduced compared to that of a wild-
`type E. coli bacterium, wherein the level of β-
`galactosidase activity comprises between 0.05 and
`200 units;
`(iii) an inactivating mutation in a colanic acid synthesis
`gene; and
`(iv) an exogenous lactose-accepting fucosyltransferase
`gene;
`culturing said bacterium in the presence of lactose; and
`retrieving a fucosylated oligosaccharide from said bacterium or
`from a culture supernatant of said bacterium.
`
`- 12 -
`
`

`

`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`C.
`
`Prosecution History of the ’018 Patent’s Great-Grandparent: the
`’230 Patent
`With few exceptions (discussed in the following section), little of relevance
`
`to this Petition occurred during the ’018 patent’s prosecution history. However,
`
`much occurred during prosecution of the patent’s great-grandparent that informs
`
`the issues here. Accordingly, a discussion of the relevant prosecution history must
`
`begin with the ’230 patent.
`
`The Examiner’s First Enablement Rejection
`1.
`During prosecution of the ’230 patent, Primary Examiner Rebecca Prouty
`
`rejected all of the claims for failing to meet the enablement requirement of 35
`
`U.S.C. § 112(a). Ex. 1004 at 669-704 (December 4, 2013 Non-Final Office Action
`
`at 7-12). Specifically, she noted as follows:
`
`Claims 11-20 and 39-47 [all of the pending claims] are
`rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-
`AIA), first paragraph, because the specification, while
`being enabling for methods of producing a fucosylated
`oligosaccharide by culturing in the presence of lactose an
`E. coli comprising an E. coli lacY gene, a mutation of an
`endogenous wcaJ, wzxC, wcaD, wza, wzb, or wzc gene
`which inactivate the production of colonic acid in said
`bacterium, a fucosyltransferase gene selected from the E.
`coli wbsJ gene, the Helicobacter pylori futC gene, the
`Helicobacter pylori futA gene and the Bacteroides
`fragilis wcfW gene and an E. coli lacZ gene lacking an
`operably linked promoter and optionally one or more of a
`mutation of an endogenous lacA gene such that the E.
`coli has reduced lactose acetyltransferase activity, a
`
`- 13 -
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`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`mutation of an endogenous lon gene such that the E. coli
`has reduced lon protease activity or expression of an
`exogenous E. coli rcsA and/or rcsB gene, does not
`reasonably provide enablement for methods of producing
`a fucosyltated oligosaccharide by culturing
`in
`the
`presence of lactose any enteric bacterium comprising any
`functional β-galactosidase gene, any lactose permease
`gene, any mutation of a colonic acid synthesis gene and
`any fucosyltransferase gene and optionally any mutation
`of a lacA or lon gene and expression of any exogenous
`rcsA and/or rcsB gene. The specification does not enable
`any person skilled in the art to which it pertains, or with
`which it is most nearly connected, to make and use the
`invention commensurate in scope with these claims.
`Id. at 169-70.
`
`In particular, Examiner Prouty recognized that the claims “are so broad as to
`
`encompass methods of producing a fucosylated oligosaccharide by culturing any
`
`enteric bacterium comprising any functional β-galactosidase gene, any lactose
`
`permease gene, any mutation of a colonic acid synthesis gene and any
`
`fucosyltransferase gene.” Id. at 700. She continued:
`
`The scope of the claims is not commensurate with the
`enablement provided by the disclosure with regard to the
`extremely large number of bacteria to be used in the
`methods of the claims. A skilled artisan would not expect
`all bacteria comprising a functional β-galactosidase
`(particularly any bacteria with high levels of β-gal
`activity) to be useful in the claimed methods as β-
`galactosidase degrades the lactose acceptor substrate.
`
`Id.
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`PGR2019-00023
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`Examiner Prouty also observed that the ’230 patent’s specification—the
`
`same specification as the ’018 patent—teaches only a “single” species of
`
`functional β-galactosidase gene, “which produces only 1-2 units of β-
`
`galactosidase.” Id. at 700-701.
`
`The Examiner’s Second Enablement Rejection
`2.
`On June 4, 2014, Patent Owner amended the claims to recite that the “β-
`
`galactosidase activity comprises between 0.05 and 200 units” (id. at 813),2 but
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`Examiner Prouty maintained her enablement rejection, id. at 886-889 (Aug. 8,
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`2014 Final Office Action at 7-10).
`
`In her August 8, 2014 Final Office Action, Examiner Prouty stated, “[a]
`
`skilled artisan would not expect all bacteria comprising a functional β-
`
`galactosidase having from 5-200 units of activity under inducing conditions to be
`
`useful in the claimed methods as β-galactosidase degrades the lactose acceptor
`
`substrate.” Id. at 887. She noted that, although the specification describes only a
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`“single species” capable of producing 1-2 units of β-galactosidase, “the claims
`
`encompass bacteria having up to 100-200 fold greater activity.” Id. at 888.
`
`2 This same limitation for the level of β-galactosidase activity (“between 0.05 and
`
`200 units”) also appears in the sole independent claim of the ’018 patent.
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`Patent No. 9,970,018
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`PGR2019-00023
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`She found the specification’s discussion of β-galactosidase activity at these
`
`high levels lacking: “The specification includes no evidence that the presence [of]
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`any lacZ gene which produces activity levels of from 5-200 units is not detrimental
`
`to producing a fucosylated oligosaccharide as would be expected.” Id. (emphasis
`
`added). Because “the claims clearly encompass” bacteria producing β-
`
`galactosidase at higher levels than 1-2 units, the full scope of the claims was not
`
`enabled. Id.
`
`Examiner Prouty also rejected Patent Owner’s arguments that the
`
`specification “in combination with the common knowledge in the art” overcome
`
`the specification’s failure to enable the full scope of the claimed β-galactosidase
`
`activity. Id. at 888-889. In rejecting that argument, she noted that a person of
`
`ordinary skill in the art “would expect that the claimed bacteria would degrade the
`
`lactose substrate” at high levels of β-galactosidase activity. Id. at 888.
`
`Specifically, although the specification purportedly showed that β-
`
`galactosidase activity in the narrow range of 1-2 units is not detrimental to the
`
`lactose substrate, the claims broadly recited “bacteria having levels of activity of
`
`up to 100-200 fold higher without any showing that these levels are not detrimental
`
`as would be expected.” Id. at 888-889. Finding the specification wanting for any
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`Patent No. 9,970,018
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`showing of how this higher range would enable production of fucosylated
`
`oligosaccharides, Examiner Prouty maintained her rejection. Id.
`
`The Examiner’s Third Enablement Rejection
`3.
`On February 9, 2015, the Patent Owner filed a Request for Continued
`
`Examination (RCE) containing new arguments traversing the enablement rejection.
`
`Id. at 1048-1072. Along with these arguments, Patent Owner submitted a first
`
`declaration from co-inventor John McCoy, signed February 9, 2015 (the “First
`
`McCoy Declaration”). Id. at 1068-1072.
`
`Neither the Patent Owner’s arguments nor the First McCoy Declaration were
`
`sufficient to overcome the specification’s failure to enable the full scope of the
`
`claim limitation requiring β-galactosidase activity between 0.05 and 200 units.
`
`Thus, on May 8, 2015, Examiner Prouty maintained her enablement rejection for a
`
`third time. Id. at 1100-1103. She again noted that the specification only describes
`
`production of HMOs wherein the β-galactosidase activity is around 1-2 units, not
`
`the 0.05 to 200 units recited by the claims. Id. at 1101.
`
`She also addressed the First McCoy Declaration. On that point, she
`
`explained that the declaration “does not show that the range of activity of the
`
`bacteria of Figure 2 of the declaration encompasses the claimed range of 0.05-200
`
`units claimed.” Id. at 1102. “Without any indication of the level of β-gal activity
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`Patent No. 9,970,018
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`present in the bacteria of Fig. 2 of the declaration,” she noted, “the declaration does
`
`not provide evidence that the claimed range of β-gal activities will not deplete the
`
`lactose pool such that the desired fucosylated oligosaccharide end product will not
`
`be made.” Id.
`
`The Examiner’s Fourth Enablement Rejection
`4.
`On November 9, 2015, the Patent Owner attempted to overcome the
`
`enablement rejection yet again—this time by amending certain dependent claims.
`
`Id. at 1174-75. None of those amendments, however, changed the broad range of
`
`β-galactosidase activity called for by every claim. See id.
`
`Unsurprisingly, on January 22, 2016, Examiner Prouty stood by her
`
`enablement rejection. Id. at 1186-88. Examiner Prouty noted that the Patent Owner
`
`“did not provide any argument specifically directed to [her enablement] rejection.”
`
`Id. at 1188. She also recognized that “the amendments to the claims did not alter
`
`the level of β-galactosidase activity encompassed by the claimed methods.” Id.
`
`The Second RCE
`5.
`On April 21, 2016, the Patent Owner filed a second RCE. Id. at 1218-36.
`
`However, that RCE still left the claimed range of β-galactosidase activity
`
`unmodified. See id. at 1222 (showing no amendments to independent claim 11).
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`The second RCE also included a “supplemental” declaration from Dr.
`
`McCoy (the “Second McCoy Declaration” (separately submitted here as Ex.
`
`1008)). Id. at 1328-32. That declaration purports to show 2’-FL production through
`
`thin-layer chromatogram (“TLC”) stains in E. coli strains having β-galactosidase
`
`activity measured at 1.5, 2.5, and 5.8 units. Ex. 1008 at 1593 (Table 1). Based on
`
`just these three data points, Dr. McCoy concluded that β-galactosidase activity of
`
`up to 200 units would produce acceptable amounts of 2’-FL. Id. at 1594-95 (¶11,
`
`Table 2).
`
`Following the Patent Owner’s submission of the Second McCoy
`
`Declaration, Examiner Prouty withdrew her enablement rejection and allowed the
`
`claims to issue. See Ex. 1004 at 1333-41.
`
`Prosecution History of the ’018 Patent
`D.
`Presumably to address the same enablement issues with the same claim
`
`limitation of “between 0.05 and 200 units” of β-galactosidase activity, Examiner
`
`Prouty required the Patent Owner to submit the Second McCoy Declaration in the
`
`’018 patent’s prosecution history. See Ex. 1002 at 353 (letter from Patent Owner
`
`stating that “Examiner Prouty indicated that she would allow the above-referenced
`
`application if Applicant: … (ii) submitted a Declaration of John McCoy that was
`
`originally filed in the parent of the subject application.”).
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`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`IV. CLAIM CONSTRUCTION
`For purposes of this proceeding, only one claim term needs construction.
`
`The term “units” in the claim phrase “between 0.05 and 200 units” was defined by
`
`the ’018 patent: “for unit definition see: Miller J H, Laboratory CSH. Experiments
`
`in molecular genetics. Cold Spring Harbor Laboratory Cold Spring Harbor, N.Y.;
`
`1972 [attached as Ex. 1009]; incorporated herein by reference.” Ex. 1001 at 7:30-
`
`37. Thus, the patentee unambiguously defined “units” in the claims to be the units
`
`as defined by the Miller paper.
`
`Petitioner believes that the Board can evaluate the § 112 issues in this
`
`Petition without construing any other term of the ’018 patent. See Wellman, Inc. v.
`
`Eastman Chem. Co., 642 F.3d 1355, 13661 (Fed. Cir. 2011) (“[C]laim terms need
`
`only be construed ‘to the extent necessary to resolve the controversy.’” (citations
`
`omitted)).
`
`Nevertheless, Petitioner reserves the right to respond to any claim
`
`construction positions advanced by the Patent Owner.
`
`V.
`
`STANDING
`Pursuant to 37 C.F.R. § 42.204(a), Petitioner certifies that the ’018 patent is
`
`available for post-grant review and that Petitioner is not barred or estopped from
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`Patent No. 9,970,018
`Petition for Post-Grant Review
`PGR2019-00023
`
`requesting a post-grant review challenging claims 1-28 on the grounds identified in
`
`this Petition.
`
`This Petition is timely filed u