Trials@uspto.gov
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` Entered: June 27, 2019
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`JENNEWEIN BIOTECHNOLOGIE GmbH
`Petitioner,
`
`v.
`
`GLYCOSYN LLC,
`Patent Owner.
`____________
`
`Case PGR2019-00023
`Patent 9,970,018 B2
`____________
`
`
`
`Before ERICA A. FRANKLIN, JACQUELINE T. HARLOW, and
`RICHARD J. SMITH, Administrative Patent Judges.
`
`HARLOW, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Post-Grant Review
`35 U.S.C. § 324(a)
`
`ORDER
`Denying Patent Owner’s Motion to Seal (Paper 7) without Prejudice
`37 C.F.R. § 42.55
`
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`571-272-7822
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`PUBLIC VERSION
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` Paper No. 8
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` Entered: June 27, 2019
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`JENNEWEIN BIOTECHNOLOGIE GmbH
`Petitioner,
`
`v.
`
`GLYCOSYN LLC,
`Patent Owner.
`____________
`
`Case PGR2019-00023
`Patent 9,970,018 B2
`____________
`
`
`
`Before ERICA A. FRANKLIN, JACQUELINE T. HARLOW, and
`RICHARD J. SMITH, Administrative Patent Judges.
`
`HARLOW, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Post-Grant Review
`35 U.S.C. § 324(a)
`
`ORDER
`Denying Patent Owner’s Motion to Seal (Paper 7) without Prejudice
`37 C.F.R. § 42.55
`
`
`
`
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`PUBLIC VERSION
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`PGR2019-00023
`Patent 9,970,018 B2
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`
`I. INTRODUCTION
`Petitioner, Jennewein Biotechnologie GmbH, filed a Petition
`requesting post-grant review of claims 1–28 of U.S. Patent
`No. 9,970,018 B2 (Ex. 1001, “the ’018 patent”) pursuant to 35 U.S.C.
`§§ 321–329. Paper 1 (“Pet.”). Patent Owner, Glycosyn LLC, filed a
`Preliminary Response. Paper 5 (“Prelim. Resp.”).1 Patent Owner also filed
`a Motion to Seal Exhibit 2002, designated by Petitioner as confidential in a
`related proceeding before the International Trade Commission, as well as
`portions of the Preliminary Response referring to Ex. 2002. Paper 7.
`We have authority, acting under the designation of the Director, to
`determine whether to institute post-grant review. 35 U.S.C. § 324;
`37 C.F.R. § 42.4(a). Post-grant review may be instituted only if “the
`information presented in the petition . . . demonstrate[s] that it is more likely
`than not that at least 1 of the claims challenged in the petition is
`unpatentable.” 35 U.S.C. § 324(a). Upon consideration of the Petition and
`Preliminary Response, as well as all supporting evidence, we determine that
`the Petition fails to demonstrate that it is more likely than not that the
`’018 patent is eligible for post-grant review. Accordingly, we deny
`institution of post-grant review. We also deny, without prejudice, Patent
`Owner’s Motion to Seal.
`
`
`1 Patent Owner filed unredacted (Paper 5) and redacted (Paper 6) versions of
`the Preliminary Response. Our citations are to Paper 5, the unredacted
`version.
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`A. Related Matters
`The ’018 patent is the subject of an investigation before the U.S.
`International Trade Commission, captioned Certain Human Milk
`Oligosaccharides and Methods of Producing the Same, Inv. No. 337-1120
`(USITC) (“the related ITC Investigation”). Pet. 3; Paper 3, 1. The parties
`additionally identify as a related matter Glycosyn LLC v. Jennewein
`Biotechnologie GmbH, Case 1:18-cv-10423 (D. Mass.), which is stayed in
`view of the aforementioned investigation, and concerns U.S. Patent
`No. 9,453,230 B2 (“the ’230 patent”), to which the ’018 patent claims
`priority. Pet. 3; Paper 3, 1.
`
`B. The ’018 Patent
`The ’018 patent is titled “Biosynthesis of Human Milk
`Oligosaccharides in Engineered Bacteria.” Ex. 1001, (54). As its title
`suggests, the ’018 patent discloses methods for producing purified human
`milk oligosaccharides (“HMOs”), including, in particular, fucosylated
`oligosaccharides, that are typically found in human milk. Id. at 1:26–30.
`The ’018 patent explains that HMOs, although unimportant for infant
`nutrition, play a critical role in establishing a healthy microbiome,
`preventing disease, and developing immune function. Ex. 1001, 1:34–39.
`According to the patent, however, known methods for producing HMOs at
`scale were limited by “stereo-specificity issues, precursor availability,
`product impurities, and high overall cost.” Id. at 1:40–44.
`To overcome these challenges, the ’018 patent discloses a method for
`manipulating certain genes and pathways within Escherichia coli (“E. coli”)
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`bacteria to produce purified fucosylated oligosaccharides. Ex. 1001, 2:28–
`31. In particular, the patent teaches genetically modifying E. coli bacteria to
`generate the “enhanced cellular pool of both lactose and GDP-fucose”
`required for biosynthesis of fucosylated HMOs. Id. at 16:27–29; see also id.
`at 16:29–18:60. Figure 3 of the ’018 patent, illustrating such an engineered
`bacterium is reproduced below.
`
`
`Figure 3 “is a schematic demonstrating metabolic pathways and the changes
`introduced into them to engineer 2′-fucosyllactose (2′-FL) synthesis in
`Escherichia coli (E. coli).” Id. at 12:20–30. As illustrated in Figure 3, the
`’018 patent discloses genetically modifying the host bacterium to decrease
`β-galactosidase (“lacZ”) activity, thereby increasing the intracellular pool of
`lactose available for syntheses of 2′-FL. Id. at Fig. 3.
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`a
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`fucosylated
`
`C. Illustrative Claim
`Claim 1, the sole independent claim of the ’018 patent, reproduced
`below, is illustrative of the claimed subject matter.
`1.
`A method
`for
`producing
`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.
`Ex. 1001, 111:41–57 (emphasis added).
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`D. Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 39,
`53, 56):
`
`Claims
`
`1–28
`
`1–28
`1–17, 19–24
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`Legal Basis
`Indefiniteness for failure to specify precisely how to
`measure β-galactosidase activity
`Indefiniteness for reciting that β-galactosidase
`activity “comprises” a range
`Lack of enablement
`
`Petitioner relies on the Declaration of Gregory Stephanopoulos, Ph.D.
`(Ex. 1017) to support its challenge.
`
`II. POST-GRANT REVIEW ELIGIBILITY
`Post-grant review is available only for patents “described in section
`3(n)(1)” of the Leahy-Smith America Invents Act (“AIA”), Pub L. No. 112-
`29, 125 Stat. 284 (2011). AIA § 6(f)(2)(A). Those are patents that issue
`from applications “that contain[ ] or contained at any time . . . a claim to a
`claimed invention that has an effective filing date in section 100(i) of title
`35, United States Code, that is on or after” “the expiration of the 18-month
`period beginning on the date of the enactment of” the AIA. Id. at § 3(n)(1).
`Because the AIA was enacted on September 16, 2011, post-grant
`review is available only for patents issued from applications that, at one
`point, contained at least one claim with an “effective filing date,” as defined
`by 35 U.S.C. § 100(i), on or after March 16, 2013. Entitlement to the benefit
`of an earlier date under §§ 119, 120, 121, and 365 is premised on disclosure
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`of the claimed invention in the manner provided by § 112(a) (other than the
`requirement to disclose the best mode) in the application for which the
`benefit of the earlier filing date is sought. See 35 U.S.C. §§ 119(e), 120. In
`the event that the application is not entitled to any earlier filing date or right
`of priority, the effective filing date is “the actual filing date of the . . .
`application for the patent containing a claim to the invention.” 35 U.S.C
`§ 100(i)(1)(A).
`The ’018 patent issued from an application filed on September 21,
`2017. Ex. 1001, (22). But the ’018 patent claims priority to a series of
`non-provisional applications, the earliest of which, now issued as the
`’230 patent, was filed on February 16, 2012. Id. at (60). The ’018 patent
`also claims priority to U.S. Provisional Patent Application No. 61/443,470
`(“the ’470 provisional application”), filed on February 16, 2011. Id. at (61).
`Accordingly, if every claim of the ’018 patent is entitled to an effective
`filing date before March 16, 2013, e.g., the filing date of either the
`’230 patent or the ’470 provisional application, then the ’018 patent is not
`eligible for post-grant review.
`In this regard, Petitioner contends that the ’018 patent is eligible for
`post-grant review because “at least” claims 1–17 and 19–24 are entitled to
`an earliest effective filing date of September 21, 2017, the filing date of the
`’018 patent itself. Pet. 21. Specifically, Petitioner asserts that claims 1–17
`and 19–24 of the ’018 patent are “not enabled by the disclosures of the
`’230 patent or the ’470 provisional application” (id. at 25), and, therefore,
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`the ’018 patent is not entitled to claim the filing date of either the ’230 patent
`or the ’470 provisional application as its effective filing date (id. at 21).
`Because “the ’470 Provisional Application contains no additional
`(and, in fact, less) support” for claims of the ’018 patent (id. at 10),
`Petitioner focuses its argument on whether the ’230 patent enables claims 1–
`17 and 19–24 of the ’018 patent (id. at 27–37). The thrust of Petitioner’s
`argument is that neither the disclosure of ’230 patent nor the ’018 patent
`itself enables the full range of β-galactosidase activity––0.05 to 200 units––
`required by claims 1–17 and 19–24 of the ’018 patent. Id. at 25.
`Upon consideration of the Petition and Preliminary Response, as well
`as all supporting evidence, we are not persuaded, for the reasons that follow,
`that Petitioner has sufficiently shown, for purposes of institution, that that
`the ’230 patent disclosure fails to enable at least one claim of the’018 patent,
`and thus, at least one claim of the’018 patent is entitled to an effective filing
`date after March 16, 2013. Therefore, based on the record before us, the
`’018 patent is not eligible for post-grant review.
`A. Principles of Law
`“[T]o be enabling, 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) (quoting In re Wright, 999 F.2d 1557,
`1561 (Fed. Cir. 1993)). “Whether undue experimentation is required ‘is not
`a single, simple factual determination, but rather is a conclusion reached by
`weighing many factual considerations.’” Streck, Inc. v. Research &
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`Diagnostic Sys., Inc., 665 F.3d 1269, 1288 (Fed. Cir. 2012) (quoting ALZA
`Corp. v. Andrx Pharm., LLC, 603 F.3d 935, 940 (Fed. Cir. 2010)). As
`summarized in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988), relevant
`factors may 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.
`B. The Examiner Vetted Enablement during
`Prosecution of the ’230 Patent
`Enablement was a central issue raised by the Examiner and addressed
`by the Applicants during prosecution of each of the ’230 and ’018 patents.2
`Of particular relevance here, subsequent to amendment of the claims of the
`application for the ’230 patent to recite that the “β-galactosidase activity
`comprises between 0.05 and 200 units3” (Ex. 1004, 813), the Examiner
`
`2 The ’230 and ’018 patents “have substantially the same specification and
`figures” (Pet. 9), and were before the same Examiner during prosecution.
`Compare Ex. 1001 (’018 patent) with Ex. 1003 (’230 patent); see Ex. 1002,
`424 (Notice of Allowability of the ’018 patent, signed by Examiner Prouty);
`Ex. 1004, 1337 (Notice of Allowability of the ’230 patent, signed by
`Examiner Prouty).
`
` The ’230 and ’018 patents each use the term “units” as it is defined in
`Miller, J.H., Experiments in Molecular Genetics, 352–55 (Cold Spring
`Harbor Lab. 1972). Ex. 1001, 7:34–37; Ex. 1003, 7:30–33. The parties
`agree that the “units” of the ’230 and ’018 patents are “Miller units,” as
`defined in that paper. Pet. 20; Prelim. Resp. 8. This definition was adopted
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`issued a Final Action rejecting the claims for lack of enablement (id. at 887–
`89). In that rejection, the Examiner acknowledged that “the ordinary skilled
`artisan could readily make a bacterium with the recited levels of
`β-galactosidase activity.” Id. at 888. The Examiner went on to explain,
`however, that
`the specification does not teach how a skilled artisan could use
`the full scope of such bacteria for the production of fucosylated
`oligosaccharides as the skilled artisan would expect that the
`claimed bacteria would degrade
`the
`lactose substrate.
`Applicants[’] specification demonstrates that a level of activity
`of 1–2 units is not detrimental but claims 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 888–89.
`In response, the Applicants filed a Request for Continued
`Examination, and, in an effort to traverse the enablement rejection,
`submitted a declaration by co-inventor John McCoy, Ph.D. (“First McCoy
`Declaration”). Ex. 1004, 1048–72. In his declaration, Dr. McCoy averred
`that
`
`[e]ven relatively high levels of β-galactosidase produced by the
`LacZ+ bacteria (see FIG. 2) did not deplete the lactose pool such
`that the desired fucosylated oligosaccharide end product was not
`
`in the related ITC Investigation. Ex. 2001, 22–23. Accordingly, “units” and
`“Miller units” are used interchangeably throughout this Decision. Petitioner
`contends that the claims of the ’018 patent are indefinite because the patent
`fails to specify precisely how Miller units are measured. Pet. 39–53.
`Because we determine that the ’018 patent is not eligible for post-grant
`review, however, we need not resolve this controversy.
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`made by the engineered bacteria. To balance the goal of
`producing large amounts of fucosylated oligosaccharides with
`the purification advantage of the presence of β-galactosidase at
`the end of a run to eliminate residual lactose, we determined that
`a relatively low (compared to induced wild type) level of
`β-galactosidase (i.e., in the range of 0.5–200 units) best served
`our commercial goals.
`Ex. 1004, 1071. Figure 2 of the First McCoy Declaration, which
`qualitatively depicts β-galactosidase activity levels in various strains of
`engineered bacteria, including a LacZ+ strain, is reproduced below.
`
`
`The Examiner considered the First McCoy Declaration, but
`maintained the previously described enablement rejection because “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.” Ex. 1004, 1102–1103. The Examiner explained that
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`[w]ithout any indication of the level of β-gal activity present in
`the bacteria of Fig. 2 of the declaration, 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. at 1103.
`In a further effort to overcome the enablement rejection, the
`Applicants filed a Second Request for Continued Examination (Ex. 1004,
`1218–36), and submitted a second declaration by Dr. McCoy (“Second
`McCoy Declaration”) (Ex. 1008).4 In contrast with the First McCoy
`Declaration, the Second McCoy Declaration provided a quantitative analysis
`of the effect of β-galactosidase activity on fucosylated oligosaccharide
`production in engineered bacteria.
`Figure 2 of the Second McCoy Declaration is reproduced below.
`
`
`4 The Second McCoy Declaration is also of record in the prosecution history
`of the ’018 patent. Ex. 1002, 355–59; see also id. at 353 (letter 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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`“Figure 2 is a thin layer chromatogram of normalized cell extracts from
`small-scale cultures” of engineered E. coli strains exhibiting 1.5 (E997),
`2.5 (E890x416/pG217), and 5.8 (E890x422/pG217) units of β-galactosidase
`activity. Ex. 1008, ¶ 8 (emphasis omitted); see also id. at Table 1.
`Consistent with Figure 2, Dr. McCoy observed that “good levels of 2′-FL are
`produced in all 3 strains, although, as expected, 2′-FL accumulations appear
`to slowly decrease as β-galactosidase levels increase.” Id. ¶ 8. Dr. McCoy
`concluded that “[t]he data shown in Table 1 and Figure 2 indicate useful
`production of 2′-fucosyllactose occurs even in the presence of ~ 6 Miller
`units of β-galactosidase activity.” Id. ¶ 9.
`Relying on densitometry analysis and data extrapolation, as well as
`the experimental results presented in Table 1 and Figure 2, the Second
`McCoy Declaration additionally estimated that strains of bacteria producing
`200 Miller units of β-galactosidase would be capable of producing
`significant amounts of 2′-fucosyllactose. Ex. 1008 ¶¶ 10–11, Fig. 3, Table 2.
`In this regard, Dr. McCoy explained:
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`Knowing both the 2′-FL fermentor yield of strain E997
`(i.e. 37g/L), and the above correlation between 2′-FL production
`levels and β-galactosidase activities of the three expression hosts
`(Figure 2), allows an estimate of the relationship of 2′-FL yield
`in the bioreactor to fermentation strain β-galactosidase activity
`levels. This estimate is provided in Table 2. By this estimate,
`even strains producing 200 Miller units of β-galactosidase would
`be capable of producing significant levels of 2′-FL in the
`fermentor (i.e., >2g/L).
`Ex. 1008 ¶ 11. Table 2 of the Second McCoy Declaration, reporting the
`estimated fermentor yield for bacterial strains having various β-galactosidase
`levels, is reproduced below.
`
`
`
`As depicted in Table 2, Dr. McCoy estimated that bacteria strains having
`200 units of β-galactosidase activity would produce 2.35 g/L of 2′-
`fucosyllactose. Ex. 1008, Table 2.
`Shortly after submission of the Second McCoy Declaration, the
`Examiner issued a Notice of Allowability, and the ’230 patent issued.
`Ex. 1004, 1337–1341. In the reasons for allowance, the Examiner explained
`that
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`[t]he declaration of Dr. John McCoy establishes that there is a
`reasonable expectation that microorganisms as claimed with up
`to 200 units of β-galactosidase activity will still produce useful
`amounts of fucosylated oligosaccharides from lactose and
`applicants have pointed to page 23, line 28 as providing support
`for claim 74 such that the rejections of the claims under 112, 1st
`paragraph are withdrawn.
`Ex. 1004, 1340.
`
`C. Petitioner’s Eligibility Contentions
`Despite the Examiner’s vetting of enablement during prosecution of
`the ’230 and ’018 patents, summarized above, Petitioner contends that the
`disclosure of the ’230 patent does not enable the full scope of claims
`requiring a level of β-galactosidase activity between 0.05 and 200 units, and
`thus, the ’018 patent, which includes claims stating such a requirement,
`cannot claim priority to the ’230 patent and is, therefore, eligible for
`post-grant review. Pet. 25. According to Petitioner, “the specification
`shared by both the ’230 patent and the ’018 patent fails to show that
`β-galactosidase levels above the 1–2 units mentioned in the applications as
`filed (particularly for the upper end of the range) would not be detrimental”
`to the production of fucosylated oligosaccharides. Id. at 28.
`Petitioner asserts further that “[e]valuation of each of the eight Wands
`factors shows that undue experimentation would be required to modify
`microorganisms having β-galactosidase activity for the entire range.”
`Pet. 29. As to the first three Wands factors, concerning the quantity of
`experimentation required, the amount of direction provided, and presence of
`working examples in the specification, Petitioner contends that each of these
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`factors supports a conclusion of non-enablement. Pet. 29–32. Petitioner
`reasons that “a person of ordinary skill would need to genetically modify
`bacteria so as to cover the claimed range, with a different modified
`bacterium for each amount of β-galactosidase activity within the broad
`range.” Id. at 30 (citing Ex. 1017 ¶ 139). Petitioner further avers that the
`specification of the ’230 patent “gives no guidance on how modifications
`affect β-galactosidase activity, leaving a person of ordinary skill completely
`in the dark about how to create modified bacteria that could, taken together,
`cover the entire claimed range.” Id. (citing Ex. 1017 ¶ 140; Ex. 1016). In
`particular, Petitioner asserts that the specification of the ’230 patent provides
`no guidance on expanding the disclosed exemplary strains exhibiting 1–
`2 units of β-galactosidase activity “a hundredfold to the claimed 0.05 to 200
`units, nor does it describe how modifying the bacteria strains would provide
`this level of β-galactosidase activity.” Id. at 31 (citing Ex. 1017 ¶ 140).
`Petitioner likewise asserts that the disclosure of an example having 1–2 units
`of β-galactosidase activity is insufficient to enable the entirety of the
`claimed range. Id. at 31–32.
`Turning to the fourth Wands factor, Petitioner asserts that the “highly
`complex nature of this invention also contributes to a high level of
`experimentation necessary to achieve the claimed range of β-galactosidase
`activity.” Pet. 32. Regarding the fifth Wands factor, Petitioner contends that
`the prior art does not disclose bacterial strains that “achieve β-galactosidase
`activity within the entire range of 0.05 to 200 units.” Id. Petitioner
`additionally avers that “[t]he relatively high level of ordinary skill of those
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`in the art (Wands factor 6) also shows that undue experimentation is
`necessary to achieve the claimed range.” Id. As to the seventh factor,
`Petitioner asserts, relying on cases from the mid-1980s and early-1990s that
`“[g]enetically engineering cells is a highly unpredictable area.” Id. at 33
`(citing Ex parte Forman, 230 U.S.P.Q 546, 1986 WL 83597, at *3 (B.P.A.I.
`1986); Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1214 (Fed. Cir.
`1991)). Finally, regarding the eighth Wands factor, Petitioner contends that
`the “shockingly broad range” recited in the claims of the ’018 patent
`“highlights the difficulty with enabling their full scope.” Id. at 33–34.
`Petitioner does not address the McCoy declarations in conjunction
`with its analysis of the Wands factors, but treats them separately. Pet. 34–
`36. In particular, Petitioner asserts that “[a] person of ordinary skill in the
`art would not find Dr. McCoy’s methodology reliable.” Id. at 34.
`According to Petitioner, the three experimental data points underlying the
`extrapolation presented in the Second McCoy Declaration “would be
`deemed as insufficient to show that strains having activity up to 200 units
`could in fact make 2′-FL.” Id. (citing Ex. 1017 ¶ 127). In this regard,
`Petitioner characterizes the curve fit by Dr. McCoy to the densitometry data
`presented in the Second McCoy Declaration as “inferior” and declares that a
`“better fit would be linear.” Id. at 34–35 (citing Ex. 1017 ¶ 129). Petitioner
`also asserts that the fucosylated oligosaccharide production levels estimated
`by Dr. McCoy are “inconsistent with the invention” and “do[] not make
`sense.” Id. at 35 (citing Ex. 1017 ¶ 130). Petitioner further contends that
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`“β-galactosidase activity above 5.8 units would destroy lactose too quickly
`for the cell to use it to produce 2′-FL.” Id. at 36 (citing Ex. 1017 ¶ 134).
`D. Petitioner Has Not Adequately Established That the ’018 Patent
`Is Eligible for Post-Grant Review
`We are not persuaded by Petitioner’s arguments and evidence
`attempting to show that at least one of claims 1–17 and 19–24 of the
`’018 patent is not enabled by the disclosure of the ’230 patent. In particular,
`we determine that Petitioner has not adequately shown, for purposes of
`institution, that the Second McCoy Declaration fails to provide evidence of
`enablement. We likewise find Petitioner’s analysis of the Wands factors,
`which addresses neither the Examiner’s considered enablement analysis nor
`the Second McCoy Declaration, insufficient to establish, for purposes of
`institution, that the ’018 patent is eligible for post-grant review.
`Accordingly, we deny institution of post-grant review.
`1. The Second McCoy Declaration Supports Enablement
`As discussed above, relying on experimental data, Dr. McCoy
`extrapolated the hypothetical fermentor yield that would be obtained from a
`bacterial strain exhibiting 200 units of β-galactosidase activity, and reported,
`in the Second McCoy Declaration, that such a strain would be expected to
`produce 2.35 g/L of 2′-fucosyllactose. Ex. 1008 ¶ 11. The Examiner then
`issued the ’230 patent, explaining that the Second McCoy Declaration
`“establishes that there is a reasonable expectation that microorganisms as
`claimed with up to 200 units of β-galactosidase activity will still produce
`useful amounts of fucosylated oligosaccharides from lactose.” Ex. 1004,
`
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`1340. Furthermore, although submitted after the priority date of the
`’018 patent, additional experimental data presented to the European Patent
`Office during prosecution of a foreign counterpart to the ’018 patent is
`consistent with Dr. McCoy’s data extrapolation in the Second McCoy
`Declaration. Ex. 2005, 12–13.
`Petitioner does not offer argument or evidence sufficient to call into
`question either the Second McCoy Declaration or the Examiner’s reliance on
`that declaration. Petitioner, relying on Dr. Stephanopoulos, makes several
`assertions about the accuracy and reliability of Dr. McCoy’s extrapolation,
`but neither Petitioner nor Dr. Stephanopoulos provides argument or evidence
`sufficient to substantiate these assertions.5 Pet. 33–36 (citing Ex. 1017
`¶¶ 126–131, 133, 134).
`For example, Petitioner, citing to Dr. Stephanopoulos’s testimony,
`contends that an ordinarily skilled artisan would not accept a curve fit to the
`three data points relied on by Dr. McCoy, or a curve having an R2 value of
`0.833, as a basis for extrapolating 2-fucosyllactose production levels.
`Pet. 34–35 (citing Ex. 1017 ¶¶ 127–128). But neither Petitioner nor
`Dr. Stephanopoulos elaborates on these conclusory statements or provides
`
`
`5 Indeed, fewer than 10 citations appear in the 16 paragraphs of
`Dr. Stephanopoulos’s declaration addressed to enablement, and all but one
`of those citations is to the ’018 patent or the Second McCoy Declaration.
`Exhibit 1016, the only other document cited in paragraphs 126–141 of the
`Stephanopoulos Declaration, is an article profiling Nobel Laureate Frances
`Arnold, Ph.D. See Ex. 1017 ¶ 139.
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`information to substantiate them. For instance, neither Petitioner nor
`Dr. Stephanopoulos explains why the curve fit by Dr. McCoy, which has an
`R2 value of 0.833, indicating that less than 17% of observed variations could
`not be explained by the model, and is consistent with a “good association,”
`is inaccurate. Prelim. Resp. 21 (citing Ex. 2007, 37–38 (a review article
`discussing correlation analysis that defines R2 and exemplifies an R2 value
`of 0.72 as demonstrating a “good association” of clinical usefulness)); see
`also 37 C.F.R. § 42.65(a) (“Expert testimony that does not disclose the
`underlying facts or data on which the opinion is based is entitled to little or
`no weight.”). Similarly, Dr. Stephanopoulos’s unadorned statement––
`unaccompanied by graphical, statistical, or other data––that “[a] better fit
`would be linear” (Ex. 1017 ¶ 129) does not provide adequate reason to call
`into question the data and statistical analysis presented by Dr. McCoy and
`credited by the Examiner. See 37 C.F.R. § 42.65(a).
`Petitioner’s reliance on Dr. Stephanopoulos’s perfunctory testimony
`regarding alleged inconsistencies between Dr. McCoy’s data extrapolation
`and the ’230 and ’018 patents’ teachings concerning the effect of
`β-galactosidase activity on fucosylated oligosaccharide production is
`similarly unavailing. See Pet. 35–36 (citing Ex. 1017 ¶¶ 130, 131, 133,
`134).
`The ’230 patent discloses a method for engineering bacteria “to
`produce 2′-FL, 3FL, LDFT, or sialylated fucosyl-oligosaccharides in
`commercially viable levels.” Ex. 1003, 15:65–16:1. In this regard, the
`’230 patent explains that a bacterium engineered according to the disclosed
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`invention “maintains the ability to transport lactose from the growth
`medium, and to develop an intracellular lactose pool for use as an acceptor
`sugar in oligosaccharide synthesis, while also maintaining a low level of
`intracellular beta-galactosidase activity useful for a variety of additional
`purposes.” Ex. 1003, 5:13–18; see also id. at 2:67–3:2; 7:18–41. During
`prosecution of the ’230 patent, the Applicants elaborated on the difference in
`β-galactosidase activity between bacteria expressing engineered and
`wild-type LacZ, explaining that 200 units of β-galactosidase activity is
`“much less” than the 1,000 units of β-galactosidase activity produced by
`“LacZ running off its own endogenous promoter.” Ex. 1004, 1058. The
`Applicants further explained that their “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.”6 Id. Neither Petitioner nor Dr. Stephanopoulos identifies any
`disclosure in the ’230 patent or its file history indicating that bacteria
`expressing high, i.e., wild-type, levels of β-galactosidase are incapable of
`producing fucosylated oligosaccharides. Rather, the ’230 patent teaches that
`bacteria engineered to produce reduced levels of β-galactosidase are useful
`for making fucosylated oligosaccharides at commercial scale.
`
`
`6 Reference on page 1058 of Exhibit 1004 to “0.5–200 units” instead of
`“0.05–200 units” appears to be an inadvertent typographical error.
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`Nevertheless, Dr. Stephanopoulos states, without adequate reasoning
`or support, that the expected yield of less than 1 g/L of 2′-fucosyllactose in
`the presence of 1,000 units of β-galactosidase activity predicted by
`“[c]ontinuing Dr. McCoy’s extrapolation” “is inconsistent with the low level
`of β-galactosidase activity required by the invention and does not make
`sense.” Ex. 1017 ¶ 130. But nothing in the portions of the ’018 patent to
`which Dr. Stephanopoulos points (as well as the corresponding disclosures
`in the ’230 patent relevant here) indicates that the low yield of 2′-
`fucosyllactose in the presence of 1,000 units of β-galactosidase activity
`predicted by Dr. Stephanopoulos’s extensio
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