throbber
Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`Paper 9
`Entered: June 15, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`VDF FUTURCEUTICALS, INC.,
`Petitioner,
`
`v.
`
`HANIF KAZEROONI, BAHRAM NASERNEJAD, ABBAS
`ABDOLMALAKI, AND AKBAR ZARE,
`Patent Owner.
`_______________
`
`Case IPR2017-00547
`Patent 9,327,025 B2
`_______________
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
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`Case IPR2017-00547
`Patent 9,327,025 B2
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`I.
`INTRODUCTION
`VDF Futurceuticals, Inc. (“Petitioner”) filed a Petition requesting an
`inter partes review of claims 1–9 of U.S. Patent No. 9,327,025 B2
`(Ex. 1001, “the ’025 patent”). Paper 1 (“Pet.”). Patent Owner did not elect
`to file a Preliminary Response to the Petition.
`Institution of an inter partes review is authorized by statute when “the
`information presented in the petition . . . and any response . . . shows that
`there is a reasonable likelihood that the petitioner would prevail with respect
`to at least 1 of the claims challenged in the petition.” 35 U.S.C. § 314; see
`37 C.F.R. §§ 42.4, 42.108. Upon considering the Petition, we determine that
`Petitioner has shown a reasonable likelihood that it would prevail in showing
`the unpatentability of at least one challenged claim. Accordingly, we
`institute an inter partes review of claims 1–9 of the ’025 patent.
`
`A.
`
`Related Proceedings
`According to Petitioner, there are no other judicial or administrative
`matters that would affect, or be affected by, a decision in this proceeding.
`Pet. iv; see Paper 5, 2.
`
`B.
`
`The ‘025 Patent and Relevant Background
`The ’025 Patent issued to Hanif Kazerooni, Bahram Nasernejad,
`Abbas Abdolmalaki, and Akbar Zare from U.S. Application No. 13/726,500,
`which was filed on December 24, 2012. The ’025 Patent does not, on its
`face, claim benefit of priority to any other applications.
`The ’025 patent relates to the synthesis of 10boron-enriched calcium
`fructoborate (E10BCFB) and its use in Boron Neutron Capture Therapy
`(BNCT) radio-chemotherapy. Ex. 1001, Abstract. The treatment of cancers
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`with BNCT was well known in the art. See, e.g., Ex. 1001, 1:22–2:67,
`Figs. 1, 2. According to the Specification, the therapy begins with
`preferential delivery of a 10B-enriched drug into tumor cells. Id. When the
`concentration of 10B reaches 20–35 μm per gram of tumor tissue, the tumor
`is bombarded with low energy (slow) neutrons, causing the 10B to emit
`gamma radiation and high energy alpha particles (4He and 7Li). Id. Because
`the 4He and 7Li alpha particles have a relatively short range, they
`preferentially damage only the cancerous cells, largely sparing surrounding
`healthy tissue. Id.
`Calcium fructoborate is a naturally occurring compound found in
`some vegetables. Id. at Abstract. As found in nature, however, such
`boron-containing molecules contain only about 20% of the 10B isotope, with
`the balance being 11B. Id. at 3:2–3. The low level of 10B in naturally
`occurring boron compounds renders them unsuitable for use in BNCT. Id. at
`4:4–7. Drugs for BNCT therapy are, therefore, synthesized using
`10B-enriched reactants such as commercially available 10B-enriched boric
`acid. Id. at 3:3–9. Consistent with the teaching, the prior art of record states
`that “[a]ll [BNCT] agents which enter clinical trials must be boron-10
`enriched (>95%)” and “regardless of the agent type . . . agent syntheses rest
`upon the availability of boron-10 enriched inorganic precursors.” Ex. 1024,1
`40–41.
`The ’025 patent discloses a method for making a genus of
`10B-enriched sugar complexes using 10B-enriched boric acid, most
`
`
`1 Hawthorne and Lee, “A critical assessment of boron target compounds for
`boron neutron capture therapy,” 62 J. Neuro-Oncology 33–45 (2003).
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`particularly, the E10BCFB isomers of Formula A and Formula B. See Ex.
`1001, 14:46–16:6. Drugs containing these 10B-enriched sugar complexes
`may be administered by IP, IV, or oral routes for BNCT therapy. Id. at
`13:22–48.
`
`C.
`
`Challenged Claims
`The independent claims at issue are directed to a drug containing
`certain E10BCFB isomers (claim 1); a method of synthesizing E10BCFB and
`related compounds (claim 2); and a method of treating cancer using
`E10BCFB (claim 7).
`Claim 1 recites:
`1. A novel drug containing enriched 10-Boron for cancer cell
`treatment
`in Boron Neutron Capture Therapy
`(BNCT)
`comprising an Enriched 10-Boron Calcium Fructo Borate
`(E10BCFB) having a Formula A or a Formula B, wherein the
`Formula A is represented by:
`
`Claim 2 recites:
`2. A method of synthesizing an enriched 10-Boron complex for
`Boron Neutron Capture Therapy (BNCT) comprising:
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`dissolving a monosaccharide in a solvent at room temperature
`while stirring, wherein the solvent is water or alcohol, and
`wherein the monosaccharide is selected from a group
`consisting of a glucose and a fructose;
`adding a solution of an enriched 10B boric acid with maximum
`content of 10B to form a mixture;
`adjusting a pH of the mixture, wherein the pH of the mixture is
`adjusted to be equal to 3–4;
`adding a solution of a carbonate salt of calcium to the mixture
`while continuously stirring, wherein the solution of the
`carbonate salt of calcium is added after a produced carbon
`dioxide gas is completely removed from the mixture;
`forming a bi-phase solution, wherein the bi-phase solution
`comprises a lower phase and an upper phase, wherein the
`lower phase is a boron complex and wherein the upper phase
`is an oily liquid;
`separating the lower phase by scratching the lower phase using a
`glass bar;
`collecting the lower phase; and
`grinding the lower phase to obtain an enriched 10-Boron
`complex or a composition.
`
`Depending from claim 2, claim 3 recites that “the enriched 10-Boron
`complex is Enriched 10-Boron Calcium FructoBorate (E10BCFB)”; claim 4
`further limits the enriched 10-boron complex to Formula A or Formula B as
`set forth in claim 1; and claims 5 and 6, respectively, specify molar
`concentrations of monosaccharide and 10B-enriched boric acid used in the
`reaction.
`Claim 7 recites:
`7. A method of treating cancer using Boron Neutron Capture
`Therapy (BNCT) comprising steps of:
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`administering a drug composition containing the drug at a
`predetermined concentration to a patient, wherein the drug is
`Enriched 10-Boron Calcium Fructo Borate (E10BCFB);
`allowing the accumulation of the drug in the tumor cells; and
`bombarding the tumor cells from outside the body using thermal
`or epithermal neutron beams;
`wherein the tumor cells are destroyed when the thermal or
`epithermal neutron beams come in to contact with the
`E10BCFB.
`
`D.
`
`The Asserted Prior Art and Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 7):
`
`Ground Claim(s)
`1
`1
`2
`2, 3, 5, and 6
`3
`4
`
`4
`5
`
`7 and 9
`8
`
`References
`Scorei I2 and Scorei II3
`Scorei I and Miljkovic4
`Scorei I, Scorei II, and
`Miljkovic
`Scorei I and Barth5
`Scorei I, Barth, and Kirihata6
`
`Basis
`§ 103
`§ 103
`§ 103
`
`§ 103
`§ 103
`
`
`2 Scorei, “Calcium fructoborate: plant-based dietary boron as potential
`medicine for cancer therapy,” S3 Frontiers in Bioscience 205–215 (2011).
`Ex. 1006.
`3 Scorei and Rotaru, “Calcium Fructoborate–Potential Anti-inflammatory
`Agent,” Biol. Trace Elem. Res. (2011). Ex. 1007.
`4 Miljkovic, US 5,962,049, issued Oct. 5, 1999. Ex. 1005.
`5 Barth et al., “Boron Neutron Capture Therapy of Brain Tumors: An
`Emerging Therapeutic Modality,” 44(3) Neurosurgery 433–451 (1999). Ex.
`1008.
`6 Kirihata et al., US 2011/0184175 A1, published July 28, 2011. Ex. 1009.
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`Petitioner further relies on the testimony of George W. Kabalka,
`Ph.D.7
`
`II.
`
`ANALYSIS
`
`A.
`
`Person of Ordinary Skill in the Art
`For the purpose of this Decision, we accept Petitioner’s presently
`undisputed contention that a person of ordinary skill in the art as of the
`effective filing date of the ’025 patent would have had “at least a master’s
`degree in chemistry or biochemistry, or 4 years of experience in medicine or
`medical research dealing with BNCT.” Pet. 18 (citing Ex. 1003 ¶ 42). This
`level of ordinary skill is consistent with the prior art asserted in the Petition.
`See Chore-Time Equip., Inc. v. Cumberland Corp., 713 F.2d 774, 779 n.2
`(Fed. Cir. 1983) (indicating that the prior art itself may reflect the
`appropriate level of ordinary skill in the art).
`
`B.
`
`Claim Construction
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable construction in light of the
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016)
`(upholding the use of the broadest reasonable interpretation standard).
`Under that standard, we presume that a claim term carries its “ordinary and
`customary meaning,” which “is the meaning the term would have to a person
`of ordinary skill in the art in question” at the time of the invention. In re
`
`
`7 Declaration of George W. Kabalka Regarding U.S. Patent No. 9,327,025.
`Ex. 1003.
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`Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007); see also
`Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under
`a broadest reasonable interpretation, words of the claim must be given their
`plain meaning, unless such meaning is inconsistent with the specification
`and prosecution history.”). Any special definition for a claim term must be
`set forth in the specification with reasonable clarity, deliberateness, and
`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`i. “enriched 10-Boron complex”
`Petitioner proposes that we interpret the claim term “enriched 10-
`Boron complex” as “refer[ing] to compounds containing boron in which the
`relative abundance of 10B is greater than its naturally-occurring amount of
`about 20%.” Pet. 18 (citing Ex. 1003 ¶¶ 121–125). Absent Patent Owner’s
`arguments to the contrary, we provisionally adopt this definition in light of
`the Specification’s disclosure that “Boron compositions found in nature
`contain 80.1 [ ]% of 11B and 19.9 [ ]% of 10B. Hence, the percentage of 10B
`has to be increased for synthesizing the active compositions in BNCT. This
`process of increasing 10B is called enrichment process.” Ex. 1001, 3:2–6;
`see Ex. 1003 ¶ 47; Ex. 1019 ¶ 75.8
`ii. “enriched 10B boric acid with maximum content of 10B”
`Claim 2 recites the step of “adding a solution of an enriched 10B boric
`acid with maximum content of 10B to form a mixture.” Petitioner proposes
`that we interpret “enriched 10B boric acid with maximum content of 10B” in
`that phrase as meaning “boric acid in which the relative abundance of 10B is
`near 100%.” Pet. 19–20 (citing Ex. 1003 ¶¶ 126–127). Petitioner reasons
`
`
`8 Zhu and Widjaja, WO 2008/018838 Al, published Feb. 14, 2008.
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`that boric acid containing >99% 10B is commercially available (citing Ex.
`1047)9 and, in synthesizing a compound for BNCT, the skilled artisan would
`want to use boric acid highly enriched for 10B “because the effectiveness of a
`BNCT drug relates directly to its ability to deliver 10B—and not 11B—to
`tumor cells.” Pet. 19–20.
`Petitioner’s definition is reasonable in light of the Specification, and
`presently unopposed by Patent Owner. See, e.g., Ex. 1001, 2:55–57
`(discussing the requirement for “a sufficient number of 10B atoms . . . [that]
`must be delivered selectively to the tumor”); 3:2–6 (noting the requirement
`for enriched starting materials). Accordingly, for the purpose of this
`Decision, we adopt Petitioner’s definition of “enriched 10B boric acid with
`maximum content of 10B” as meaning “boric acid in which the relative
`abundance of 10B is near 100%.”
`iii. “administering a drug composition containing the drug at a
`predetermined concentration”
`Petitioner proposes that the broadest reasonable interpretation of
`“administering a drug composition containing the drug at a predetermined
`concentration” in claims 7 and 9 refers to “administration of a drug
`composition such that the concentration of 10B in a tumor site is sufficient
`for effective BNCT.” Pet. 20–21 (citing, inter alia, Ex. 1003 ¶¶ 131–132).
`Petitioner points, for example, to the Specification’s teaching that “[t]he
`predetermined concentration” for BNCT is 20–35 micrograms 10B per gram
`of tumor tissue. See Ex. 1001, 7:31–32; see also claim 7. Petitioner’s
`expert, Dr. Kabalka, explains that it was well known that this was the
`
`9 Sigma Aldrich Catalog (2005) (listing for sale boric acid having
`“99 atom % 10B”).
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`minimum concentration of 10B that must be delivered to a tumor for
`successful BNCT. See Ex. 1003 ¶ 134 and citations therein.
`
`Although we do not doubt that the claim phrase “administering a drug
`composition containing the drug at a predetermined concentration” may
`include the “administration of a drug composition such that the
`concentration of 10B in a tumor site is sufficient for effective BNCT,” the
`plain language of claims 7 and 9 do not require the administration of a
`particular concentration or even a single effective dose. The claimed
`methods could be practiced, for example, through the administration of a
`multiplicity of doses of the same or different drug compositions that
`collectively result in a sufficient accumulation of 10B in a tumor site. See
`e.g., Ex. 1009 ¶¶ 38, 39 (stating that a 10boron-containing compound for
`BNCT “can be administered at a time, or can be sequentially administered”);
`Ex. 1024, 1222 (suggesting multi-agent therapy wherein the administration
`of each 10B-containing agent is timed to reach maximum effectiveness at the
`time of irradiation); Ex. 1008, 436 (referencing the administration of
`multiple boron compounds for BNCT). Accordingly, on the present record,
`we construe the “predetermined concentration” of the claim phrase
`“administering a drug composition containing the drug at a predetermined
`concentration” as referring to any concentration that is determined in
`advance of its administration.
`iv. “Formula A”
`Relying on the testimony of its expert, Dr. Kabalka, Petitioner
`contends that Formula A, as depicted in claims 1 and 4, inadvertently omits
`a hydroxyl moiety and, “as drawn, could not be synthesized with the
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`procedure disclosed in the ’025 patent.” Pet. 24–25 (citing Ex. 1003
`¶ 188).10 Absent this alleged typographical error, Petitioner contends that
`Formulas A and B, as claimed, correspond to the formulas for α-D-
`fructofuranose borate and β-D-fructofuranose borate depicted Figures 1a and
`1b, respectively, of Scorei II. Pet. at 25 (citing Ex. 1007, 3; Ex. 1003
`¶¶ 192–193).
`Although we discern no reason to doubt Dr. Kabalka’s testimony on
`the current record, our decision to institute trial does not depend on the
`scope and meaning of Formula A. To the contrary, each of the challenged
`claims is directed to a genus of 10B-enriched sugar compounds
`encompassing Formula B. As discussed in section II(D)(iii)(1) below,
`Formula B corresponds to the β-D-fructofuranose borate disclosed in Figure
`1b of Scorei II. Accordingly, we decline to construe the claim element
`Formula A at this time, focusing instead on the compound of Formula B.
`See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
`1999) (holding that only those terms that are in controversy need be
`construed, and only to the extent necessary to resolve the controversy).
`
`C.
`
`Principles of Law
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which that
`
`
`10 To the extent this may be a typographical error, we note that the identical
`structure for Formula A is depicted throughout the Specification. See Spec.
`6:15–26, 55–60, 7:60–67,11:1–10, 35–45, 12:60–65,15:10–17.
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`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations including: (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and (4) objective evidence of
`nonobviousness, if present. Graham v. John Deere Co., 383 U.S. 1, 17–18
`(1966).
`“[T]he [obviousness] analysis need not seek out precise teachings
`directed to the specific subject matter of the challenged claim, for a court
`can take account of the inferences and creative steps that a person of
`ordinary skill in the art would employ.” KSR, 550 U.S. at 418.
`“[I]nterrelated teachings of multiple patents; the effects of demands known
`to the design community or present in the marketplace; and the background
`knowledge possessed by a person having ordinary skill in the art, all [can
`provide] . . . an apparent reason to combine the known elements in the
`fashion claimed.” Id.
`“[I]f a technique has been used to improve one device, and a person of
`ordinary skill in the art would recognize that it would improve similar
`devices in the same way, using the technique is obvious unless its actual
`application is beyond his or her skill.” Id. at 417. “The combination of
`familiar elements according to known methods is likely to be obvious when
`it does no more than yield predictable results.” Id. at 416. Accordingly,
`“[i]f a person of ordinary skill can implement a predictable variation, § 103
`likely bars its patentability.” Id.
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`D.
`
`Analysis of Grounds I–V
`As discussed above in section I(D), Petitioner challenges claims 1–9
`as obvious under 35 U.S.C. § 103(a) based on Scorei I, in light of one or
`more additional references. We address each of Petitioner’s five grounds
`below.
`
`i. Ground I: Obviousness of Claim 1 in View of Scorei I and Scorei II
`1. Overview of Scorei I
`Scorei I reviews emerging research on the use of boron compounds,
`most particularly, calcium fructoborate, in chemoprevention and
`chemotherapy. See generally Ex. 1006, Abstract. Scorei I teaches that in
`addition to anti-oxidant and anti-inflammatory properties, calcium
`fructoborate has inhibitory effects on certain breast cancer cells. Id.,
`Abstract, 206, 209; see, e.g., id. at 206 (“Inside cells [calcium fructoborate]
`acts as an antioxidant and induces the overexpression of apoptosis-related
`proteins and eventually apoptosis.”).
`Scorei I posits that calcium fructoborate, like fructose, enters cells
`largely via the sugar transporter GLUT5, which is highly overexpressed in
`many cancer cells. Id. at Abstract, 210; see also id. at 210 (“In Caco2 cells
`and in highly proliferative cancer cells, GLUT5 expression is significant
`enough that it appears to be a good marker of malignancy or high
`proliferation rate.”). Inferring that fructose compounds will preferentially
`concentrate in cancer cells, Scorei I proposes the use of 10B-enriched
`calcium fructoborate (i.e., E10BCFB) for BNCT radio-chemotherapy. Id. at
`209–210. Thus, according to Scorei I, “enriched 10-Boron-Fructoborate
`(EBF) may become an important chemical challenger in the fight against
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`some cancers. EBF transport inside cancerous cells induces a pro-apoptosis
`effect . . . enhancing the BNCT effect.” Id. at 210.
`
`2. Overview of Scorei II
`Scorei II teaches calcium fructoborate (“CF”) as a nutritional
`supplement having useful anti-inflammatory properties and “negligible
`adverse effects on humans.” Ex. 1007, Abstract. Scorei II also references
`Scorei I with respect to certain “biological activities [of calcium
`fructoborate] that might have a therapeutic potential. Id. at 1–2 (citing
`reference 3).
`With respect to the chemical structure of calcium fructoborate, Scorei
`II states:
`
`The structural formula of the CF is Ca[(C6H10O6)2B]2·4H2O.
`The fructoborate anion, which comprises two fructose molecules
`complexes to a single B atom, has a molecular weight of 367.13
`g mol−1 and may exist in three isomeric forms depending on the
`linkages and the ring structure of the fructose. These forms
`include two isomers with 5-membered rings (α- and β-
`fructofuranose borate) and one isomer with 6-membered rings
`(α-fructopyranose borate) which associate and dissociate
`spontaneously in dynamic equilibrium with the predominating β-
`fructofuranose borate form.
`Id. at 2 (endnote numbers omitted). Scorei II discloses the structure of the
`α- and β- fructofuranose isomers in Figure 1, reproduced below.
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`Scorei Figure 1 shows the structural formulas of calcium α-D-
`fructofuranose borate (Fig. 1a) and calcium β-D-fructofuranose borate (Fig
`1b); see Ex. 1003 ¶ 168 (further noting that “B” in the structural formulas
`encompasses both the boron-10 and boron-11 isotopes).
`
`3. Analysis of Ground I
`Petitioner asserts that claim 1 of the ’025 Patent would have been
`obvious in view of Scorei I and Score II. Pet. 22–27; see Ex. 1002 ¶¶ 186–
`196. Claim 1 is directed to a drug containing enriched 10B for use in BNCT
`comprising E10BCFB having the structure of Formula A or Formula B. As
`noted above in section II(F)(iv), we focus our analysis on Formula B.
`As we understand Petitioner’s position, one of ordinary skill in the art
`would understand Scorei I and Scorei II as part of an interrelated body of art,
`and “represent[ing] part of the finite number of identifiable, predictable
`solutions to the design need of providing boron (including 10B) to human
`cells.” Pet. 23 (citing Ex. 1003 ¶ 186). Accordingly, it “would be merely
`the application of known elements to achieve predictable results” for one of
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`ordinary skill in the art to use a calcium β-D-fructofuranose borate isomer as
`taught by Scorei I to make a E10BCFB 10boron source for the BNCT taught
`by Scorei I. Id. at 23–24
`On the present record, we find that Petitioner’s unopposed arguments
`and evidence establish a reasonable likelihood that Petitioner would prevail
`in demonstrating the unpatentability of claim 1 over the combination of
`Scorei I and Scorei II.
`
`ii. Ground II: Obviousness of Claims 2, 3, 5, and 6 in View of Scorei I
`and Miljkovic
`1. Overview of Miljkovic
`Miljkovic is directed to sugar-boron complexes, most preferably
`calcium fructoborate, as nutritional supplements and pharmaceutical
`ingredients. Ex. 1005, Abstract, 2:45–47; 5:12–22. Miljkovic discloses a
`chemical structure encompassing calcium fructoborate and a method of
`synthesizing a sugar-boron complex, exemplified by the synthesis of
`calcium fructoborate from D-fructose and boric acid as a source of boron.
`Id. at Fig. 1, 2:54–57, 5:25–59; see Ex. 1003 ¶¶ 71, 72, 74. Although the
`reference does not exemplify the synthesis of an E10BCFB, it states that
`“[t]he boron contemplated to be used herein may predominantly comprise
`any mixture of the two naturally occurring forms of boron, namely 10B and
`11B.” Ex. 1005, 4:46-48.
`
`2. Analysis of Ground II
`Petitioner asserts that claims 2, 3, 5, and 6 of the ’025 Patent would
`have been obvious in view of Scorei I and Miljkovic. Pet. 27–39; see Ex.
`1003 ¶¶ 198–216. Claim 2 recites a method of synthesizing an enriched
`10boron complex for BNCT using solutions of glucose or sucrose and
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`enriched 10B boric acid; claim 3 specifies that the enriched 10boron complex
`is E10BCFB; and claims 5 and 6 specify the molarity of the monosaccharide
`and 10B boric acid solutions, respectively.
`Petitioner asserts that “it would be impossible to review [Scorei I]
`without appreciating the relevance of Miljkovic,” and that the these
`references “represent part of the finite number of identifiable, predictable
`solutions to the design need of providing boron (including 10B) to human
`cells.” Pet. 28. Accordingly, Petitioner contends,
`
`it would have been obvious to combine the well-known elements
`disclosed by these references as a matter of common sense and
`routine innovation and would be merely the application of known
`elements to achieve predictable results, with a reasonable
`expectation of success. For example, one of ordinary skill in the
`art would have naturally applied Miljkovic 1997’s teachings
`regarding the structure and preparation of CF to Scorei (I)
`teachings regarding the use of enriched CF for BNCT in order to
`arrive at the method of preparing enriched CF for BNCT claimed
`in the ’025 Patent.
`Id. at 29 (citing, e.g., Ex. 1003 ¶197).
`In support, Petitioner provides detailed claim charts purporting to
`show that each element of the asserted claims are found in, or obvious in
`light of the cited references. Id. at 29–31, 37, 38. With respect to “minor,
`obvious differences,” such as relating to the use of 10B-enriched boric acid
`for the production of an enriched 10boron complex, Petitioner asserts that
`“Miljkovic [] recognizes that the compound may be enriched.” Id. at 31–32
`(citing Ex. 1005, 4:46-49; see Ex. 1003 ¶ 209. Moreover, Petitioner argues,
`one of ordinary skill in the art synthesizing a compound for BNCT would
`have found it obvious to use 10B-enriched boric acid having a maximum
`
`17
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`

`Case IPR2017-00547
`Patent 9,327,025 B2
`
`
`
`content of 10B, noting that “boric acid containing greater than 99% 10B was
`commercially available and is specifically marketed as a precursor for
`BNCT drugs.” Id. at 32–33 (citing, e.g., Ex. 1003 ¶¶ 202–203); see also id.
`at 36 (arguing that the claimed “grinding . . . step would be obvious if one
`wanted the final product to contain consistently sized particles”).
`On the present record, we find that Petitioner’s unopposed arguments
`and evidence establish a reasonable likelihood that Petitioner would prevail
`in demonstrating the unpatentability of claims 2, 3, 5, and 6 over the
`combination of Scorei I and Miljkovic.
`
`iii. Ground III: Obviousness of Claim 4 in View of Scorei I, Scorei II,
`and Miljkovic
`1. Analysis of Ground III
`Petitioner asserts that claim 4 of the ’025 Patent would have been
`obvious in view of Scorei I, Scorei II, and Miljkovic. Pet. 39–40; Ex. 1003
`¶¶ 217–219. Depending from claim 2, claim 4 limits the enriched 10boron
`complex to the compound of Formula A or Formula B. The combination of
`Scorei I and Miljkovic is discussed above in section II(D)(ii) with respect to
`claim 2. We further accept Petitioner’s presently unopposed evidence that
`Scorei II discloses Formula B, which is depicted in Figure 1b of that
`reference. See Pet. at 24, 25, 40; Ex. 1007, 3; Ex. 1003 ¶¶ 192–193), 40. On
`the present record, we find that Petitioner’s unopposed arguments and
`evidence establish a reasonable likelihood that one of ordinary skill in the art
`would have found it obvious to use a calcium β-D-fructofuranose borate
`isomer as taught by Scorei I to make a E10BCFB 10boron source for the
`BNCT taught by Scorei I. Accordingly, on the record before us, we find that
`Petitioner’s unopposed arguments and evidence establish a reasonable
`
`18
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`

`Case IPR2017-00547
`Patent 9,327,025 B2
`
`
`
`likelihood that Petitioner would prevail in demonstrating the unpatentability
`of claim 4 over the combination of Scorei I, Scorei II, and Miljkovic.
`
`iv. Ground IV: Obviousness of Claims 7 and 9 in View of Scorei I and
`Barth
`1. Overview of Barth
`Barth teaches that BNCT is biologically targeted modality with the
`“potential [] to destroy malignant cells dispersed in the brain, providing that
`sufficient amounts of 10B and thermal neutrons can be delivered to the target
`volume.” Ex. 1008, 433. In particular, “only those tumor cells that have
`accumulated sufficient amounts of 10B will be capable of sustaining a lethal
`10B (n, α) 7Li capture reaction.” Id. at 440. Accordingly:
`
`Critical to the success of BNCT is the requirement that
`boron compounds possess
`the following properties: 1)
`selectively target tumor versus normal cells, preferably with
`intracellular localization so as to more effectively deliver high
`LET radiation to the tumor cell nucleus; 2) attain cellular
`concentrations of ~ 109 boron-10 atoms/cell or ~20–35 μg/g
`tumor when administered alone or in combination with other
`boron compounds; 3) achieve tumor-to-normal tissue ratios in
`excess of 3 to 4:1; 4) persist at constant concentrations in the
`tumor during the radiation procedure because this is essential for
`estimating the radiation doses delivered to tumor, normal brain,
`and the vascular endothelium; and 5) be sufficiently nontoxic to
`attain adequate in vivo tumor concentrations.
`Id. at 436 (emphasis added, endnote numbers omitted).
`
`2. Analysis of Ground IV
`Petitioner asserts that claims 7 and 9 of the ’025 Patent would have
`been obvious in view of Scorei I and Barth. Pet. 40–47; see Ex. 1003 ¶¶
`220–232. Claim 7 is directed to a method of treating cancer using BNCT
`
`19
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`

`

`Case IPR2017-00547

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