Trials@uspto.gov
`571-272-7822
`
`Paper 9
`Date: May 13, 2020
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`BAUSCH HEALTH COMPANIES INC. AND
` BAUSCH HEALTH US LLC,
`Petitioner,
`
`v.
`
`FLOW PHARMA INC.,
`Patent Owner.
`
`IPR2020-00165
`Patent 8,138,157 B2
`
`
`
`
`
`
`
`
`
`Before SUSAN L. C. MITCHELL, ROBERT A. POLLOCK, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`
`
`
`SCHNEIDER, Administrative Patent Judge.
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314, 37 C.F.R. § 42.4
`
`
`
`
`
`
`
`
`571-272-7822
`
`Paper 9
`Date: May 13, 2020
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`BAUSCH HEALTH COMPANIES INC. AND
` BAUSCH HEALTH US LLC,
`Petitioner,
`
`v.
`
`FLOW PHARMA INC.,
`Patent Owner.
`
`IPR2020-00165
`Patent 8,138,157 B2
`
`
`
`
`
`
`
`
`
`Before SUSAN L. C. MITCHELL, ROBERT A. POLLOCK, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`
`
`
`SCHNEIDER, Administrative Patent Judge.
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314, 37 C.F.R. § 42.4
`
`
`
`
`
`
`
`
`
`IPR2020-00165
`Patent 8,138,157 B2
`
`I.
`
`INTRODUCTION
`
`A. Background and Summary
`
`Bausch Health Companies Inc. and Bausch Health US LLC
`
`(collectively “Petitioner”) filed a Petition to institute an inter partes review
`
`of claim 1 of U.S. Patent 8,138,157 B2 (Ex. 1001, “the ’157 patent”). Paper
`
`1 (“Pet.”). Flow Pharma Inc. (“Patent Owner”) filed a Preliminary
`
`Response. Paper 8. (“PO Resp.”).1 We have jurisdiction under 35 U.S.C.
`
`§ 314, which provides that an inter partes review may not be instituted
`
`unless the information presented in the Petition shows “there is a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 claim of
`
`the claims challenged in the petition.” 35 U.S.C. § 314(a) (2018); see also
`
`37 C.F.R. § 42.4(a). Upon consideration of the Petition and Preliminary
`
`Response, we are persuaded that Petitioner has met its burden of showing a
`
`reasonable likelihood that it would prevail in showing that at least one of the
`
`challenged claims is unpatentable.
`
`B. Real Parties in Interest
`
`Bausch Health Companies Inc. and Bausch Health US LLC identify
`
`themselves as the real parties-in-interest. Petitioner noted that Bausch
`
`Health US LLC was formerly known as Valeant Pharmaceuticals North
`
`America LLC.
`
`
`1 On February 19, 2020, Patent Owner filed a document titled “Response.”
`Paper 7. On February 20, 2020, Patent Owner filed a document titled
`“Preliminary Response.” Paper 8. In the Preliminary Response, Patent
`Owner stated “This preliminary response replaces the one filed on February
`18, 2020 which can now be discarded.” PO Resp. 1. For purposes of this
`decision we have only considered the arguments and evidence presented in
`the document titled “Preliminary Response.”
`
`2
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`IPR2020-00165
`Patent 8,138,157 B2
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`C.
`
`Related Matters
`
`The parties state that the ’157 patent is the subject of litigation in
`
`Flow Pharma, Inc. v. Bausch Health Companies Inc. et al., Case No. 4-18-
`
`cv-05769 (N.D.Cal.). Pet. ix.; Paper 6, 2.
`
`D. The ’157 Patent
`
`The ’157 patent generally relates to antimicrobial particles comprising
`
`an antimicrobial agent and a biocompatible controlled release polymer. Ex.
`
`1001, col. 2, ll. 29–35. The antimicrobial agent may comprise an antibiotic
`
`such as gentamicin. Id. at col. 4, ll. 9–12. The polymer may comprise
`
`polylactic-co-glycolic acid (“PLGA”). Id. at col. 4, ll. 13–15. The particles
`
`are designed to release the antimicrobial agent over time ranging from 1 to 7
`
`days. Id. col. 2, ll. 45–48.
`
`One embodiment encompasses a method administering the controlled
`
`release particles into a wound to provide a therapeutically effective dose of
`
`the antimicrobial agent over time. Id. at col. 6, ll. 60–67. The wound can be
`
`the result of implantation of an orthopedic device. Id. In one embodiment
`
`the invention includes treating osteomyelitis in connection with surgical
`
`implants. Id. at col. 9, ll. 31–33. “Osteomyelitis is an infection involving
`
`the bone.” Id. at col. 10, l. 38.
`
`E. Illustrative Claim
`
`The ’165 patent has 16 claims. Claim 1, the only claim challenged in
`
`the Petition, reads as follows:
`
`1. A method of treating osteomyelitis, comprising:
`implanting an orthopedic implant into a surgical wound
`
`site;
`
`administering to the wound site a formulation comprised
`of a plurality of particles which particles are comprised of an
`antimicrobial drug and a biocompatible polymer; and
`
`3
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`Patent 8,138,157 B2
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`allowing drug from the formulation to dissolve into the
`wound site over a period of time not less than one day
`and not more than seven days and provide a therapeutically
`effective dose of the drug over the period of time to thereby
`treat osteomyelitis.
`
`Ex. 1001, col. 28, ll. 29–39.
`
`F. Evidence
`
`Petitioner relies on the following references:
`
`Friess and Schlapp, Modifying the Release of Gentamicin from
`
`Microparticles Using a PLGA Blend, 7 Pharm. Devel. And Tech. 235 (2002)
`
`(Ex. 1016)(“Friess”).
`
`Ipsen et al., Gentamicin-collagen sponge for local applications: 10
`
`cases of chronic osteomyelitis followed for 1 year, 62 Acta Orthop. Scand.
`
`592 (1991) (Ex. 1018) (“Ipsen”).
`
`Wachol-Drewek et al., Comparative investigation of drug collagen
`
`implants saturated in antibiotic solutions and a sponge containing
`
`gentamicin, 17 Biomaterials 1733 (1006) (Ex. 1017) (“Wachol-Drewek”).
`
`Renvert et al., Treatment of Incipient Peri-Implant Infections Using
`
`Topical minocycline Microspheres Versus Topical Chlorhexidine Gel as an
`
`Adjunct to Mechanical Debridement, 6 J. Int’l Acad. Periodont. 154 (2004)
`
`(Ex. 1020) (“Renvert”)
`
`Williams et al., Treatment of Periodontitis be Local Administration of
`
`Minocycline Microspheres: A Controlled Test, 72 Periodontol. 1535 (2001)
`
`(Ex. 1019) (“Williams”).
`
`Petitioner also relies on the Declarations of Paul Ducheyne, M. Sc.,
`
`Ph.D. (Ex. 1003) and Timothy G. Donley, DDS, MSD (Ex. 1004).
`
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`G. Prior Art and Asserted Grounds
`
`Petitioner asserts that claim 1 would have been unpatentable on the
`
`following grounds:
`
`Claim(s)
`Challenged
`1
`1
`1
`
`35 U.S.C. §
`
`References
`
`102
`103(a)
`103(a)
`
`
`
`Friess
`Friess, Ipsen, Wachol-Drewek
`Renvert, Williams, Friess
`
`II. ANALYSIS
`
`A. Legal Standards
`
`“In an [inter partes review], the petitioner has the burden from the
`
`onset to show with particularity why the patent it challenges is
`
`unpatentable.” Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed.
`
`Cir. 2016) (citing 35 U.S.C. § 312(a)(3) (requiring inter partes review
`
`petitions to identify “with particularity . . . the evidence that supports the
`
`grounds for the challenge to each claim”)). This burden of persuasion never
`
`shifts to the patent owner. See Dynamic Drinkware, LLC v. Nat’l Graphics,
`
`Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015) (discussing the burden of proof in
`
`inter partes review).
`
`1. Anticipation
`
`Section 102(a) provides that “[a] person shall be entitled to a patent
`
`unless . . . the claimed invention was patented [or] described in a printed
`
`publication . . . before the invention thereof by the applicant for patent.”
`
`35 U.S.C. § 102(a) (2002).2 Accordingly, unpatentability by anticipation
`
`
`2 The provisions of the Leahy-Smith America Invents Act (“AIA”) regarding
`novelty and obviousness apply to patents containing at least one claim
`having an effective filing date on or after March 16, 2013. Pub L. 112–29,
`125 Stat. 284 (2011). AS discussed more fully below, the ’157 patent has an
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`requires that the four corners of a single, prior art document describe every
`
`element of the claimed invention, either expressly or inherently. See Atlas
`
`Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999); In re
`
`Paulsen, 30 F.3d 1475, 1479 (Fed. Cir. 1994).
`
` A reference can anticipate a claim even if it does not expressly spell
`
`out all the limitations arranged or combined as in the claim, if a person of
`
`skill in the art, reading the reference, would ‘at once envisage’ the claimed
`
`arrangement or combination. Blue Calypso, LLC v. Groupon, Inc., 816 F.3d
`
`1331, 1341 (Fed. Cir. 2016) (citing Kennametal, Inc. v. Ingersoll Cutting
`
`Tool Co., 780 F.3d 1376, 1381 (Fed. Cir. 2015)).
`
`2. Obviousness
`
`The question of obviousness is resolved on the basis of underlying
`
`factual determinations including (1) the scope and content of the prior art,
`
`(2) any differences between the claimed subject matter and the prior art, (3)
`
`the level of skill in the art, and (4) where in evidence, so-called secondary
`
`considerations. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). If
`
`the differences between the claimed subject matter and the prior art are such
`
`that the subject matter, as a whole, would have been obvious at the time the
`
`invention was made to a person having ordinary skill in the art to which said
`
`subject matter pertains, the claim is unpatentable under 35 U.S.C. § 103(a).
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007).
`
`A proper § 103 analysis requires “a searching comparison of the
`
`claimed invention—including all its limitations—with the teaching of the
`
`prior art.” In re Ochiai, 71 F.3d 1565, 1572 (Fed. Cir. 1995).
`
`
`effective filing date of July 10, 2003. Therefore, the pre-AIA provisions of
`35 U.S.C. §§ 102 and 103 apply to this decision.
`
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`“Obviousness requires more than a mere showing that the prior art
`
`includes separate references covering each separate limitation in a claim
`
`under examination.” Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352,
`
`1360 (Fed. Cir. 2011). “Rather, obviousness requires the additional showing
`
`that a person of ordinary skill at the time of the invention would have
`
`selected and combined those prior art elements in the normal course of
`
`research and development to yield the claimed invention.” Id.
`
`B. Level of Ordinary Skill in the Art
`
`The level of ordinary skill in the art is a factual determination that
`
`provides a primary guarantee of objectivity in an obviousness analysis. Al-
`
`Site Corp. v. VSI Int’l Inc., 174 F.3d 1308, 1324 (Fed. Cir. 1999) (citing
`
`Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966); Ryko Mfg. Co. v. Nu-
`
`Star, Inc., 950 F.2d 714, 718 (Fed. Cir. 1991)).
`
`Petitioner contends that one of ordinary skill in the art
`
`would have had a Master’s or a Ph.D. degree in a field of
`natural science such as biology, biochemistry, microbiology,
`immunology, pharmacy, pharmacology or a related field or an
`M.D. degree, with knowledge and several years of experience
`in the subject of controlled release pharmaceutical formulations
`and their use for infection control and treatment of disease, such
`as osteomyelitis. Alternatively, such person could have a
`Bachelor’s degree with a greater number of years of relevant
`experience. To the extent needed, a PHOSITA would have
`collaborated with others having ordinary skill in the areas
`pertinent to the subject matter of the ’157 patent.
`
`Pet. 17–18; see Ex. 1002 ¶ 26–27. Patent Owner does not address the level
`
`of ordinary skill in the art in its Response to the Petition. Because
`
`Petitioners’ proposed definition is unopposed and not inconsistent with the
`
`cited prior art, we adopt it for the purposes of this Decision. See also
`
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (explaining that
`
`7
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`specific findings regarding ordinary skill level are not required “‘where the
`
`prior art itself reflects an appropriate level and a need for testimony is not
`
`shown’” (quoting Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755
`
`F.2d 158, 163 (Fed. Cir. 1985)).
`
`C. Claim Construction
`
`We interpret a claim “using the same claim construction standard that
`
`would be used to construe the claim in a civil action under 35 U.S.C.
`
`282(b).” 37 C.F.R. § 42.100(b) (20182019). Under this standard, we
`
`construe the claim “in accordance with the ordinary and customary meaning
`
`of such claim as understood by one of ordinary skill in the art and the
`
`prosecution history pertaining to the patent.” Id. Furthermore, at this stage
`
`in the proceeding, we need only construe the claims to the extent necessary
`
`to determine whether to institute inter partes review. See Nidec Motor
`
`Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d 1013, 1017 (Fed.
`
`Cir. 2017) (“[W]e need only construe terms ‘that are in controversy, and
`
`only to the extent necessary to resolve the controversy . . . .’” (quoting Vivid
`
`Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999))).
`
`In its claim construction briefing in parallel district court litigation
`
`Patent Owner asserted that the claim terms “treating osteomyelitis” and
`
`“treat osteomyelitis” mean “preventing, inhibiting or relieving
`
`osteomyelitis/prevent, inhibit or relieve osteomyelitis.” Ex. 1032, Ex. A, 1.
`
`According to Petitioner, Patent Owner further argued before the district
`
`court that “treat[ing] osteomyelitis” encompasses “treat[ing] peri-
`
`implantitis.” Pet. 31 and fn.5 (citing Ex. 1031 ¶ 23; Ex. 1035, 7). Petitioner
`
`contends that we should adopt those same constructions here. Pet. 30–31.
`
`Patent Owner’s prior construction of “treat[ing] osteomyelitis” is
`
`consistent with our plain reading of the claim language in view of the ’157
`
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`Specification. We further recognize that Specification teaches that the
`
`invention “includes treating osteomyelitis in connection with surgical
`
`implants and in particular surgical screws,” (Spec., col. 9, ll. 31–33) and that
`
`dental implants involve the use of a surgical screw that is embedded into the
`
`jaw bone (Ex. 1033, 17).
`
`In view of the above, we provisionally adopt Petitioner’s presently
`
`uncontested proposal to construe “treating osteomyelitis” to mean
`
`“preventing, inhibiting or relieving osteomyelitis including preventing,
`
`inhibiting or relieving peri-implantitis.” We similarly provisionally construe
`
`the term “treat osteomyelitis” to mean “prevent, inhibit, or relieve
`
`osteomyelitis including prevent, inhibit, or relieve peri-implantitis.”
`
`D. Ground 1 – Anticipation by Friess
`
`Petitioner contends that claim 1 is anticipated by Friess. Pet. 32–43.
`
`Patent Owner opposes. PO Resp. 4-8.
`
`1. Friess (Exhibit 1016)
`
`Friess discloses the results of a study regarding the use of
`
`microparticles comprising PLGA and gentamicin to provide release of the
`
`antibiotic over a period of a week. Ex. 1016, 235. Friess evaluated the
`
`release profiles of five different sets of particles containing different PLGA
`
`polymers and well as compositions comprising mixtures of different PLGA/
`
`gentamicin particles. Id. According to Friess, “the goal of the study was a
`
`biodegradable local delivery system with the controlled release of
`
`[gentamicin] for approximately one week.” Id. at 236.
`
`Friess found that while none of the individual PLGA polymer based
`
`particles yielded the desired release profile, “preparing microparticles from a
`
`50/50 blend of Resomer® RG502H, an uncapped variety, and Resomer® 503,
`
`an endcapped polymer, yielded the targeted liberation profile.” Id. at 235.
`
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`Friess teaches “[t]he microparticles should be spread onto the open
`
`wound during surgery or injected into the infection site.” Id. at 236.
`
`2. Analysis
`
`Petitioner contends that Friess discloses all the limitations of claim 1.
`
`Pet. 39–41. Patent Owner disputes this contention. PO Resp. 4–8. We
`
`analyze whether Friess teaches each step of the method of claim 1 below.
`
`a) “A method for treating osteomyelitis”
`
`Where the body of a claim fully and intrinsically sets forth all of the
`
`limitations of the claimed invention, and the preamble merely states the
`
`purpose or intended use of the invention, and not a distinct definition of any
`
`claimed limitation, the preamble is not considered limiting and is of no
`
`significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-
`
`Packard Co., 182 F.3d 1298, 1305 (Fed. Cir. 1999). Neither party addresses
`
`directly whether the preamble of claim 1 is limiting, but implicitly concede
`
`that it is. For the purpose of institution, we presume without deciding that
`
`the preamble of claim 1 is limiting, and invite the parties to further address
`
`this issue in future briefing.
`
`Petitioner contends that Friess discloses this preamble in that Friess
`
`discloses that gentamicin has been used during surgery to treat bone
`
`infections. Pet. 39 (citing Ex. 1016, 236). Petitioner also contends that
`
`osteomyelitis is another name for bone infection. Id. (citing Ex. 1003 ¶¶ 41
`
`and 78.
`
`Patent Owner contends that Friess does not use the word osteomyelitis
`
`and that the opinion of Dr. Ducheyne is inadmissible to ascribe such a
`
`teaching to Fries because Dr. Ducheyne’s opinions “not a printed
`
`publication.” PO Resp. 4.
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`We are not presauded that Dr. Ducheyne’s testimony is inadmissible.
`
`Expert testimony may be helpful in evaluating, for example, the “prior art as
`
`viewed with the knowledge of one of skill in the art at the time of
`
`invention.” Trintec Indus., Inc. v. Top-U.S.A. Corp., 295 F.3d 1292, 1297
`
`(Fed. Cir. 2002).
`
`Friess discloses a method for treating infections including bone
`
`infections. Ex. 1016, 236. The Specification teaches “Osteomyelitis is an
`
`infection involving the bone.” Ex. 1001, col. 10, l. 38. On the present
`
`record, we are persuaded that Petitioner has demonstrated that Friess
`
`discloses a method for treating osteomyelitis.
`
`b) “Implanting an orthopedic implant into a surgical wound site”
`
`Petitioner contends that Friess discloses this limitation. Pet. 39.
`
`Petitioner contends that Friess references implants in orthopedic surgery and
`
`the Friess states that bone infection is a feared complication in orthopedic
`
`surgery thereby disclosing this limitation. Id. (citing Ex. 1016, 236.).
`
`Petitioner also contends that Friess discloses that the particles of PLGA and
`
`gentamicin can be spread onto the wound during surgery and that orthopedic
`
`implants require surgery. Id. at 40 (citing Ex. 1016, 236 and Ex. 1003
`
`¶¶ 79–81. Petitioner contends “the disclosure and teaching in Friess is
`
`directed to a local treatment for bone infection after an orthopedic implant
`
`has been surgically implanted.” Id. (citing Ex. 1003 ¶¶ 79–81).
`
`Patent Owner contends that Friess does not specifically mention
`
`implanting an orthopedic implant. PO Resp. 4. Patent Owner contends that
`
`Friess is limited to disclosing “in-vitro experiments on how to manipulate
`
`polymers with a goal of obtaining a release rate that exceeds 7 days.” Id.
`
`Friess disclose the use of a biodegradable local delivery system with
`
`controlled release of gentamicin to prevent infections that might arise during
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`surgery such as orthopedic surgery. Ex. 1016, 236. Friess teaches the
`
`administration of local delivery system to a surgical wound site. Id.
`
`On this record, we agree with Dr. Ducheyne that
`
`A PHOSITA would have at once envisaged that
`orthopedic implants require surgery to be implanted, and that
`this surgery necessarily creates a surgical wound site. A
`PHOSITA would have at once envisaged that Friess provides a
`local treatment for this bone infection that occurs following
`implantation of an orthopedic implant.
`
`Ex. 1003 ¶ 81. Thus, we find on this record that Dr. Ducheyne’s testimony
`
`concerning Fries is not inadmissible because it appropriately opines on what
`
`one of skill in the art would glean from the printed publication, Fries.
`
`
`
`Having considered the arguments advanced by the parties and the
`
`evidence of record, we conclude that Petitioner has shown a reasonable
`
`likelihood of prevailing in showing that Friess discloses this limitation.
`
`While we agree with Patent Owner that Friess does not specifically teach the
`
`implanting of a surgical implant, on the record presently before us we find
`
`that given the disclosure of Friess, one skilled in the art could readily
`
`envision the claimed method.
`
`c) “Administering to the wound site a formulation comprised of a plurality
`of particles which particles are comprised of an antimicrobial drug and
`a biocompatible polymer.”
`
`Petitioner contends that Friess teaches this limitation. Pet. 51.
`
`Petitioner contends that Friess discloses the formulation of microparticles
`
`comprising PLGA and gentamicin, which can be administered to an open
`
`surgical wound. Id.
`
`Patent Owner contends that Friess is limited to in vitro experiments
`
`“on how to manipulate polymers with a goal of obtaining a release rate that
`
`exceeds 7 days.” PO Reps. 4. Patent Owner contends that Petitioner’s
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`arguments are supported solely by the inadmissible testimony of
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`Dr. Ducheyne. Id. For the reasons discussed in section D.2.a, above, Patent
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`Owner does not persuade us the Dr. Ducheyne’s testimony is inadmissible.
`
`Although Friess reports the results of in vitro experiments regarding
`
`the release profile of certain microparticles, Friess states
`
`The microparticles should be spread onto the open
`wound during surgery or injected into the infection site. As an
`alternative, the spheres could be further processed to be
`embedded into a porous carrier system such as a collagen
`sponge and the resulting composite may be implanted in the
`course of an operative procedure.
`
`Ex. 1016, 236.
`
`Having considered the arguments advanced by the parties and the
`
`evidence presently of record, we conclude that Petitioner has shown a
`
`reasonable likelihood of prevailing in showing that Friess discloses this
`
`limitation.
`
`d) “Allowing the drug from the formulation to dissolve into the wound site
`over a period of time not less than one day and not more than seven days
`and provide a therapeutically effective does of the drug over the period
`of time to thereby treat osteomyelitis”
`
`Petitioner contends that Friess discloses this limitation. Pet. 43.
`
`Petitioner contend that Friess discloses a formulation using PLGA polymer
`
`RH502H that released gentamicin over a period of from 4 days to a week.
`
`Id. (citing Ex. 1016 235, 240, 241, Fig. 1(a) and Ex. 1003 ¶ 84). Petitioner
`
`also contends that Fries discloses a composition comprising blends of
`
`microparticles which release gentamicin over the course of a week. Id.
`
`(citing Ex. 1016, 235, 240, 244, Fig. 1(b); Ex. 1003 ¶ 84).
`
`With respect to the amount to gentamicin release, Petitioner contends
`
`that Friess discloses that the particles release 200 mg of gentamicin of a
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`period of from 4 days to a week. Pet. 42 (citing Ex. 1016, 135, 136, 240,
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`Fig. 1(a); Ex. 1003 ¶¶ 84–84). Petitioner also contends that Friess discloses
`
`that the microparticles met the goal of providing therapeutic amounts of
`
`gentamicin to treat bone infections for approximately one week. Id. (citing
`
`Ex. 1016 236; Ex. 1003 ¶ 84).
`
`Patent Owner contends that Friess does not disclose the release of a
`
`therapeutically effective amount of gentamicin for a period of one to seven
`
`days. PO Resp. 4–5. Patent Owner contends that Friess does not disclose
`
`the levels of drugs release by the particles and thus does not address the
`
`requirement of a therapeutically effecting dose. Id. at 4. Patent Owner also
`
`contends that Friess discloses that some of the formulations tested has
`
`release profiles that extended beyond seven days and that Friess only teaches
`
`that it is possible to formulate particles with a one week profile. Id. at 5.
`
`Patent Owner also contend that the art reference in Friess, Wachol-Drewek
`
`teaches a release time of greater than a week. Id. at 6.
`
`Although we agree with Patent Owner that some of the formulations
`
`discussed in Friess do not exhibit the desired release profile, Fries does
`
`disclose at least one formulation that releases gentamicin over a week.
`
`Carrier systems for local gentamicin (GS) treatment
`based on collagen sponges and polymethylmethacrylate beads
`show pharmacokinetic disadvantages in their GS release
`profiles. Therefore, poly(lactic-co-glycolic acid) (PLGA)
`microparticles were devised. None of the five poly(a-hydroxy
`acid)s tested resulted in the desired antibiotic release over
`approximately one week. However, preparing microparticles
`from a 50/50 blend of Resomer® RG 502H, an uncapped
`variety, and Resomer RG 503, an endcapped polymer, yielded
`the targeted liberation profile.
`
`Ex. 1016, 235 (emphasis added). Friess goes on to disclose that
`
`14
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`IPR2020-00165
`Patent 8,138,157 B2
`
`the goal of this study was a biodegradable local delivery system
`with controlled release of GS for approximately one week.
`This was to be achieved by GS loaded PLA or poly(lactic-co-
`glycolic acid) (PLGA) microparticles locally delivering 200mg
`GS per dose corresponding to the GS content of the commercial
`collagen sponge (Sulmycinw implant).
`
`Id.
`
`Based on this disclosure in Friess, we agree with Dr. Ducheyne that
`
`on this record a person of ordinary skill in the art reading Friess would have
`
`at once envisaged using this composition disclosed in Friess
`
`to release the antimicrobial drug over not less than one and not more than
`
`seven days, and provide a therapeutically effective amount of the
`
`antimicrobial drug over that same period of time (not less than one and not
`
`more than seven days). Friess explicitly teaches how to make such
`
`formulations, and explicitly teaches that prevention of “bone infection” due
`
`to orthopedic implant surgery is a purpose of the disclosed formulations.Ex.
`
`1003 ¶ 85.
`
`e) Conclusion
`
`Based on the foregoing, we conclude that, for purposes of this
`
`decision, Petitioner has demonstrated a reasonable likelihood of prevailing
`
`in showing that claim 1 is anticipated by Friess.
`
`
`
`E. Ground 2 – Obviousness based on Friess combined Ipsen and
` Wachol-Drewek
`
`Petitioner contends that the subject matter of claim 1 would have been
`
`obvious to one of ordinary skill in the art at the time of the invention over
`
`Friess combined with Ipsen and Wachol-Drewek. Pet. 44–60. Patent Owner
`
`opposes. PO Resp. 8–9.
`
`15
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`IPR2020-00165
`Patent 8,138,157 B2
`
`1. Ipsen (Ex. 1018)
`
`Ipsen discloses the use of collagen sponges containing gentamicin to
`
`treat osteomyelitis. Ex. 1018, 592. Ipsen teaches that bovine collagen
`
`sponges containing gentamicin were implanted into 10 patients with chronic
`
`osteomyelitis. Id. at 593-593. Ipsen teaches that an average of 351 mg of
`
`gentamicin was implanted and that the medium serum gentamicin levels
`
`were more than 1µg/ml for 24 hours. Id. at 593.
`
`Ipsen also teaches that when two sponges were implanted, the
`
`maximum serum level of gentamicin was 4.0 µg/mL and that after 48 hours
`
`the level of gentamicin in the serum fell to 0.7 µg/mL or less. Id. Ipsen
`
`teaches that the highest serum levels of gentamicin were observed in the first
`
`4 to 12 hours and that the gentamicin was completely released within 2
`
`weeks. Id. at 594.
`
`According to Ipsen, “[t]he release of gentamicin from the carrier
`
`depends on the surface from which it is spread to the surrounding tissue by
`
`diffusion . . . [and] the rapid release of gentamicin from the collagen sponges
`
`is most likely due to their large surface.” Id. at 593.
`
`2. Wachol-Drewek (Exhibit 1017)
`
`Wachol-Drewek relates to local antibiotic therapy to treat bone
`
`infections. Ex. 1017, Abstract. Wachol-Drewek reports an in vitro drug
`
`delivery study comparing antibiotic-saturated collagen implants with a
`
`sponge containing gentamicin. Id. Wachol-Drewek teaches that an
`
`antibiotic delivery of 3 to 4 days was achieved by a sponge containing
`
`gentamicin. Id. Wachol-Drewek teaches that the sponges investigated were
`
`not suitable for delayed release over a period of 5 to 10 days and that further
`
`investigation is needed to develop a system for release over a period of 8 to
`
`15 days. Id.
`
`16
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`IPR2020-00165
`Patent 8,138,157 B2
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`3. Analysis of Claim 1
`
`Petitioner contends that the subject matter of claim 1 is taught or
`
`suggested by the combination of Friess, Ipsen and Wachol-Drewek. Pet.
`
`44–60. Patent Owner contends that the cited references do not teach “any
`
`method for treating osteomyelitis and do not teach any method for treating
`
`osteomyelitis in connection with a bone implant wherein the drug is released
`
`over a period of time of not less than one day and not more than 7 days.”
`
`PO Resp. 9.
`
`We address whether each limitation is taught or suggested by the
`
`asserted combination and whether one of skill in the art would have a reason
`
`to combine such teachings with a reasonable expectation of success.
`
`a) “A method for treating osteomyelitis”
`
`To the extent the preamble is limiting, Petitioner contends that Friess
`
`discloses “[a] method for treating osteomyelitis” because osteomyelitis is
`
`another name for bone infection and Friess discloses the use of gentamicin
`
`during surgery to treat bone infections. Pet. 52 (citing Ex. 1016, 236;
`
`Ex. 1003 ¶¶ 41 and 78). Petitioner contends that Ipsen and Wachol-Drewek
`
`teach this limitation as well. Id. at 52-53. Petitioner points out that Ipsen
`
`specifically mentions treating osteomyelitis. Id. (citing Ex. 1018, 592).
`
`Petitioner also contends that Wachol-Drewek teaches the use of sponges
`
`containing gentamicin to treat bone infections. Id. (citing Ex. 1017, 1733:
`
`Ex. 1003 ¶ 108).
`
`Patent Owner responds that the term osteomyelitis does not appear
`
`anywhere in Friess or Wachol-Drewek and that only Ipsen teaches treating
`
`osteomyelitis. PO Resp. 8. Patent Owner contends that the references teach
`
`treating osteomyelitis by administering an antibiotic for up to two weeks and
`
`not the one to seven days as recited in claim 1. Id. at 8–9.
`
`17
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`IPR2020-00165
`Patent 8,138,157 B2
`
`We are not persuaded by Patent Owner’s arguments. Whereas Patent
`
`Owner focuses on the perceived failings of individual references, the test for
`
`obviousness is what the combined teachings of the references would have
`
`suggested to those of ordinary skill in the art.” In re Keller, 642 F.2d 413,
`
`425 (CCPA 1981). Each reference must be read, not in isolation, but for
`
`what it fairly teaches in combination with the prior art as a whole. See In re
`
`Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
`
`Here, Friess and Wachol-Drewek each discloses the use of gentamicin
`
`to treat bone infections. Ex. 1016, 236: Ex. 1017, 1733. Friess also
`
`discloses that the particles comprised of PLGA and gentamicin should be
`
`applied to the wound site. Ipsen specifically teaches the treatment of
`
`osteomyelitis and the Specification teaches that “[o]steomyeltis is an
`
`infection involving the bone.” Ex. 1018, 592; Ex. 1001, co. 10, l. 38. We
`
`have considered the arguments presented by the parties and the evidence of
`
`record and conclude on this record that Friess combined with Ipsen and
`
`Wachol-Drewek teaches a method for treating osteomyelitis.. We agree
`
`with Petitioner that it has shown sufficiently on this record for purposes of
`
`institution that the combination of references teaches treating osteomyelitis.
`
`b) Implanting an orthopedic implant into a surgical wound site
`
`Petitioner contends that Friess teaches this limitation as Friess teaches
`
`controlling infections during surgery including orthopedic surgery. Pet. 54–
`
`55 (citing Ex. 1016, 236; Ex. 1003 ¶¶ 105 and 113–115). Petitioner
`
`contends that implanting an orthopedic implant necessarily involves surgery
`
`and creation of a surgical wound site. Id. (citing Ex. 1003 ¶¶ 110 and 112).
`
`Petitioner contends that Friess teaches that the disclosed particles are to be
`
`spread on an open wound during surgery or implanted in the course of an
`
`operative procedure. Id. at 54 (citing Ex. 1016, 236; Ex. 1003 ¶ 111.)
`
`18
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`IPR2020-00165
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`
`Patent Owner does not specifically address this limitation other than
`
`to contend that the references “do not teach any method for treating
`
`osteomyelitis in connection with a bone implant wherein the drug is released
`
`over a period of time not less than one day and not more than 7 days.” PO
`
`Resp. 9. We do not find Patent Owner’s argument persuasive.
`
`Friess teaches applying particles containing gentamicin to a wound
`
`created during surgery and refers to both trauma and orthopedic surgery.
`
`Ex. 1006, 236. Dr. Ducheyne testifies “[i]mplanting an orthopedic implant
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