Trials@uspto.gov
`571-272-7822
`
`Paper 8
`Date: July 12, 2021
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS, INC.,
`Petitioner,
`v.
`AMGEN, INC.,
`Patent Owner.
`
`IPR2021-00326
`Patent 9,856,287 B2
`
`
`
`
`
`
`
`
`
`Before ZHENYU YANG, CHRISTOPHER G. PAULRAJ, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`SCHNEIDER, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`571-272-7822
`
`Paper 8
`Date: July 12, 2021
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS, INC.,
`Petitioner,
`v.
`AMGEN, INC.,
`Patent Owner.
`
`IPR2021-00326
`Patent 9,856,287 B2
`
`
`
`
`
`
`
`
`
`Before ZHENYU YANG, CHRISTOPHER G. PAULRAJ, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`SCHNEIDER, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`
`I.
`INTRODUCTION
`Lupin, Ltd. and Lupin Pharamaceuticals, Inc. (collectively
`“Petitioner”) filed a Petition (Paper 1, “Pet.”) requesting an inter partes
`review of claims 1–30 of U.S. Patent No. 9,856,287 B2 (“the ’287 patent,”
`Ex. 1001). Amgen, Inc. and Amgen Manufacturing, Limited (collectively
`“Patent Owner”) filed a Preliminary Response. Paper 7 (“Prelim. Resp.”).
`We have authority to determine whether to institute an inter partes
`review. 35 U.S.C. § 314. Upon consideration of the Petition and the
`Preliminary Response, and in light of Board precedent, we conclude
`Petitioner has not demonstrated a reasonable likelihood of showing that at
`least one claim is unpatenable
`A. Real Parties-in-Interest
`Petitioner identifies Lupin, Ltd., Lupin Pharmaceuticals, Inc., Lupin,
`Inc., and Nanomi BV as the real parties-in-interest for Petitioner. Pet. 2
`Patent Owner identifies Amgen, Inc. and Amgen Manufacturing, Limited as
`the real parties-in-interest for Patent Owner. Paper 4, 1.
`B. Related Matters
`Petitioner states that there is no pending district court action involving
`the ’287 patent and that the ’287 patent was the subject of litigation in three
`district court actions:
`- Amgen Inc. et al. v. Tanvex BioPharma USA, Inc. et al., 19-cv-
`01374, S.D. Cal. (the “Tanvex litigation”), which was dismissed December
`19, 2019.
`- Amgen Inc. et al. v. Adello Biologics, LLC et al., 18-cv-3347, D.N.J.,
`(the “Adello litigation”), which was dismissed November 25, 2019.
`- Amgen Inc. et al. v. Accord BioPharma USA, Inc. et al., 18-cv-
`61828, S.D. Fl., which was dismissed November 15, 2019.
`
`2
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`
`Petitioner also states that there are no currently pending Patent Trial
`and Appeal Board (“PTAB”) proceedings that address the validity of the
`’287 patent and that the ’287 patent was the subject of three prior PTAB
`proceedings:
`- PGR2019-00001, Adello Biologics, LLC et al. v. Amgen Inc. et al.
`(the “Adello PGR”) was terminated on December 6, 2019. PGR2019-00001,
`Paper 28 (PTAB Dec. 6, 2019).
`- IPR2019-00971, Fresenius Kabi USA, LLC et al. v. Amgen, Inc. et
`al. (the “2019 Fresenius IPR”), was denied institution under § 314(a) as
`duplicative of the then-pending Adello PGR, without evaluation on the
`merits. See 2019 Fresenius IPR, Paper 13 (PTAB Oct. 16, 2019).
`- IPR2020-00314, Fresenius Kabi USA, LLC et al. v. Amgen, Inc. et
`al. (the “2020 Fresenius IPR”) was terminated on June 19, 2020. Fresenius
`IPR, Paper 17 (PTAB. Jun. 19, 2020).
`C. The ’287 Patent
`The ’287 patent relates to a method of refolding proteins expressed in
`non-mammalian cells. Ex. 1001, 2:62–3:4. Such refolding is necessary in
`some non-mammalian expression systems, such as bacteria, because of the
`“inability of a bacterial host cell to fold recombinant proteins properly at
`high levels of expression.” Id. at 1:25–32. As a result, the improperly-folded
`proteins are insoluble and precipitate out of solution to form inclusion
`bodies. Id. According to the ’287 patent, prior art refolding techniques did
`not demonstrate refolding of larger, more complex protein molecules at high
`concentrations, i.e., 2.0g/L or higher, at a scale suitable for industrial
`applications. Id. at 2:8–32.
`
`3
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`
`D. Illustrative Claims
`Petitioner challenges claims 1–30. Claims 1, 10, 16, and 26 are the
`independent claims. Claim 1 is illustrative and is reproduced below:
`1. A method refolding proteins expressed in a
`nonmammalian expression system, the method comprising:
`contacting the proteins with a preparation that supports the
`renaturation of at least one of the proteins to a biologically
`active form, to form a refold mixture, the preparation
`comprising:
`at least one ingredient selected from the group consisting
`of a denaturant, an aggregation suppressor and a protein
`stabilizer;
`an amount of oxidant; and
`an amount of reductant;
`wherein the amounts of the oxidant and the reductant are
`related through a thiol-pair ratio and a thiol-pair buffer strength,
`wherein the thiol-pair ratio is in the range of 0.001-100; and
`wherein the thiol-pair buffer strength maintains the solubility of
`the preparation; and incubating the refold mixture so that at
`least about 25% of the proteins are properly refolded.
`
`
`Ex. 1001, 18:21–41.
`
`E. Evidence
`Petitioner relies on the following evidence:
`Vallejo, et al., EP 1449848 A1, published August 25, 2004. (Ex. 1003
`“Vallejo”).
`Schlegl, US 2007/0238860 A1, published October 11, 2007 (Ex. 1004
`“Schlegl”).
`Hevehan, D. and Clark, E., “Oxidative Renaturation of Lysozyme at
`High Concentrations,” 54:3 BIOTECHNOLOGY AND
`BIOENGINEERING. 221–230 (May 1997) (Ex. 1005 “Hevehan”).
`
`4
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`Schafer et al., “Redox Environment of the Cell as Viewed Through the
`Redox State of the Glutathione Disulfide/Glutathione Couple,” 30 Free
`Radical Biol. Med. 1191–1212 (2001) (Ex. 1007 “Schafer”).
`Ruddon et al., WO 95/32216, published November 30, 1995. (Ex.
`1006 “Ruddon”).
`Petitioner also relies on the Declaration of George Georgiou, Ph.D.
`(Ex. 1002 “Georgiou Decl.”).
`F. Prior Art and Asserted Grounds
`Petitioner asserts that claims 1–30 would have been unpatentable on
`the following grounds:
`Claim(s) Challenged
`1–4, 7–19, 22–30
`1–4, 7–19, 22–30
`1–30
`1–6, 8–21, 23–30
`8–9, 14–15, 23–25,
`30
`8–9, 14–15, 23–25,
`30
`
`
`
`II. ANALYSIS
`A. Legal Standards
`1. Burden of Proof
`At this stage of the proceeding, the burden rests on the petitioner to
`establish a reasonable likelihood that it will prevail in showing that at least
`one of the challenged claims is unpatentable. 35 U.S.C. § 314(a) (2018).
`
`
`1 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112–29, 125
`Stat. 284, 287–88 (2011), amended 35 U.S.C. §§ 102 and 103. Because the
`’287 patent was filed before March 16, 2013 (the effective date of the
`relevant amendments), the pre-AIA versions of §§ 102 and 103 apply.
`
`5
`
`35 U.S.C. §1
`102(b)
`102(b)
`103(a)
`103(a)
`103(a)
`
`Reference(s)/Basis
`Vallejo
`Schlegl
`Vallejo, Hevehan
`Schlegl, Hevehan
`Vallejo, Schafer, Ruddon
`
`103(a)
`
`Schlegl, Schafer, Ruddon
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`
`2. Anticipation
`“Under 35 U.S.C. § 102, every limitation of a claim must identically
`appear in a single prior art reference for it to anticipate the claim.” Gechter
`v. Davidson, 116 F.3d 1454, 1457 (Fed. Cir. 1997). “[U]nless a [prior art]
`reference discloses within the four corners of the document not only all of
`the limitations claimed but also all of the limitations arranged or combined
`in the same way as recited in the claim, it cannot be said to prove prior
`invention of the thing claimed and, thus, cannot anticipate under 35 U.S.C. §
`102.” Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1371 (Fed. Cir.
`2008).
`
`3. 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).
`“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,
`
`6
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`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” with a reasonable
`expectation of success. Id.
`B. Level of Ordinary Skill in the Art
`Petitioner proposes that an ordinary artisan “would have had a Ph.D.
`in biochemistry or chemical engineering and several years of experience in
`the fields of biochemical manufacturing, protein purification and/or protein
`refolding” or, alternatively, “would have had an equivalent level of
`education and experience, including a Bachelor’s or Master’s degree with
`more practical work experience in the above field(s).” Pet. 21–22 (citing Ex.
`1002 ¶ 29). Patent Owner does not dispute, and we adopt, for purposes of
`this Decision, Petitioner’s proposed definition of level of skill.
`We further note that, in this case, the prior art itself demonstrates the
`level of skill in the art at the time of the invention. See Okajima v. Bourdeau,
`261 F.3d 1350, 1355 (Fed. Cir. 2001) (explaining that 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) (2020). 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
`
`7
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`history pertaining to the patent.” Id. Furthermore we need only construe the
`claims to the extent necessary to determine the patentability of the
`challenged claims. 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))).
`The only dispute between the parties with respect to claim
`construction centers on the term “is calculated,” which appears in several
`dependent claims. See Pet. 24–26; Prelim. Resp. 36–38. As seen from the
`analysis below, we find it unnecessary to resolve the meaning of this term.
`D. Grounds Based on Vallejo
`Vallejo discloses “a method of producing a biologically active
`recombinant cystine-knot protein comprising (a) solubilisation of inclusion
`bodies comprising said cystine-knot protein produced in a bacterium . . . ;
`[and] (b) renaturation of the solubilized cystine-knot protein in batch or by
`pulse addition of said solubilized cystine-knot protein to a refolding buffer . .
`. .” Ex. 1003 ¶ 1.
`Petitioner argues that claims 1–4, 7–21, and 30 are anticipated by
`Vallejo; claims 1–6, 7–19, and 30 are unpatentable as obvious over Vallejo
`alone or in combination with Hevehan; and claims 8, 9, 14, 15, 23–25, and
`30 are unpatenable as obvious over Vallejo in combination with Schafer and
`Ruddon. Pet. 28–41, 52–56, and 63–64. Patent Owner disputes these
`contentions. Prelim. Resp. 39–44. Based on the record before us, we find
`Patent Owner’s arguments persuasive.
`All of the challenged claims recite “wherein the thiol-pair ratio is in
`the range of 0.001-100.” Petitioner’s arguments with respect to this
`
`8
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`
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`IPR2021-00326
`Patent 9,856,287 B2
`limitation are based on calculations performed by its expert Dr. Georgiou,
`who opined that the “standard renaturation buffer” used in Example 6 of
`Vallejo was the buffer disclosed in Example 8. Pet. 32–33; Ex. 1002 ¶¶ 101–
`102. Using the solution described in Example 8, which included glutathione,
`Dr. Georgiou calculated a thiol-pair ratio of 3. Pet. 34; Ex. 1002 ¶ 103.
`However, as Patent Owner points out, in Example 4, Vallejo discloses
`a different “standard redox solution.” Prelim. Resp. 42; Ex. 1003 ¶ 47. The
`redox solution of example 4 does not contain glutathione. Ex. 1003 ¶ 49.
`Given that the thiol-pair calculation is based, in part, on the presence of
`glutathione, the absence of glutathione would yield a different “thiol-pair
`ratio” than that calculated by Dr. Georgiou.
`Dr. Georgiou does not point to nor do we discern any disclosure in
`Vallejo that would lead one skilled in the art to conclude that the redox
`solution described in Example 8 was the redox solution used in Example 6.
`In fact, the discussion in Example 6 suggests that the redox solution used
`was that of Example 4. See Ex. 1003 ¶ 47 (Example 6 only references the
`presence of guanidium salt with no mention of glutathione). Thus, we agree
`with Patent Owner that Petitioner has not shown that Vallejo discloses all of
`the limitations arranged or combined in the same way as recited in the
`challenged claims.
`The challenged claims also call for the thiol-pair buffer to maintain
`the solubility of the solution or preparation. See, e.g. Ex. 1001, 8:38–39.
`Petitioner contends that Vallejo inherently discloses this limitation as
`refolding would not be possible unless solubility were maintained. Pet. 36;
`Ex. 1002 ¶¶ 109–110. However, Vallejo discloses in Example 6 that the
`protein precipitates. Ex. 1003 ¶ 49, Figs. 3 and 8. Thus, we agree with Patent
`
`9
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`Owner that Petitioner has not shown that Vallejo discloses that the thiol-pair
`buffer maintains the solubility of the solution.
`Grounds 3 and 5 assert that the challenged claims are unpatentable
`over Vallejo alone or in combination with Hevehan, Ruddon, and/or Schafer.
`In its analysis Petitioner again relies on the assumption that the redox
`solution used in Example 6 of Vallejo is that disclosed in Example 8. See
`Pet. 53, 59. Nowhere in its analysis of either ground does Petitioner address
`the issue of Vallejo teaching two different redox solutions or the fact that the
`method of Vallejo results in proteins precipitating out of solution. See id. at
`53–56, 59–63. The additional references do not correct the deficiencies of
`Vallejo.
`Based on the foregoing we conclude that Petitioner has failed to
`demonstrate a reasonable likelihood of showing that claims 1–30 are
`unpatentable based on the teachings of Vallejo alone or in combination with
`the secondary references.
`E. Grounds Based on Schlegl
`Schlegl discloses
`a method for obtaining a biologically active recombinant protein
`by reconstituting the protein from a denatured state to its active
`form, said method containing a steps of mixing a feed solution
`containing the protein in its denatured form and/or its
`biologically inactive intermediate forms with a refolding buffer
`under conditions that approximate ideal mixing.
`
`Ex. 1004 ¶ 24.
`Petitioner contends that claims 1–4, 8–19, and 23–30 are anticipated
`by Schlegl. Pet. 41. Petitioner also contends that claims 1–6, 8–21, and 23–
`30 are unpatentable as obvious over Schlegl, alone or in combination with
`Hevehan and that claims 8, 9, 14, 15, 23–25, and 30 are unpatentable as
`
`10
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`obvious over Schleglor in combination with Schafer and Ruddon. Id. at 56,
`63. Patent Owner disputes these contentions. Prelim. Resp. 44–49. Based on
`the record before us, we find Patent Owner’s arguments persuasive.
`As noted above, the challenged claims recite the limitation calling for
`the thiol-pair buffer to maintain the solubility of the solution or preparation.
`Petitioner contends that the method of Schlegl meets this limitation as the
`method results in biologically active proteins and that this result would not
`occur if the protein and other components did not remain in solution. Pet. 48;
`Ex. 1002 ¶ 131. Alternatively, Petitioner contends that one skilled in the art
`would understand that the high refolding yields reported in Schlegl would
`lead one skilled in the art to understand that the solubility of the proteins and
`other components had been maintained. Id. at 57; Ex. 1002 ¶ 152.
`Petitioner supports its contentions with the testimony of Dr. Georgiou.
`Dr. Georgiou, however, offers no support for his conclusions that the results
`achieved in Schlegl would not have been achieved unless the solubility of
`the components were maintained. Ex. 1002 ¶ 65. While not expressed in
`terms of inherency, we interpret Dr. Georgiou’s testimony as stating that the
`maintenance of solubility is inherent in the process of Schlegl in that the
`process produces properly refolded proteins in significant amounts.
`However, inherency requires that the missing element “‘is necessarily
`present, or inherent, in the single anticipating reference.’ The inherent result
`must inevitably result from the disclosed steps; ‘[i]nherency . . . may not be
`established by probabilities or possibilities.’” In re Montgomery, 677 F.3d
`1375, 1379–80 (Fed. Cir. 2012) (citations omitted). We agree with Patent
`Owner that Petitioner has failed to establish that maintenance of solubility is
`inherent in the method of Schlegl. Prelim. Resp. 48.
`
`11
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`Schlegl teaches that the thiol containing redox systems such as
`reduced glutathione/oxidized glutathione is optional. Ex. 1004 ¶ 36. Thus,
`the method of Schlegl can be practiced without a thiol-pair. In addition, as
`discussed above, the process of Vallejo, which yields bioactive proteins, also
`results in protein precipitating out of solution. Ex. 1003 ¶ 49, Figs. 3 and 8.
`Thus, the teachings of Schlegl and Vallejo contradict Dr. Georgiou’s opinion
`that the proper refolding of the proteins can only occur if the proteins and
`other components remain in solution. Petitioner does not address this
`discrepancy. Thus, we find that Petitioner has not shown that the system of
`Schlegl would inherently maintain the protein and other components in
`solution.
`Based on the foregoing we find that Petitioner has not demonstrated a
`reasonable likelihood of showing that the challenged claims are unpatentable
`as anticipated by Schlegl or obvious over Schlegl alone or in combination
`with the secondary references.
`III. DISCRETION UNDER 35 U.S.C. §§ 314 AND 325
`Patent Owner has argued that we should exercise our discretion and
`deny the petition under either 35 U.S.C. § 314(a) or 35 U.S.C. § 325(d).
`Prelim Resp. 6–35. Petitioner argues that we should not. Pet. 5–10.
`As discussed above, we find that Petitioner has not demonstrated a
`reasonable likelihood of showing at least one of the challenged claims to be
`unpatentable. Having denied the Petition on this basis, we do not reach the
`issue of whether we should exercise our discretion to deny the Petition under
`§ 314(a) or § 325(d).
`
`12
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`
`IV. CONCLUSION
`Based on the foregoing we conclude that Petitioner has not
`demonstrated a reasonable likelihood of showing that at least one of the
`challenged claims is unpatentable.
`V. ORDER
`In consideration of the foregoing, it is hereby:
`ORDERED that, pursuant to 35 U.S.C. § 314, the Petition is denied
`and no inter partes review is instituted.
`
`
`
`
`
`
`13
`
`
`
`IPR2021-00326
`Patent 9,856,287 B2
`PETITIONER:
`
`Thomas J. Meloro
`Michael W. Johnson
`WILLKIE FARR & GALLAGHER LLP
`tmeloro@willkie.com
`mjohnson1@willkie.com
`
`
`PATENT OWNER:
`
`Megan Raymond
`J. Steven Baughman
`PAUL, WEISS, RIFKIND,
`WHARTON & GARRISON LLP
`mraymond@paulweiss.com
`sbaughman@paulweiss.com
`
`14
`
`
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