Trials@uspto.gov
`Tel: 571-272-7822
`
`
`Paper 39
`Entered: August 2, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`LUPIN LIMITED,
`Petitioner,
`
`v.
`
`VERTEX PHARMACEUTICALS INCORPORATED,
`Patent Owner.
`_______________
`
`Case IPR2016-00558
`Patent 6,436,989 B1
`_______________
`
`
`Before LORA M. GREEN, SHERIDAN K. SNEDDEN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`Determining Claims 2, 3, and 10–12 Not Shown to be Unpatentable
`35 U.S.C. § 318(a); 37 C.F.R. § 42.73
`
`
`
`
`

`

`IPR2016-00558
`Patent 6,436,989 B1
`
`I. INTRODUCTION
`
`This is a Final Written Decision in an inter partes review challenging
`
`the patentability of claims 2, 3, and 10–12 (collectively, “the challenged
`
`claims”) of U.S. Patent No. 6,436,989 B1 (Ex. 1001; “the ’989 Patent”). We
`
`have jurisdiction under 35 U.S.C. § 6. For the reasons that follow, we
`
`determine that Petitioner failed to demonstrate, by a preponderance of
`
`evidence, that claims 2, 3, and 10–12 are unpatentable.
`
`A. Procedural History
`
`Lupin Limited (“Petitioner”) filed a Petition (Paper 1; “Pet.”) to
`
`institute an inter partes review of claims 2, 3, and 10–12 of the ’989 Patent.
`
`Vertex Pharmaceuticals Incorporated (“Patent Owner”) filed a Patent Owner
`
`Preliminary Response. Paper 8 (“Prelim. Resp.”). Based on these
`
`submissions, we instituted trial on the following grounds of unpatentability
`
`asserted by Petitioners:
`
`Reference[s]
`
`Basis
`
`Claims challenged
`
`Roy1 and Grobelny2
`
`§ 103(a)
`
`2
`
`Roy, Grobelny, and Bighley3
`
`§ 103(a)
`
`3, 10–12
`
`Decision to Institute (Paper 9, “Dec.”).
`
`
`1 Ex. 1021, U.S. Patent No. 6,730,679 B1, issued May 4, 2004 to Roy et al.
`(hereinafter “Roy” or “the ’679 Patent”).
`
`2 Ex. 1022, International Patent Application Publication Number
`WO 95/07269, published March 16, 1995, and naming Damian Grobelny as
`the sole inventor (hereinafter “Grobelny” or “the ’269 Publication”).
`
`3 Ex. 1027, Bighley, et al., Salt Forms of Drugs and Absorption, in 13
`ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY 453499 (James
`Swarbrick & James C. Boylan eds. 1996) (hereinafter “Bighley”).
`
` 2
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`

`IPR2016-00558
`Patent 6,436,989 B1
`
`
`After institution of trial, Patent Owner filed a Patent Owner Response
`
`(Paper 13, “PO Resp.”), to which Petitioners filed a Reply (Paper 24,
`
`“Reply”).
`
`Petitioners rely on the Declarations of Jed Fisher (Ex. 1002 and
`
`Ex. 1096) in support of the proposed grounds of unpatentability.
`
`Patent Owner relies on the Declaration of Richard Ogden, Ph.D.
`
`(Ex. 2017).
`
`Patent Owner filed a motion to exclude certain of Petitioners’
`
`evidence. Paper 27. Petitioners filed an opposition (Paper 29), and Patent
`
`Owner filed a reply (Paper 30).
`
`Oral argument was conducted on April 5, 2017. A transcript is
`
`entered as Paper 38 (“Tr.”).
`
`B. The ’989 Patent (Ex. 1001)
`
`The ’989 patent is directed to prodrugs of HIV aspartyl protease
`
`inhibitors, pharmaceutical compositions thereof, and methods of treating
`
`mammals therewith. Ex. 1001, 1:517. Prodrugs generally are inactive
`
`compounds that convert to an active form in the body. Id. at 2:716,
`
`33:2534. Usually, a prodrug has some improved pharmacological property
`
`over the active drug, such as improved stability or solubility. Id. The
`
`prodrugs of the ’989 patent are said to have favorable aqueous solubility, to
`
`have high oral bioavailability and facile in vivo generation of the active
`
`ingredient, and to be particularly well suited for decreasing pill burden and
`
`increasing patient compliance. Id. at 1:615.
`
`The relevant compound of the ’989 patent is a prodrug of the known
`
`HIV aspartyl protease inhibitor, VX-478 (4-amino-N-((2-syn, 3S)-2-
`
`hydroxy-4-phenyl-2((S)-tetrahydrofuran-3-yl-oxycarbonylamino)butyl-N-
`
` 3
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`IPR2016-00558
`Patent 6,436,989 B1
`
`isobutyl-benzenesulfonamide), also known as amprenavir. Id. at 1:3042,
`
`30:2934:67; Prelim. Resp. 18; Ex. 1002, ¶ 20, n.1. Amprenavir has the
`
`following structure:
`
`.
`
`Ex. 1001, 30:3231:5.
`
`Examples 27 to 30 detail the process for forming phosphate ester
`
`derived prodrugs of amprenavir. Id. at 57:160:14. Example 30, in
`
`particular, describes a disodium phosphate ester salt prodrug of amprenavir.
`
`Id. at 59:920, 60:121.
`
`C. Challenged Claims
`
`The challenged “claims cover the drug Lexiva® (fosamprenavir
`
`calcium), which is marketed for the treatment of human immunodeficiency
`
`virus-1 (‘HIV’).” PO Resp. 1; see Pet. 4–5. Challenged claims 2 and 3
`
`depend from claim 1 of the ’989 patent. Challenged claims 10–12 depend
`
`from claim 4 of the ’989 patent. Claims 1–4 and 10–12 of the ’989 patent
`
`are reproduced below:
`
` 4
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`IPR2016-00558
`Patent 6,436,989 B1
`
`
`1. A compound of the formula:
`
`
`
`
`
`
`
`2. The compound according to claim 1, wherein:
`
`R7 is selected from —PO3
`
`2−Na2
`
`
`
`+, —PO32−K2
`
`+, or —PO3
`
`2−Ca2+.
`
`3. The compound according
`2−Ca2+.
`is — PO3
`
`to claim 2, wherein R7
`
`4. A pharmaceutical composition, comprising a compound
`according to any one of claims 1 to 3 in an amount effective to
`treat infection by a virus that is characterized by a virally-
`encoded aspartyl protease; and a pharmaceutically acceptable
`carrier, adjuvant or vehicle.
`
` 5
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`IPR2016-00558
`Patent 6,436,989 B1
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`
`10. A method for treating HIV infection in a mammal comprising
`the step of administering to said mammal a pharmaceutical
`composition according to claim 4.
`
`11. The method according to claim 10, wherein said mammal is
`additionally administered one or more additional agents
`independently selected from an anti-viral agent, an HIV protease
`inhibitor, or an immunostimulator, either as a part of a single
`dosage form with said pharmaceutical composition or as a
`separate dosage form.
`
`12. The method according to claim 11, wherein said one or more
`additional agents are selected from zidovudine (AZT),
`zalcitabine (dideoxycytidine, ddC), didanosine (ddI), stavudine
`(d4T), lamivudine (3TC), abacavir (1592U89), saquinavir (Ro
`31-8959), indinavir (L-735,524), ritonavir (ABT 538, A84538),
`nelfinavir (AG 1343), XM 450, CGP 53,437, polysulfated
`polysaccharides, ganciclovir,
`ribavirin, acyclovir, TIBO,
`nevirapine, IL-2, GM-CSF, interferon alpha, or erythropoietin
`(EPO).
`
`Ex. 1001, 74:24–76:17.
`
`II. DISCUSSION
`
`Petitioner bears the burden of proving unpatentability of the
`
`challenged claims, and the burden of persuasion never shifts to Patent
`
`Owner. Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375,
`
`1378 (Fed. Cir. 2015). To prevail, Petitioner must establish the facts
`
`supporting its challenge by a preponderance of the evidence. 35 U.S.C.
`
`§ 316(e); 37 C.F.R. § 42.1(d). Below, we explain why Petitioner has failed
`
`to meet its burden with respect to the challenged claims.
`
`A. Claim Interpretation
`
`We interpret claims using the “broadest reasonable construction in
`
`light of the specification of the patent in which [they] appear[].” 37 C.F.R.
`
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`IPR2016-00558
`Patent 6,436,989 B1
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`§ 42.100(b); see Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`
`(2016). Under that standard, claim terms generally are given their ordinary
`
`and customary meaning, as would be understood by one of ordinary skill in
`
`the art in the context of the entire disclosure. In re Translogic Tech., Inc.,
`
`504 F.3d 1249, 1257 (Fed. Cir. 2007). “Absent claim language carrying a
`
`narrow meaning, the PTO should only limit the claim based on the
`
`specification . . . when [it] expressly disclaim[s] the broader definition.” In
`
`re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004) (citation omitted).
`
`“Although an inventor is indeed free to define the specific terms used to
`
`describe his or her invention, this must be done with reasonable clarity,
`
`deliberateness, and precision.” In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
`
`1994).
`
`Neither party provides any express claim constructions for terms in
`
`the challenged claims. Pet. 17; PO Resp. 24. Except as discussed below, we
`
`determine that no claim term requires express construction. See, e.g., Vivid
`
`Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)
`
`(“[O]nly those terms need be construed that are in controversy, and only to
`
`the extent necessary to resolve the controversy.”).
`
`We acknowledge and agree, however, with Patent Owner’s general
`
`contention that claims 10–12, “as understood by a person of ordinary skill in
`
`the art at the time of the invention, would require bioavailability of the
`
`parent compound upon administration of the prodrug.” PO Resp. 24.
`
`Claims 10–12 are directed to a method of treating HIV infection, which
`
`requires the compound to enter the blood in an amount effective to treat
`
`HIV. Ex. 2017 ¶ 7; Ex. 2003, 203:14–205:14, 206:3–18. In this regard, the
`
`terms of the challenged claims are given their plain and ordinary meaning as
`
` 7
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`IPR2016-00558
`Patent 6,436,989 B1
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`set forth above.
`
`B. Obviousness Analysis
`
`1. 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 said
`
`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 skill in the art; and (4) objective evidence of nonobviousness,
`
`i.e., secondary considerations. Id. (citing Graham v. John Deere Co.,
`
`383 U.S. 1, 17–18 (1966)).
`
`Secondary considerations include commercial success, long-felt but
`
`unsolved needs, failure of others, and unexpected results. KSR, 550 U.S. at
`
`406; In re Soni, 54 F.3d 746 (Fed. Cir. 1995). Secondary considerations are
`
`“not just a cumulative or confirmatory part of the obviousness calculus but
`
`constitute[] independent evidence of nonobviousness . . . and enable[] the
`
`court to avert the trap of hindsight.” Leo Pharm. Prods., Ltd. v. Rea, 726
`
`F.3d 1346, 1358 (Fed. Cir. 2013) (internal quotation marks and citations
`
`omitted). “This objective evidence must be ‘considered as part of all the
`
`evidence, not just when the decision maker remains in doubt after reviewing
`
`the art.’” Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling
`
`USA, Inc., 699 F.3d 1340, 1349 (Fed. Cir. 2012) (citations omitted).
`
` 8
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`IPR2016-00558
`Patent 6,436,989 B1
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`
`The obviousness analysis requires that “the factfinder should further
`
`consider whether a person of ordinary skill in the art would [have been]
`
`motivated to combine those references, and whether in making that
`
`combination, a person of ordinary skill would have [had] a reasonable
`
`expectation of success,” even “[i]f all elements of the claims are found in a
`
`combination of prior art references.” Merck & Cie v. Gnosis S.p.A., 808
`
`F.3d 829, 833 (Fed. Cir. 2015). The “motivation to combine” and
`
`“reasonable expectation of success” factors are subsidiary requirements for
`
`obviousness subsumed within the Graham factors. Pfizer, Inc. v. Apotex,
`
`Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007).
`
`The degree of unpredictability in the art and guidance in the art must
`
`also be considered in determining whether a person of ordinary skill in the
`
`art would have had a reasonable expectation of success. Pfizer, 480 at 1364;
`
`In re O’Farrell, 853 F.2d 894, 903 (Fed.Cir.1988) (The prior art must
`
`provide more than “general guidance as to the particular form of the claimed
`
`invention or how to achieve it.”). “To the extent an art is unpredictable, as
`
`the chemical arts often are, KSR’s focus on [ ] ‘identified, predictable
`
`solutions’ may present a difficult hurdle because potential solutions are less
`
`likely to be genuinely predictable.” Eisai Co. v. Dr. Reddy's Labs., Ltd., 533
`
`F.3d 1353, 1359 (Fed. Cir. 2008) (quoting KSR, 550 U.S. at 402). Indeed,
`
`[c]ases following KSR have considered whether a given
`molecular modification would have been carried out as part of
`routine testing. See, e.g., [Takeda Chem. Indus., Ltd. v.
`Alphapharm Pty., Ltd., 492 F.3d 1350, 1360 (Fed. Cir. 2007)]
`(discussing the district court’s finding that a modification was
`not known to be beneficial and was not considered “routine”).
`When a person of ordinary skill is faced with “a finite number of
`identified, predictable solutions” to a problem and pursues “the
`known options within his or her technical grasp,” the resulting
`
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`IPR2016-00558
`Patent 6,436,989 B1
`
`
`discovery “is likely the product not of innovation but of ordinary
`skill and common sense.” KSR, 127 S.Ct. at 1742. So too,
`“[g]ranting patent protection to advances that would occur in the
`ordinary course without real innovation retards progress.” Id. at
`1741. In other cases, though, researchers can only “vary all
`parameters or try each of numerous possible choices until one
`possibly arrive[s] at a successful result, where the prior art
`[gives] either no indication of which parameters [are] critical or
`no direction as to which of many possible choices is likely to be
`successful.” In re O’Farrell, 853 F.2d 894, 903 (Fed.Cir.1988).
`In such cases, “courts should not succumb to hindsight claims of
`obviousness.” In re Kubin, 561 F.3d 1351 (Fed.Cir.2009).
`Similarly, patents are not barred just because it was obvious “to
`explore a new technology or general approach that seemed to be
`a promising field of experimentation, where the prior art gave
`only general guidance as to the particular form of the claimed
`invention or how to achieve it.” In re O’Farrell, 853 F.2d at 903.
`
`Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 996–997
`
`(Fed. Cir. 2009).
`
`We analyze the asserted grounds of unpatentability in accordance with
`
`the above-stated principles.
`
`2. Scope and Content of the Prior Art
`
`a. Summary of Roy
`
`Roy discloses an oral pharmaceutical composition of amprenavir that
`
`results in effective treatment of the HIV virus upon administration. Ex.
`
`1021, 1:382:16, 2:4357.
`
`Roy discloses that amprenavir is difficult to formulate due to its
`
`limited solubility. In particular, Roy states that “the aqueous solubility of
`
`[amprenavir] is only 0.095 mg/mL at room temperature and does not
`
`significantly vary with pH. In addition, [amprenavir] is poorly wetted.
`
`Therefore, formulating the compound using standard formulary techniques is
`
`
`
`10
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`

`IPR2016-00558
`Patent 6,436,989 B1
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`difficult and leads in any event to a formulation with low bioavailability.”
`
`Id. at 2:3238 (citing Roy, Fig. 1).
`
`Roy discloses a solution formulation of amprenavir having improved
`
`solubility and oral bioavailability. Id. at 2:4547, 5358.
`
`b. Summary of Grobelny
`
`Grobelny discloses retroviral protease inhibitors, such as HIV
`
`protease inhibitors, comprising a solubilizing group. Ex. 1022, Abstract.
`
`Grobelny describes the problem of HIV protease inhibitors having poor
`
`solubility and, thus, low oral absorption as follows:
`
`HIV proteases which have hitherto been described . . . typically
`exhibit low to very low water solubility. Inhibitors of HIV
`proteases which have hitherto been described, and many other
`pharmaceutically or veterinarily active substances also typically
`exhibit low to very low water solubility. This property tends to
`cause the bioavailability of such substances to be relatively low.
`There is thus a need for a HIV protease inhibitor having
`enhanced water solubility.
`
`Id. at 74:710.
`
`Grobelny describes the inclusion of a “solubilising group Px” to
`
`enhance water solubility of HIV protease inhibitors. Id. at 74:1175:11; see
`
`also id. at 37:1922 (“Typically, the solubilising group is a sodium or
`
`potassium salt of a phosphate or phosphite residue.”). Grobelny discloses
`
`that “substances in accordance with the invention which include a
`
`solubilising group Px exhibit superior bioavailability, including superior is
`
`oral bioavailability, compared to compounds in accordance with the
`
`invention which do not include a solubilising group Px.” Id. at 74:1116.
`
`Example 5 of Grobelny describes introducing a disodium phosphate
`
`ester to the hydroxyl group of a known HIV protease inhibitor. Id. at
`
`
`
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`11
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`

`IPR2016-00558
`Patent 6,436,989 B1
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`87:187:19. Example 8 of Grobelny describes blood and animal
`
`experiments performed using the product of Example 5. Id. at 89:2090:29;
`
`Ex. 1002 ¶¶ 6566. The results are summarized in the follow excerpt from
`
`Grobelny:
`
`When prodrug was administered to a dog orally at a dose of
`20mg/kg, the blood plasma concentration of drug was found to
`be 0.044, 0.141, 0.189, 0.172, 0.164, 0.132, 0.089 and 0.060 μM,
`respectively, after 5, 15, 30, 47, 63, 93, 124 and 155 minutes.
`When prodrug was administered to a second dog orally at a dose
`of 10mg/kg, the blood plasma concentration of drug was found
`to be 0.137, 0.371, 0.297, 0.242, 0.176, 0.11, 0.071, and 0.050
`μM, respectively, after 5, 15, 30, 45, 60, 94, 123 and 154 minutes.
`
`Ex. 1022, 90:24–29.
`
`3. Petitioner’s Ground 1: Obviousness of Claim 2 over the
`
`Combination of Roy and Grobelny
`
`Petitioner contends that claim 2 of the ’989 patent would have been
`
`obvious over the combination of Roy and Grobelny. Pet. 2536. Claim 2
`
`includes a disodium phosphate ester of amprenavir.
`
`Petitioner contends that Roy discloses amprenavir as an “especially
`
`effective” protease inhibitor of HIV virus. Id. at 26 (Ex. 1021, 1:15–67).
`
`Due to amprenavir’s solubility-related problems, however, it was known that
`
`amprenavir required relatively large amounts of excipients in each capsule to
`
`improve oral absorption. Ex. 1002 ¶ 59. The result is that each capsule
`
`contains a relatively small amount of amprenavir and, as such, a large
`
`number of capsules is required to achieve therapeutic dosages. Id. at 60.
`
`Such a large number of capsules each day to obtain therapeutic dosages
`
`would have negatively affected patient compliance, which would have been
`
`disfavored because “patient compliance with the dosing regimen was
`
`
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`IPR2016-00558
`Patent 6,436,989 B1
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`considered essential to prevent HIV from developing drug-resistant
`
`mutations.” Pet. 27, 60 (citing Ex. 1002 ¶ 60). Accordingly, Petitioner
`
`contends that a person of ordinary skill in the art would have sought to
`
`modify amprenavir to address the known solubility-related problems. Id. at
`
`25–31.
`
`Petitioner contends that a person of ordinary skill would have been
`
`motivated to modify amprenavir using the methods disclosed in Grobelny to
`
`improve its solubility. Id. Grobelny discloses introducing phosphate esters
`
`salts to the hydroxyl group of HIV protease inhibitors for improving the
`
`solubility of HIV protease inhibitors.4 Id. at 2728 (citing Ex. 1022,
`
`74:1775:12, 37:1920, 90:10–29; Ex. 1002 ¶¶ 8790, 95). Specifically,
`
`Grobelny disclose derivatizing a free hydroxyl positioned similarly to that of
`
`the free hydroxyl of amprenavir, and that this modification improved the
`
`solubility of the compound. Pet. 2932; Ex. 1022, 86:815, 76:47; Ex.
`
`1002 ¶¶ 65, 87–90, 96. Petitioner further describes the similarities in
`
`structure between amprenavir and the exemplary compound of Grobelny,
`
`namely the presence of a free hydroxyl group between a phenylalanine
`
`mimetic and an N-alkyl group, as exemplified in the comparative structures
`
`from the Petition reproduced below. Pet. 3233; Ex. 1002 ¶¶ 93–95.
`
`
`
`
`4 Grobelny does not disclose amprenavir.
`
`
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`IPR2016-00558
`Patent 6,436,989 B1
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`Id.
`
`The figure above is purported to be a comparison of the structures
`
`disclosed in Grobelny (labeled as “Prior Art”) with that of amprenavir. Pet.
`
`32–33; Ex. 1002 ¶ 94. According to Petitioner, the figure highlights
`
`structural similarities between the two compounds and, in particular, a
`
`hydroxyl group positioned between the circled “phenylalanine mimetic” and
`
`“N-alkyl” moieties, with the remaining portions of the structures drawn in
`
`phantom lines. Id. Given the structural similarities between amprenavir and
`
`the HIV protease inhibitor of Grobelny, along with Grobelny’s disclosure of
`
`a precise method for modifying that compound, Petitioner argues that there
`
`was a reasonable likelihood that one of ordinary skill in the art would have
`
`been successful in preparing a derivative of amprenavir having the claimed
`
`structure with similar improvement in solubility and bioavailability (i.e.,
`
`fosamprenavir), using the teachings of Grobelny. Pet. 3235.
`
`4. Petitioner’s Ground 2: Obviousness of Claims 3 and 10–12
`
`over the Combination of Roy, Grobelny and Bighley
`
`Petitioner contends that claims 3 and 10–12 of the ’989 patent would
`
`have been obvious over the combination of Roy, Grobelny, and Bighley.
`
`Pet. 3649.
`
`a. Claim 3
`
`Claim 3 recites a “compound according to claim 2, wherein R7 is —
`
`PO3 2−Ca2+,” which Petitioner identifies as the calcium phosphate ester of
`
`amprenavir (i.e., fosamprenavir calcium). Pet. 5, 38.
`
`Petitioner contends that the claimed compound would have been
`
`obvious to one of ordinary skill in the art in light of Gorbelny’s “teach[ing]
`
`that pharmaceutically acceptable salts for acidic HIV protease inhibitors
`
`
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`14
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`IPR2016-00558
`Patent 6,436,989 B1
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`include cation-addition salts of sodium, potassium, calcium, and
`
`magnesium.” Id. 36 (citing Ex. 1022, 35:911). Petitioner further contends
`
`that the “decision tree” and disclosure of the “four most common salts” of
`
`Bighley evinces that calcium salts were known alternative salts to the
`
`sodium, potassium, and magnesium salts disclosed by Grobelny. Id. at 36–
`
`37 (citing Ex. 1027, 456; Ex. 1002 ¶¶ 7680, 100–103). Accordingly,
`
`Petitioner argues that the teachings of Grobelny would have prompted a
`
`person of ordinary skill in the art to prepare the calcium phosphate ester of
`
`amprenavir as set forth in claim 3.
`
`b. Claims 1012
`
`Claims 1012 are drawn to methods for treating HIV infection
`
`comprising administering the pharmaceutical compositions of claim 4. Ex.
`
`1001, 75:1776:15.
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`Petitioner contends that Roy and Grobelny disclose pharmaceutical
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`compositions and methods of treating HIV infection meeting the elements of
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`claims 1012. Pet. 3949; Ex. 1021, 6:1315, 6:5961, 6:667:24; Ex.
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`1022, 76:2628, 78:2227. Petitioner’s position is that claims 1012 recite
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`elements that naturally would follow using an HIV protease as indicated by
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`the teachings of Roy and Grobelny. Specifically, Petitioner contends that:
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`(1) “HIV is inherently characterized by a virally-encoded aspartyl protease”
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`(Pet. 39 (citing Ex. 1007,5 9697)) and administering the phosphate ester
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`salt of [amprenavir] would inherently inhibit aspartyl protease activity; (2)
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`5 Stuart Noble & Diana Faulds, Saquinavir: A Review of its Pharmacology
`and Clinical Potential in the Management of HIV Infection, 52 DRUGS 93–
`112 (July 1996).
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`“[t]he phosphate ester salt of amprenavir would have been expected to
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`reconvert to amprenavir in the body to provide a potent HIV protease
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`inhibitor” (id. (citing Fisher Decl. ¶ 95)); (3) and “[o]nly routine
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`optimization was needed to identify suitable dosages for treating HIV using
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`the phosphate ester salt of amprenavir based on its known dosages [for
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`amprenavir]” (id. (citing Fisher Decl. ¶ 105–6)). Thus, according to
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`Petitioner, a person of ordinary skill would have used the prodrug of
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`amprenavir in a similar way to other HIV protease inhibitors, and in
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`particular, similar to amprenavir. Id.
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`5. Analysis
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`The issue of whether a person of ordinary skill in the art would have
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`combined the teachings of Roy and Grobelny to achieve the compound of
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`claims 2 and 3 is dispositive to each of Petitioner’s ground, and is addressed
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`below.
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`a. No Reasonable Expectation of Success that
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`Fosamprenavir Would Be a Successful Drug
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`To decide whether fosamprenavir was obvious in light of the prior art,
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`we must determine whether, at the time of invention, a person having
`
`ordinary skill in the art would have had a reasonable expectation of success
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`in making fosamprenavir, a bioavailable prodrug to amprenavir, based on
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`guidance in the prior art. Procter & Gamble Co., 566 F.3d at 997; In re
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`O’Farrell, 853 F.2d at 903.
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`As discussed above, Grobelny teaches that the inclusion of a
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`solubilizing group to a protease inhibitor compound having low water
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`solubility for the purposes of improving water solubility and bioavailability
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`of those compounds. Ex. 1022, 74:1116. In this regard, Grobelny provides
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`general guidance for using a solubilizing agent phosphate ester salt to solve
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`the solubility problem of amprenavir. However, the success of discovering
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`fosamprenavir was not discovering a compound with improved solubility.
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`Rather, the success was finding a compound that had the requisite
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`bioavailability to treat HIV and minimize the development of drug-
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`resistance mutations in patients.6 The evidence of record does not support a
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`finding that a person of ordinary skill in the art would have had a reasonable
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`expectation of success in developing fosamprenavir, a protease inhibitor
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`prodrug having the same or improved bioavailability as its parent drug.
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`First, we note that the evidence of record fails to demonstrate that
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`Grobelny’s compound was anything more than a “physiological failure”.
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`Ex. 2003, 303:19–304:10. The data presented in Grobelny—along with the
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`data contained in Tyssen7,8—shows that the prodrug of Grobelny did not
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`deliver the parent compound consistently in animal models. Ex. 1022,
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`89:22–90:29; Ex. 1056. Specifically, the data shows variable delivery of the
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`parent compound in rats ranging from “0% to greater than 35%”, suggesting
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`that certain rats received 0% of the active ingredient in their system. Ex.
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`
`6 We are persuaded by Patent Owner’s argument and evidence that
`variability of the bioavailability of the drug is just as problematic as
`noncompliance by the patient as both can lead to poor treatment and
`development of drug resistance. PO Resp. 3132; Ex. 2016, 276:11–277:9.
`
`7 Ex. 1056, Tyssen, D. et al., “Nonclinical Pharmacokinetics of an HIV
`Protease Inhibitor,” Australasian Society for HIV Med., 8th Annual
`Conference, 8:14 (1996) (hereinafter “Tyssen”).
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`8 Petitioner argues that Tyseen confirms Grobelny’s success, however, we
`are not persuaded that the results disclosed in Tyseen are different from
`those disclosed in Grobelny.
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`2061 ¶¶ 76, 82–83; Ex. 2017 ¶¶ 115, 120.
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`Example 8 of Grobelny discloses the results of an experiment in
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`which a prodrug was administered orally to two individual dogs. Ex. 1022,
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`90:24–29. Patent Owner provides a table, reproduced below, summarizing
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`the data presented in Example 8.
`
`
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`PO Resp. 30. The data shows that some conversion of the prodrug to the
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`parent occurred, but that conversion was highly variable. Ex. 2061 ¶¶ 65–
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`72. Indeed, as noted by Patent Owner, “[t]hese data show that the second
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`dog, which received a lower dose of 10mg/kg of the prodrug, achieved a
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`higher concentration of the parent in its bloodstream than the first dog,
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`which received a higher 20mg/kg dose.” PO Resp. 29.
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`Hoy9 discloses a study of Grobelny’s prodrug, DG17, in healthy
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`human volunteers. Ex. 2040. Hoy concludes that the prodrug “was well
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`tolerated, and single dose pharmacokinetics in healthy volunteers reveal
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`good oral bioavailability.” Id. Although we agree with Petitioner that such
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`a statement may provide encouragement to a person of ordinary skill in the
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`art for the “good oral bioavailability” of Grobelny’s prodrug (see Reply, 16–
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`18), we credit the testimony from Drs. Ogden and Sinko that the raw data
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`presented in Hoy continues to show variability in the bioavailability of the
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`9 Ex. 2040, Hoy, et al., “Pharmacokinetics of DG17, a Protease Inhibitor, in
`Healthy Volunteers,” Australasian Society for HIV Med., 8th Annual
`Conference, 8:184 (1996) (hereinafter “Hoy”).
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`Grobelny’s prodrug. Ex. 2061 ¶¶ 77–82; Ex. 2017 ¶¶ 118–121.
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`Even if we could conclude that the bioavailability data for Grobelny’s
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`compound was sufficient to show that Grobelny’s compound would work
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`within a reasonable expectation of success, the evidence of record does not
`
`establish that the same prodrug approach disclosed in Grobelny would work
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`for all protease inhibitors. Rather, we note that the preponderance of
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`evidence shows that the development of HIV protease inhibitors prodrugs
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`was not at all predictable, but produced compounds with varying degree of
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`effectiveness. PO Resp. 43–44, 59; Ex. 2061 ¶¶ 106–109; Ex. 1040, 128
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`(“the success of the [prodrug] strategy has been limited”); Ex. 200410, 2965
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`(discussing the importance of structural features in the vicinity of the
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`phosphate ester on the rate at which prodrug reverted to back to parent
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`drug).
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`The varying degree of effectiveness of prodrugs is partly explained by
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`the complexity of in vivo conversion, which rendered prodrugs unpredictable
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`for achieving adequate conversion at the time of the invention. PO Resp.
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`11–14; Ex. 2061 ¶¶ 118–122; Ex. 2017 ¶¶ 128–130, 133–136. Patent Owner
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`summarizes its position, which we adopt, in the following excerpt:
`
`Researchers often investigate creating a prodrug in order to
`address characteristics of an active compound that may limit its
`effectiveness, but in doing so, new problems may arise. Ex.
`2061, Sinko ¶ 91; Ex. 1002 Fisher ¶ 50. For instance, an oral
`prodrug designed to increase aqueous solubility often results in
`a decreased ability to cross through the intestinal membrane for
`delivery to the site of infection. Ex. 1019 at 361. Thus, it is
`
`
`10 Ex. 2004, DeGoey, et al., Water-Soluble Prodrugs of the Human
`Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir, J.
`Med. Chem., 52:2964–70 (2009).
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`critical that reconversion from such a prodrug to the parent
`compound take place at the site of absorption, and that the
`kinetics and mechanism of the conversion are such that the parent
`drug will be absorbed into the bloodstream. Ex. 1019 at 361; Ex.
`1002 Fisher ¶ 55 (explaining the desired site for conversion of a
`phosphate ester prodrug). Therefore, identification of an oral
`prodrug that can address the limitations of the parent compound
`is a complex task.
`
`In large part, the complexity exists because of the
`numerous variables associated with the GI tract . . . . If the
`prodrug converts to the parent drug too soon, then the parent
`drug’s insoluble nature will cause it to precipitate within the GI
`tract, rendering it unable to cross into the bloodstream. Ex. 2061,
`Sinko ¶ 98; Ex. 2003, 150:16-21, 152:9-153:5. On the other
`hand, if the prodrug fails to reconvert to the active parent drug at
`the brush border, then its polarity will diminish its ability to cross
`the GI membrane into the bloodstream. Ex. 2061, Sinko ¶ 98;
`Ex. 2003, 185:11-186:7.
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`PO Resp. 11–13.
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`Furthermore, developing a phosphate ester prodrug would have been
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`particularly challenging in the treatment of HIV. Prodrugs using phosphate
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`ester promoieties were made to target reconversion by alkaline phosphatase
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`in the intestine. Ex. 205211, 934, 939. (“The increased permeability for the
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`phosphate prodrug is the result of alkaline phosphatase activity [in the upper
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`small intestine].”) However, it was known at the time of the invention that
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`HIV-infected patients showed decreased alkaline phosphatase activity as
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`compared to heal