Trials@uspto.gov
`Tel: 571-272-7822
`
`
`Paper 13
`Entered: July 9, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`LUPIN LIMITED,
`Petitioner,
`
`v.
`
`VERTEX PHARMACEUTICALS INCORPORATED,
`Patent Owner.
`_______________
`
`Case IPR2015-00405
`Patent 6,436,989 B1
`_______________
`
`
`
`Before LORA M. GREEN, SHERIDAN K. SNEDDEN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 1 of 27
`
`
`Tel: 571-272-7822
`
`
`Paper 13
`Entered: July 9, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`LUPIN LIMITED,
`Petitioner,
`
`v.
`
`VERTEX PHARMACEUTICALS INCORPORATED,
`Patent Owner.
`_______________
`
`Case IPR2015-00405
`Patent 6,436,989 B1
`_______________
`
`
`
`Before LORA M. GREEN, SHERIDAN K. SNEDDEN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 1 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`
`I.
`INTRODUCTION
`Lupin Limited (“Petitioner”) filed a corrected Petition (Paper 7;
`“Pet.”) to institute an inter partes review of claims 112 of U.S. Patent
`No. 6,436,989 B1 (Ex. 1001; “the ’989 Patent”) (“challenged claims”).
`Vertex Pharmaceuticals Incorporated (“Patent Owner”) filed a Patent Owner
`Preliminary Response. Paper 11 (“Prelim. Resp.”).
`We have jurisdiction under 35 U.S.C. § 314. The standard for
`instituting an inter partes review is set forth in 35 U.S.C. § 314(a), which
`states that an inter partes review may not be instituted unless “the
`information presented in the [Petition and Preliminary Response] shows that
`there is a reasonable likelihood that the petitioner would prevail with respect
`to at least 1 of the claims challenged in the petition.”
`Upon consideration of the above-mentioned Petition and Preliminary
`Response, we determine that the Petition demonstrates that there is a
`reasonable likelihood that Petitioner would prevail with respect to claims 1
`and 49 of the ’989 Patent. We determine, however, that Petitioner has not
`demonstrated a reasonable likelihood of prevailing on its challenge of claims
`2, 3, and 1012 on any ground asserted in the Petition. Therefore, we
`authorize an inter partes review to be instituted only as to claims 1 and 49
`of the ’989 Patent.
`
`A. Related Proceedings
`
`The parties inform us of no related pending litigations. Pet. 1;
`Paper 4.
`
` 2
`
`
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 2 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`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, 1:517. Prodrugs generally are inactive
`compounds that convert to an active form in the body. Id. at 2:716,
`33:2534. 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 1:715.
`The relevant compound of the ’989 Patent is a prodrug of a known
`HIV aspartyl protease inhibitor commonly referred to as VX-478
`(“amprenavir”; 4-amino-N-((2-syn, 3S)-2-hydroxy-4-phenyl-2((S)-
`tetrahydrofuran-3-yl-oxycarbonylamino)butyl-N-isobutyl-
`benzenesulfonamide). Id. at 1:3042, 30:2934:67; Prelim. Resp. 18. VX-
`478 has the following structure:
`
`.
`
` 3
`
`
`
` Ex. 1001, 30:3231:5.
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 3 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`
`Examples 27 to 30 detail the process for forming phosphate ester
`derived prodrugs of VX-478. Id. at 57:160:14. Example 30, in particular,
`describes a disodium phosphate ester salt prodrug of VX-478. Id. at
`59:920, 60:120.
`
`C. Challenged Claims
`
`Claim 1 is the only independent claim among the challenged claims,
`and is reproduced below:
`1. A compound of the formula:
`
`
`
`
`
` 4
`
`
`
`
`
`Ex. 1001, 74:2450.
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 4 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`
`Claims 212 depend from claim 1, either directly or indirectly.
`Claims 4, 9, and 10 are illustrative of the dependent claims and are
`reproduced below.
`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.
`
`9. A method for inhibiting aspartyl protease activity in a
`mammal, comprising the step of administering to said mammal
`a pharmaceutical composition according to claim 4.
`
`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.
`
`Id. at 74:5862, 75:1419.
`
`D. Prior Art and Supporting Evidence
`
`Petitioner relies on the following prior art:
`Ex. 1021, U.S. Patent No. 6,730,679 B1, issued May 4, 2004 to Roy et
`al. (hereinafter “Roy” or “the ’679 Patent”).
`
`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”).
`
`Ex. 1027, Bighley, et al., Salt Forms of Drugs and Absorption, in 13
`ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY 453499 (James
`Swarbrick & James C. Boylan eds. 1996) (hereinafter “Bighley”).
`
`Ex. 1031, International Patent Application Publication Number
`WO 97/35587, published October 2, 1997, and naming Roy, et al. as
`inventors (hereinafter “Roy II” or “the ’587 Publication”).
`
` 5
`
`
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 5 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`See Pet. 78.
`Petitioner relies also on the Declaration of Jed Fisher,1 in support of
`the proposed grounds of unpatentability. Dr. Fisher is a faculty member of
`the Department of Chemistry and Biology at the University of Notre Dame
`with more than 35 years of medicinal chemistry experience, in particular,
`approximately seven (7) years of experience “researching and developing
`aspartyl protease inhibitors,” including extensive research and development
`of HIV protease inhibitors. Fisher Decl. ¶¶ 1, 2, 7. Dr. Fisher has several
`publications directed to HIV protease inhibitors and aspartyl protease
`inhibitors. Fisher Decl. ¶¶ 4, 5. Patent Owner does not direct us to any
`reason to doubt Dr. Fisher’s qualifications to testify as an expert in the field
`of HIV aspartyl protease inhibitors. On the record now before us, we find
`Dr. Fisher to be qualified to testify concerning issues raised in this
`proceeding.
`
`E. Asserted Grounds
`
`Petitioner challenges claims 1–12 of the ’989 Patent on the following
`grounds. Pet. 7–8.
`Reference[s]
`
`Roy and Grobelny
`
`Basis
`§ 103(a)
`
`Claims challenged
`12
`
`Roy, Grobelny, and Bighley
`
`§ 103(a)
`
`312
`
`Roy II and Grobelny
`
`§ 103(a)
`
`12
`
`Roy II, Grobelny, and Bighley
`
`§ 103(a)
`
`312
`
`
`1 Ex. 1002, Declaration of Jed Fisher, Ph.D., executed December 5, 2014
`(hereinafter “Fisher Declaration” or “Fisher Decl.”).
`
` 6
`
`
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 6 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`
`
`A. Claim Interpretation
`
`II. ANALYSIS
`
`We interpret claims using the “broadest reasonable construction in
`light of the specification of the patent in which [they] appear[].” 37 C.F.R.
`§ 42.100(b); see also Office Patent Trial Practice Guide, 77 Fed. Reg.
`48,756, 48,766 (Aug. 14, 2012). Under the “broadest reasonable
`construction” standard, claim terms are given their “ordinary and customary
`meaning,” as would be understood by one of ordinary skill in the art at the
`time of the invention. 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).
`The Petition does not require explicit construction of any claim term
`at this time. See, e.g., Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355,
`1361 (Fed. Cir. 2011) (“[C]laim terms need only be construed ‘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)). Our views on claim
`construction shall not be deemed final until the record is complete, we have
`finished our review of the complete record, and rendered our Final Decision.
`
` 7
`
`
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 7 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`B. 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)).
`Relevant 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
`decisionmaker 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).
`We analyze the asserted grounds of unpatentability in accordance with
`the above-stated principles.
`
` 8
`
`
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 8 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`C. Asserted Grounds of Unpatentability
`
`1. Petitioner’s Proposed Obviousness Grounds for Claims 1 and 2
`over the Combination of Roy and Grobelny
`
`a. Summary of Roy
`Roy discloses an oral pharmaceutical composition of VX-478 that
`results in effective treatment of the HIV virus upon administration. Roy,
`1:382:16, 2:4357.
`Roy discloses that VX-478 is difficult to formulate due to its limited
`solubility:
`the aqueous solubility of [VX-478] is only 0.095 mg/mL at
`room temperature and does not significantly vary with pH. In
`addition
`the compound of [VX-478]
`is poorly wetted.
`Therefore, formulating the compound using standard formulary
`techniques is difficult and leads in any event to a formulation
`with low bioavailability.
`
`Id. at 2:3036 (citing Roy, Fig. 1).
`Roy discloses a solution formulation that improves oral absorption.
`Id. at 2:4244, 5358.
`
`b. Summary of Grobelny
`Grobelny discloses retroviral protease inhibitors, such as HIV
`protease inhibitors, comprising a solubilizing group. Grobelny, 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. 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.
`
` 9
`
`
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 9 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`Id. at 74:710.
`Grobelny describes the inclusion of a “solubilising group Px” to
`enhance water solubility of HIV protease inhibitors. Id. at 74:1175:12; see
`also id. at 37:1922 (“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 74:1116.
`Examples 4, 5, and 8 of Grobelny together describe introducing a
`disodium phosphate ester to the hydroxyl group of a known HIV protease
`inhibitor. Id. at 86:887:19, 89:2290:29; Fisher Decl. ¶¶ 6566.
`
`c. Combination of Roy and Grobelny
`Petitioner contends that claims 1 and 2 of the ’989 Patent would have
`been obvious over the combination of Roy and Grobelny. Pet. 2842.
`Petitioner contends that Roy discloses VX-478 as a known and effective
`HIV protease inhibitor with poor solubility. Id. at 29 (citing Roy, 1:1567,
`2:3036). Petitioner contends that Roy’s formulation requires relatively
`large amounts of excipients in each capsule to improve oral absorption and,
`therefore, each capsule contained a relatively small amount of VX-478. Id.
`at 5, 21, 29 (citing Fisher Decl. ¶ 59; Roy, 7:2526). A large number of
`capsules is required, therefore, to achieve therapeutic dosages. Id. at 29.
`Petitioner states, “[f]or example, thirty of the 150 mg capsules described in
`Example 1 of [Roy] would be required each day to reach the maximum
`therapeutic dose of 5000 mg.” Id. at 21 (citing Fisher Decl. ¶ 59).
`
`
`10
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 10 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`
`Petitioner contends that Grobelny discloses a water-soluble disodium
`phosphate ester salt prodrug derived from a similar HIV aspartyl protease
`inhibitor with similar solubility problems to that of VX-478. Id. at 3034
`(citing Grobelny, 74:1775:12, 37:1920, 86:12; Fisher Decl. ¶¶ 8790).
`In combining the disclosures of Roy and Grobelny, Petitioner
`contends that the known low solubility of VX-478 would have motivated a
`person of ordinary skill to modify VX-478 to improve solubility because
`doing so would reduce the number of capsules patients are required to take
`each day to obtain therapeutic dosages. Id. at 2930.
`In this regard, Grobelny teaches that “the inclusion of a solubilizing
`group Px as defined herein in a substance having low to very low water
`solubility results in enhancement of the water solubility of the substance.”
`Grobelny, 74:710; Pet. 22. Further, Grobelny defines the expression
`“solubilizing group Px” as “a group which may be used to derivatise a
`functional group so as to enhance solubility of the compound . . . in water or
`aqueous media.” Grobelny, 36:1921. Grobelny discloses a number of
`exemplary solubilizing groups including phosphate esters “or salts thereof,”
`namely “a salt of an alkali metal or ammonia, such as Na+, K+ or NH4
`+.”
`Grobelny, 36:2237:20.
`As pointed out by Petitioner, Grobelny discloses a prodrug similar in
`structure to the compound claimed in the ’989 Patent, namely a disodium
`phosphate ester salt of t-butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3-(N-
`quinaldoyl-L-asparaginyl)amino-4-phenylbutyl carbazate, purported to have
`the following structure prior to the conversion to a salt. Pet. 3037;
`Grobelny, 86:11.
`
`
`11
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 11 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`
`
`Examples 4, 5, and 8 of Grobelny disclose derivatizing a free
`hydroxyl positioned similarly to that of the free hydroxyl of VX-478, and
`that this modification improved the solubility of the compound. Pet. 3334;
`Grobelny, 86:815, 76:47; Fisher Decl. ¶¶ 53, 65, 66. Petitioner further
`describes the similarities in structure between VX-478 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. 3637;
`Fisher Decl. ¶¶ 6567.
`
`
`12
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 12 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`
`
`This figure is purported to be a comparison of the structures of VX-
`478 and the structure of Example 4 of Grobelny. Pet. 36; Fisher Decl. ¶ 65.
`The figure depicts similar structures said to be a hydroxyl group positioned
`between a “phenylalanine mimetic” and an “N-alkyl” circled, with the
`remaining portions of the structures in phantom lines.
`Petitioner further tracks the process described in Examples 4, 5, and 8
`of Grobelny against that described in the ’989 Patent, suggesting that the
`only distinction in the process is that the ’989 Patent describes conversion to
`the corresponding sodium salt under specific conditions not disclosed in
`Grobelny. Pet. 3334; Fisher Decl. ¶ 88; Ex. 1001, 57:159:6; Grobelny,
`86:887:19, 89:2225.
`Given the similarities between structures of the HIV protease inhibitor
`of Grobelny and VX-478 and disclosure of a precise method for modifying
`the similar structure, Petitioner argues that there was a reasonable likelihood
`
`
`13
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 13 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`that one of ordinary skill in the art would have been successful in preparing
`a derivative of VX-478 having the claimed structure with similar
`improvement in solubility and bioavailability as found for the HIV protease
`inhibitor of Grobelny, using the teachings of Grobelny. Pet. 3240.
`
`2. Petitioner’s Proposed Obviousness Grounds for Claims 312 over
`the Combination of Roy, Grobelny and Bighley
`
`Petitioner contends that claims 312 of the ’989 Patent would have
`been obvious over the combination of Roy, Grobelny, and Bighley. Pet.
`4254.
`
`a. Claim 3
`Petitioner contends that claim 3 “recites the calcium phosphate ester
`of VX-478 and would have been obvious to a person of ordinary skill in the
`art.” Pet. 42. Petitioner contends that Grobelny “teaches that
`pharmaceutically acceptable salts for acidic HIV protease inhibitors include
`cation addition salts of sodium, potassium, calcium, and magnesium.” Id.
`(citing Grobelny, 35:911). 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 4244 (citing Fisher Decl.
`¶¶ 7680, 100, 101). Petitioner argues that these teachings would have
`prompted a person of ordinary skill in the art to prepare the calcium
`phosphate ester of VX-478.
`
`b. Claims 412
`Claims 48 are multiple dependent claims and are drawn to
`pharmaceutical compositions comprising the compounds of clams 1, 2, or 3.
`
`14
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 14 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`Ex. 1001, 74:5775:15. Claim 9 is drawn to a method for inhibiting aspartyl
`protease activity in a mammal. Id. at 75:1416. Claims 1012 are drawn to
`methods for treating HIV infection. Id. at 75:1776:17. The methods
`comprise administering the pharmaceutical compositions of claim 4.
`Petitioner contends that Roy and Grobelny disclose pharmaceutical
`compositions and methods of treating HIV infection meeting the elements of
`claims 412. Pet. 4652 (citing Roy, 6:1315, 6:5961, 6:667:24;
`Grobelny, 76:2628, 78:2227). Petitioner’s position is that claims 412
`recite elements that naturally would follow using an HIV protease as
`indicated by the teachings of Roy and Grobelny. Pet. 4546. Specifically,
`Petitioner contends as follows: (1) “HIV is inherently characterized by a
`virally-encoded aspartyl protease” (id. at 47 (citing Ex. 1007,2 9697)) and
`administering the phosphate ester salt of VX-478 would inherently inhibit
`aspartyl protease activity; (2) “The phosphate ester salt of VX-478 would
`have been expected to reconvert to VX-478 in the body to provide a potent
`HIV protease inhibitor” (id. at 46 (citing Fisher Decl. ¶ 94)); (3) and “It
`would have been a matter of routine optimization to identify suitable
`dosages for treating HIV using the phosphate ester salt of VX-478 based on
`the known dosages for VX-478 (id. at 47 (citing Fisher Decl. ¶ 104)). Thus,
`according to Petitioner, a person of ordinary skill would have used the
`prodrug of VX-478 in a similar way to other HIV protease inhibitors, and in
`particular, similar to VX-478. Id.
`
`
`2 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).
`
`
`15
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 15 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`
`3. Patent Owner’s Preliminary Response
`
`a. No Reasonable Expectation of Success
`Patent Owner contends that there was not a reasonable expectation of
`success that a phosphate ester salt derivative of VX-478 would have been
`successful as a bioavailable alternative to VX-478. Prelim. Resp. 2627.
`Patent Owner contends that the ultimate goal for a person of ordinary skill in
`the art of creating an improved protease inhibitor was to provide sufficient
`bioavailability of drug to treat HIV while minimizing resistance. Id. at 28.
`Patent Owner contends that the complexity of in vivo conversion renders
`prodrugs unpredictable for achieving this goal. Id. at 911. Patent Owner
`summarizes its position in the following excerpt:
`A 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 (“While
`such a modification may improve aqueous drug transport, an
`increase in polarity . . . may limit transport through intestinal
`membranes.”) Thus, it is critical that reconversion from the
`prodrug to the parent compound takes 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).
`
`Id. at 9.
`Patent Owner further contends that the data presented in Grobelny—
`along with the data contained in the abstract of animal testing—shows that
`the prodrug of Grobelny did not deliver the parent compound consistently.
`Prelim. Resp. 2728. Example 8 of Grobelny discloses the results of an
`
`
`16
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 16 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`experiment in which a prodrug was administered orally to two individual
`dogs. 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.
`
`Grobelny, 90:24–29. Patent Owner contends that “[t]hese data show that the
`second dog that received a lower dose of 10mg/kg of the prodrug achieved a
`higher concentration of the parent in its bloodstream as compared to the first
`dog that received the higher 20mg/kg dose.” Prelim. Resp. 15; see also id at
`2829 (citing Ex. 2003,3 289:1416 (describing the Grobelny dog data as
`lacking statistical significance), 288:712 (“[w]hen a scientist says that we
`don’t have statistical significance, that is saying there is variability”)).
`Patent Owner further directs our attention to Ex. 2015,4 an abstract
`containing data for testing of Sprague-Dawley rats using the prodrug
`disclosed in Example 5 of Grobelny. Id. at 1516. Patent Owner contends
`that the data presented in Ex. 2015 “reveal that upon the oral administration
`of the prodrug a portion of the rats achieved low concentrations of the parent
`compound in plasma, urine and some tissues with the bioavailability of the
`parent compound for the tested rats ranging from 0%35%.” Id. at 16
`
`3 Deposition transcript of Jed Fisher, PhD (hereinafter “Fisher Tr.”).
`4 Tyssen, D & Riddell, M, Australasian Society for HIV Med., 8th Annual
`Conference, vol. 8, 14 (1996).
`
`
`17
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 17 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`(citing Ex. 2015; Fisher Tr. 302:13–304:9). Patent Owner further contends
`that Dr. Fisher described these data as showing “a physiological failure with
`respect to the prodrug.” Id. (citing Fisher Tr. 303:19304:10; Ex. 2015).
`Patent Owner contends that variable bioavailability is a problem as a
`physician “because administration of the prodrug may enhance the
`likelihood of the development of resistant forms of HIV.” Id. at 3132
`(citing Fisher Tr. 276:11–277:9).
`
`b. Objective Indicia of Non-Obviousness
`Patent Owner refers to the prodrug of amprenavir, or VX-478, as
`fosamprenavir. Prelim. Resp. 23, 33. The calcium salt of fosamprenavir
`(known as “fosamprenavir calcium”) is FDA approved. Id. at 39. Patent
`Owner contends that, “[a]s the difference between fosamprenavir and
`amprenavir is the patented invention, i.e., the addition of a phosphate
`moiety,” a nexus can be established between objective indicia of non-
`obviousness and the invention. Patent Owner argues objective indicia of
`non-obviousness in the form of unexpected results, long-felt need, copying
`of others, failure of others, and commercial success. Id. at 3339.
`Regarding unexpected results, Patent Owner contends that
`fosamprenavir has improved pharmacokinetics, as compared with
`amprenavir, in the form of statistically significantly higher Cmin and lower
`Cmax with equal extent of absorption. Id. at 3334 (citing Ex. 20135).
`
`
`5 Robin Wood et al., Six-Week Randomized Controlled Trial to Compare the
`Tolerabilities, Pharmacokinetics, and Antiviral Activities of GW433908 and
`Amprevanir in Human Immunodeficiency Virus Type 1-Infected Patients,
`48 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 116–23 (Jan. 2004).
`
`18
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 18 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`Further, Patent Owner contends that the improved pharmacokinetics are
`accompanied with lower number of gastrointestinal side effects. Id.
`Patent Owner also presents evidence showing that fosamprenavir has
`a different and improved resistance profile as compared to amprenavir.
`Specifically, the absence of a selection for the I50V mutation, which is
`unexpected “because fosamprenavir delivers amprenavir.” Id. at 3435
`(citing Ex. 2014,6 112; Ex. 2017,7 84; Ex. 20308 (Abstract No. 598);
`Ex. 2031,9 652).
`Regarding long-felt need, Patent Owner contends that fosamprenavir
`addressed the issue of lack of patient compliance by reducing the size and
`number of pills required to deliver an effective dose and reducing
`gastrointestinal side effects. Id. at 3536 (citing Fisher Tr. 107:20–109:20;
`
`
`6 R.D. Tung et al., Design and Synthesis of Amprenavir, A Novel HIV
`Protease Inhibitor, in PROTEASE INHIBITORS IN AIDS THERAPY 101–118
`(Richard C. Ogden & Charles W. Flexner eds. 2001).
`7 W. Snowden et al., Development of Amprenavir Resistance in NRTI-
`Experienced Patients: Alternative Mechanisms and Correlation with
`Baseline Resistance to Concomitant NRTIs, in ABSTRACTS: 4TH
`INTERNATIONAL WORKSHOP ON HIV DRUG RESISTANCE & TREATMENT
`STRATEGIES 84 (June 12–16, 2000).
`8 S. MacManus et al., GW433908 in ART-naive Subjects: Absence of
`Resistance at 48 Weeks with Boosted Regimen and APV-like Resistance
`Profile with Unboosted Regimen, in ABSTRACTS: 10TH CONFERENCE ON
`RETROVIRUSES AND OPPORTUNISTIC INFECTIONS 271 (Feb. 10–14, 2003).
`9 S. MacManus et al., GW433908/Ritonavir Once Daily in Antiretroviral
`Therapy-naive HIV-infected Patients: Absence of Protease Resistance at 48
`Weeks, 18 AIDS 651–55 (2004).
`
`
`19
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 19 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`Ex. 2023,10 175758; Ex. 2024,11 1592, Fig. 3; Ex. 2025,12 577; Ex. 2018,13
`551 (“early PI [protease inhibitor] therapy posed a number of challenges to
`clinicians and patients. The first marketed PIs were generally large pills
`with high pill burden that required frequent dosing. They were frequently
`associated with significant gastrointestinal side effects, including diarrhea,
`nausea and vomiting”).
`Regarding copying and failure of others, Patent Owner contends that
`others have attempted to use the prodrug concept by attaching a phosphate
`ester to the central hydroxyl group to known HIV protease inhibitors. Id. at
`3536. These other prodrugs, however, failed to revert to the patent
`compound. Id. at 37 (citing Ex. 2026,14 Table 1). Patent Owner further
`notes that the prodrug disclosed in Grobelny was never commercialized. Id.
`at 38.
`With regard to commercial success, Patent Owner notes that the FDA
`approved fosamprenavir calcium as a new chemical entity that replaced
`
`
`10 Pierre Vierling & Jacques Greiner, Prodrugs of HIV Protease Inhibitors,
`9 CURRENT PHARMACEUTICAL DESIGN 175570 (2003).
`11 Andrew Spaltenstein et al., Discovery of Next Generation Inhibitors of
`HIV Protease, 5 CURRENT TOPICS IN MEDICINAL CHEMISTRY 15891607
`(2005).
`12 Brian A. Boyle, The Continuing Evolution of HIV Therapy, 13 THE AIDS
`READER 57678, 582 (Dec. 2003).
`13 Jeffrey Nadler, New Anti-HIV Protease Inhibitors Provide More
`Treatment Options, 17 AIDS PATIENT CARE AND STDS 55164 (2003).
`14 David A. DeGoey et al., Water-Soluble Prodrugs of the Human
`Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir,
`52 J. MED. CHEM. 2964–70 (2009).
`
`
`20
`
`
`
`NOVARTIS EXHIBIT 2084
`Par v Novartis, IPR 2016-00084
`Page 20 of 27
`
`
`
`IPR2015-00405
`Patent 6,436,989 B1
`
`amprenavir (VX-478) as an HIV treatment. Id. at 3839 (citing Exs. 203215
`& 203316).
`
`4. Analysis
`
`a. Claims 13, Directed to a Compound
`At the time of the invention, the evidence shows that a well-known
`problem for HIV protease inhibitors, including VX-478, was low solubility,
`which is said to be attributed to phenylalanine-like and/or proline-like
`portions common to all HIV protease inhibitors. Roy, 2:2036; Grobelny,
`74:610; Fisher Decl. ¶¶ 44, 47. Roy discloses that an objective at the time
`was “lower quantities of drug administered to achieve the same therapeutic
`effect and fewer dosages required at less frequent intervals thereby
`improving patient compliance.” Roy, 2:3741. As discussed above,
`Grobelny teaches that the inclusion of a solubilizing group to a protease
`inhibitor compound having low water solubility for the purposes of
`improving water solubility and bioavailability of those compounds.
`Grobelny, 74:1116. Thus, we agree with Petitioner that Grobelny provides
`an exemplary roadmap for using a phosphate ester salt derivative at the free
`hydroxyl of VX-478 for solving the solubility problem of VX-478 that was
`missing in the teaching of Roy. Pet. 3041.
`Set against Petitioner’s evidence, however, is the array of objective
`evidence Patent Owner puts forward in support of the nonobviousness of the
`
`
`15 Mark Cichocki, Agenerase Discontinued / New 500mg Invirase,
`http://aids.about.com/od/hivmedi
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
