`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________
`
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`Patent Owner
`
`__________
`
`
`Case IPR2018-00459
`Patent 9,561,197
`
`__________
`
`
`HORIZON THERAPEUTICS, INC.’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`

`

`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
`
`
`TABLE OF CONTENTS
`
`I.
`II.
`
`INTRODUCTION ....................................................................................... 1
`BACKGROUND ......................................................................................... 5
`
`
`
`
`
`
`
`RAVICTI® Litigation........................................................................ 5
`Technical Background ....................................................................... 6
`1.
`UCDs and Treatment ............................................................... 6
`2.
`Response to Lupin’s Technical Background ...........................10
`’197 Patent Prosecution History ........................................................12
` Overview of the ’197 Patent .............................................................15
`1.
`“A method of treating a [UCD] in a subject” ..........................17
`2.
`“a subject having a plasma PAA to PAGN ratio outside
`of the target range of 1 to 2 [or 2.5]” .......................................18
`“administering to [the] subject … a dosage of glyceryl
`tri-[4-phenylbutyrate] (HPN-100) effective to achieve a
`plasma PAA to PAGN ratio within the target range of 1
`to 2 [or 2.5]” ...........................................................................19
`
`3.
`
`
`
`
`
`
`
`III. LEVEL OF ORDINARY SKILL IN THE ART .........................................20
`IV. CLAIM CONSTRUCTION ........................................................................23
`“PAA” and “PAGN” .........................................................................24
`“A method of treating a [UCD] in a subject” ....................................24
`“a subject having a plasma PAA to PAGN ratio outside the target
`range of 1 to 2 [or 2.5]” ....................................................................26
`“administering … a dosage of glyceryl tri-[4-phenylbutyrate]
`(HPN-100) effective to achieve a plasma PAA to PAGN ratio
`within the target range of 1 to 2 [or 2.5]” ..........................................27
`
`
`
`i
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`

`V.
`
`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
`
`THE BOARD SHOULD DENY LUPIN’S PETITION...............................29
`Lupin’s Petition Fails to Articulate a Prima Facie Case of
`Obviousness Because It Fails to Identify Prior Art Describing or
`Suggesting Each Element of the Claims ............................................29
`
`
`
`
`
`2.
`
`The Claimed Methods Are Not Obvious Over the Prior Art ..............35
`1.
`Scope and Content of the Prior Art .........................................36
`a.
`Enns 2010 .....................................................................36
`b. MacArthur ....................................................................37
`c.
`Piscitelli ........................................................................40
`Differences Between the Claimed Invention and the Prior
`Art ..........................................................................................43
`a.
`No Teaching or Suggestion of Plasma PAA:PAGN
`Ratio .............................................................................43
`No Teaching or Suggestion of Target Range .................48
`No Teaching or Suggestion of Utility of
`PAA:PAGN Ratio in a Method of Treating UCD
`Patients .........................................................................51
`
`b.
`c.
`
`3.
`
`Teaching Away .............................................................52
`d.
`Secondary Considerations .......................................................54
`a.
`Surprising and Unexpected Results ...............................54
`b.
`Long-Felt But Unmet Need ...........................................55
`VI. LUPIN’S PETITION PRESENTS SUBSTANTIALLY THE SAME
`ART AND ARGUMENTS CONSIDERED DURING
`PROSECUTION .........................................................................................56
`VII. CONCLUSION ..........................................................................................58
`
`
`
`ii
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`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
`
`
`TABLE OF AUTHORITIES
`
`Cases
`
`BSP Software LLC v. Motio, Inc.,
`IPR2013-00307, Paper 10 (P.T.A.B. Nov. 29, 2013) .........................................34
`Coalition for Affordable Drugs V LLC v. Biogen MA Inc.,
`IPR2015-01136, Paper 23 (P.T.A.B. Sept. 2, 2015) ...........................................35
`Coalition for Affordable Drugs VII LLC v. Pozen Inc.,
`IPR2015-01718, Paper 40 (P.T.A.B. Feb. 21, 2017) ..........................................55
`Envtl. Designs, Inc. v. Union Oil Co.,
`713 F.2d 693 (Fed. Cir. 1983) ...........................................................................23
`Google Inc. v. EveryMD.com LLC,
`IPR2014-00347, Paper 9 (P.T.A.B. May 22, 2014)............................................34
`Hosp. Core Servs. LLC v. Nomadix, Inc.,
`IPR2016-00052, 2016 WL 2909164 (P.T.A.B. Apr. 27, 2016) ..........................23
`In re Smith Int’l, Inc.,
`871 F.3d 1375 (Fed. Cir. 2017)..........................................................................24
`Kinetic Techs. Inc. v. Skywords Solutions, Inc.,
`IPR2014-00530, Paper 8 (P.T.A.B. Sept. 29, 2014) ...........................................32
`Mayo Collaborative Servs. v. Prometheus Labs. Inc.,
`132 S.Ct. 1289 (2012) .......................................................................................15
`Merck Sharp & Dohme B.V. v. Warner Chilcott Co., LLC,
`711 F. App’x 633 (Fed. Cir. 2017) .............................................................. 50, 51
`Monsanto Co. v. Pioneer Hi-Bred Int’l, Inc.,
`IPR2013-00023, Paper 32 (P.T.A.B. Apr. 11, 2013) ................................ 5, 32, 34
`NVIDIA Corp. v. Polaris Innovations Ltd.,
`IPR2017-00382, Paper 10 (P.T.A.B. June 23, 2017) ..........................................32
`Varian Med. Sys., Inc. v. William Beaumont Hosp.,
`IPR2016-00162, Paper 69 (P.T.A.B. May 4, 2017)............................................56
`
`iii
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`

`

`Statutes
`
`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
`
`
`35 U.S.C. § 103 ................................................................................................ 1, 15
`35 U.S.C. § 313 ..................................................................................................... 1
`
`35 U.S.C. § 314(a) ................................................................................................29
`35 U.S.C. § 325(d) ................................................................................................56
`Regulations
`
`37 C.F.R. § 42.107 ................................................................................................. 1
`
`
`
`
`iv
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`

`

`I.
`
`INTRODUCTION
`
`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
`
`
`Pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, Horizon Therapeutics,
`
`LLC (“Horizon”) submits this Preliminary Response to the Petition (Paper 3, “Pet.”
`
`or “Petition”) for Inter Partes Review (“IPR”) of U.S. Patent No. 9,561,197 (“the
`
`’197 patent”) filed by Lupin Ltd. and Lupin Pharmaceuticals, Inc. (collectively,
`
`“Lupin” or “Petitioner”).
`
`Lupin’s Petition should be rejected because Lupin has not met its burden of
`
`demonstrating a reasonable likelihood of unpatentability under 35 U.S.C. § 103 for
`
`claims 1 and 2 of the ’197 patent (“the claimed methods”). Lupin’s Petition is
`
`deficient because it fails to identify a single piece of prior art describing or even
`
`recognizing the utility of a PAA:PAGN ratio in a method of treating urea cycle
`
`disorder (“UCD”) patients. Lupin’s Petition is further deficient because it fails to
`
`identify any prior art describing or recognizing the existence of the claimed target
`
`range of PAA:PAGN ratio values, as is recited by the ’197 patent claims.
`
`The ’197 patent claims are directed to methods for individualized dose
`
`adjustment of glycerol tri-[4-phenylbutyrate] (“HPN-100”) based on a target range
`
`of a plasma ratio of phenylacetic acid (“PAA”) to phenylacetylglutamine (“PAGN”)
`
`in a UCD patient. UCDs are rare, potentially fatal, genetic metabolic disorders
`
`characterized by the accumulation of toxic levels of ammonia in the plasma and brain
`
`arising from the body’s inability to remove excess ammonia, also known as
`1
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`Case No. IPR2018-00459
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`hyperammonemia. UCD treatment involves a complex regimen of dietary protein
`
`restriction, amino acid supplementation, and nitrogen-scavenging drugs. One such
`
`nitrogen-scavenging drug, HPN-100, metabolizes in the body into phenylbutyrate,
`
`which subsequently metabolizes into PAA, which in turn reacts with waste ammonia
`
`to form PAGN, thus removing waste nitrogen and providing ammonia control in
`
`UCD patients.
`
`Prior to the ’197 patent, however, there was no metric or biomarker that could
`
`guide clinicians in dosing HPN-100 in UCD patients so as to avoid risk of toxicity
`
`due to overdosing. There was therefore a need in the art for a simple test that could
`
`be administered to UCD patients, at any time of the day, regardless of when the
`
`patient last ate a meal or took medication, that could provide useful information
`
`regarding the efficacy and safety of the dose being given.
`
`Prior to the ’197 patent, clinicians treating UCD patients did not consider the
`
`PAA:PAGN ratio in making dosing decisions for any nitrogen-scavenging drug.
`
`Clinicians expected that higher plasma levels of PAA would simply result in higher
`
`levels of PAGN and thus greater ammonia removal. Also, there was no recognition
`
`in the art that the relationship between PAA and PAGN levels (e.g., the PAA:PAGN
`
`ratio) could provide meaningful drug dosing information given the significant
`
`fluctuations of both plasma PAA and PAGN levels throughout the day.
`
`2
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`Case No. IPR2018-00459
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`Additionally, there was no recognition in the art of the existence of a target range of
`
`PAA:PAGN ratios, let alone its utility in the treatment of UCD patients.
`
`Lupin’s assertion that the “prior art expressly taught persons of ordinary skill
`
`in the art to optimize the plasma PAA:PAGN ratio in optimizing the dose of nitrogen
`
`scavenging drugs” (Pet. at 2) is false. None of Lupin’s prior art references even
`
`mentions a plasma PAA:PAGN ratio, let alone teaches or suggests using the claimed
`
`methods’ target range for a plasma PAA:PAGN ratio for treating UCD patients with
`
`a nitrogen-scavenging drug. According to UCD expert Dr. Sutton, the first
`
`publication reporting the use of a PAA:PAGN ratio was not until 2013, when the
`
`inventors Mokhtarani and Scharschmidt and others published their work following
`
`the filing of the ’197 patent application.
`
`Rather than identify prior art actually teaching the use of a PAA:PAGN ratio
`
`or target range of PAA:PAGN ratios, Lupin’s Petition relies upon conclusory and
`
`unsupported testimony from Dr. Vaux who asserts that a person of ordinary skill in
`
`the art (“POSA”) could arrive at the claimed use of the PAA:PAGN ratio in a method
`
`of treatment via “routine” dose optimization. This is also false and should be
`
`rejected. Dr. Vaux fails to explain how a POSA through mere routine optimization
`
`could arrive at the key aspects of the claimed methods, including the utility of the
`
`PAA:PAGN ratio and the existence of a target range of PAA:PAGN ratios.
`
`3
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`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
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`Although Dr. Vaux suggests that a POSA would be concerned about PAA
`
`toxicity when administering HPN-100 to UCD patients (a position that is contrary
`
`to the position Dr. Vaux has taken in other IPRs relating to a separate invention
`
`involving a method of reducing risk of hyperammonemia through improved control
`
`of plasma ammonia levels), Dr. Vaux fails to explain how the POSA would discern
`
`a PAA:PAGN ratio that could reliably predict a UCD patient’s risk of PAA toxicity.
`
`Dr. Vaux cherry picks data showing a ratio falling within the claimed target ranges,
`
`but the data points he chooses are for subjects who were not UCD patients and who
`
`were not experiencing PAA toxicity. Lupin’s Petition fails to provide a credible
`
`reason as to why a POSA would have assumed that data from healthy subjects and
`
`cancer patients, as described in MacArthur and Piscitelli, would apply to UCD
`
`patients with HPN-100, or why a POSA reviewing the clinical data set forth therein
`
`would expect any disclosed ratio of PAA:PAGN to have utility in a method of UCD
`
`treatment given the significant fluctuations in PAA and PAGN levels during the time
`
`periods studied following administration of intravenous PAA.
`
`Lupin’s Petition combines oversimplification with improper hindsight
`
`analysis in a poor attempt to establish that the claimed method of treatment is
`
`obvious. For all these reasons, the Board should deny Lupin’s Petition. See
`
`Monsanto Co. v. Pioneer Hi-Bred Int’l, Inc., IPR2013-00023, Paper 32 at 7-8
`
`4
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`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
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`(P.T.A.B. Apr. 11, 2013) (denying petition where petitioner’s expert’s opinions were
`
`conclusory and unsupported, and further failed to identify all claim limitations).
`
`II. BACKGROUND
`
` RAVICTI® Litigation
`Horizon markets glycerol tri-[4-phenylbutyrate] oral liquid as an FDA-
`
`approved drug product under the tradename RAVICTI®.1 RAVICTI® is approved
`
`for use as a nitrogen-binding agent for chronic management of adult and pediatric
`
`patients at least two years of age with UCDs. Horizon is the holder of approved
`
`New Drug Application (“NDA”) No. 20-3284 for the RAVICTI® product, which
`
`was first approved on February 1, 2013.
`
`The ’197 patent is owned by Horizon and is listed in the FDA “Orange Book”
`
`(formally known as Approved Drug Products with Therapeutic Equivalence
`
`Evaluations) in connection with NDA No. 20-3284 because it claims the approved
`
`drug product and an approved use of the drug product that is the subject of that NDA.
`
`Lupin Ltd. filed Abbreviated New Drug Application (“ANDA”) No. 207694
`
`with the FDA seeking approval to market a generic version of RAVICTI® before
`
`
`
`1 Glycerol tri-[4-phenylbutyrate] is commonly referred to as glycerol
`
`phenylbutyrate or HPN-100. (Ex. 1001 at 2:23-27.)
`
`5
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`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
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`the expiration of the ’197 patent. Lupin’s ANDA includes a “Paragraph IV”
`
`certification asserting that the ’197 patent is invalid or would not be infringed by the
`
`manufacture, use or sale of the Lupin ANDA product.
`
`Horizon has sued Lupin for infringement of the ’197 patent in the United
`
`States District Court for the District of New Jersey. (See Horizon Therapeutics, LLC
`
`v. Lupin Ltd., Civil Action No. 17-cv-5900-KM-MAH (D.N.J.), D.I. 1.)
`
`
`
`Technical Background
`UCDs and Treatment
`1.
`The ’197 patent is directed to methods of treating UCD patients with HPN-
`
`100. UCDs are extremely rare: It is estimated that only one out of 35,000 live births
`
`have this disorder, resulting in only 113 new patients in the U.S. per year. (See Ex.
`
`2001 ¶ 27; Ex. 2003 at 180; Ex. 2004 at 1-2.) UCD patients lack the necessary
`
`enzymes or transporters used by the urea cycle to remove waste nitrogen (i.e.,
`
`ammonia) produced upon digestion of dietary protein in the body. (Ex. 2001 ¶ 27;
`
`Ex. 2005 at S30; Ex. 1001 at 1:19-21.) Ammonia is toxic and the presence of excess
`
`ammonia in the blood is an extremely dangerous medical condition referred to as
`
`“hyperammonemia” that can be fatal if not treated immediately. (Ex. 2001 ¶¶ 27-
`
`28; Ex. 2006 at 207; Ex. 2007 at 21.) In one study, two-thirds of the severely affected
`
`babies diagnosed with a UCD during the first month of life died by the age of 6, even
`
`with rescue treatment during hyperammonemia. (Ex. 2001 ¶ 28; Ex. 2008 at 1423,
`
`6
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`Fig. 3.) With the development of newer chronic treatments, survival rates increased,
`
`but one in five of severely affected newborns diagnosed with a UCD within the first
`
`month of life still died within the first year. (Ex. 2001 ¶ 28; Ex. 1013 at 3; Ex. 1008
`
`at S46.) Even with treatment, hyperammonemia can lead to neurological
`
`complications, such as brain damage, coma and death. (Ex. 2001 ¶ 28 Ex. 2006 at
`
`207; Ex. 2009 at S65.) In fact, only 21% of UCD patients age 12-74 months had an
`
`IQ over 70. (Ex. 2001 ¶ 28; Ex. 2009 at S68.) Thus, despite the existence of new
`
`drug therapies, outcomes for UCD patients remain poor. (Ex. 2001 ¶ 28; Ex. 2010
`
`at 1608S; Ex. 2011 at 1502; Ex. 2012 at 33-34.)
`
`Horizon’s expert Dr. Sutton explains that UCDs can be extremely difficult to
`
`diagnose and to treat because the severity and clinical presentation of UCDs is highly
`
`variable. (Ex. 2001 ¶ 29; Ex. 2013 at 101, 109; Ex. 2014 at S56; Ex. 2015 at 3-4.)
`
`Patients must be constantly monitored by a medical team lead by a physician who is
`
`a specialist in UCD treatment. (Ex. 2001 ¶ 30; Ex. 2009 at S66-67; Ex. 2005 at S30-
`
`S33; Ex. 2006 at 13; Ex. 2004 at 12-13; Ex. 2014 at S56; Ex. 2015 at 18.) But, even
`
`well-controlled UCD patients remain at risk for
`
`life-threatening episodic
`
`hyperammonemia, which can lead to brain damage, coma, and death. (Ex. 2001 ¶¶
`
`28, 40; Ex. 2006 at 207; Ex. 2009 at S65.) The long-term prognosis of patients with
`
`UCDs is generally poor. (Ex. 2001 ¶ 28; Ex. 2009 at S65; Ex. 2010 at 1608S; Ex.
`
`2011 at 1502; Ex. 2012 at 33-34.)
`
`7
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`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
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`The majority of UCD patients are prescribed drugs, known as nitrogen- or
`
`ammonia-scavenging agents, that chemically react with waste ammonia in the body
`
`enabling it to be removed by a pathway other than the urea cycle. (Ex. 2001 ¶¶ 31-
`
`34; Ex. 2004 at 12-13; Ex. 2005 at S35; Ex. 2006 at 9; Ex. 2007 at 30; Ex. 1008 at
`
`S47; Ex. 2012 at 32; Ex. 2013 at 104; Ex. 1001 at 2:10-21.) One such drug is HPN-
`
`100. (Ex. 2001 ¶ 34; Ex. 2009 at S68-S69; Ex. 1007 at [0022].)
`
`When introduced, HPN-100 was referred to as a PAA prodrug because the
`
`body rapidly converts HPN-100 to PBA, which in turn converts to PAA. (Ex. 2001
`
`¶ 35; Ex. 1001 at 2:17-56; Ex. 1007 at [0022].) PAA then reacts with an ammonia
`
`precursor, glutamine, to form PAGN. (Ex. 2001 ¶ 35; Ex. 1001 at 2:17-56; Ex. 1007
`
`at [0022].) PAGN is then excreted in the urine. (Ex. 2001 ¶ 35; Ex. 1001 at 2:17-
`
`56; Ex. 1007 at [0022].) Accordingly, waste ammonia is removed from the UCD
`
`patient. (Ex. 2001 ¶ 35; Ex. 1001 at 2:17-56; Ex. 1007 at [0022].)
`
`Dr. Sutton explains that the rate of conversion for a PAA prodrug into PAA,
`
`and then into PAGN varies widely between individuals. (Ex. 2001 ¶ 36; Ex. 1001
`
`at 9:19-26; Ex. 1016 at 343-44.) Similarly, the level of glutamine in individuals
`
`varies widely. (Ex. 2001 ¶ 36; Ex. 1001 at 9:58-62.)
`
`Dr. Sutton notes that in some individuals, the body’s ability to convert PAA
`
`to PAGN can be impaired such that excess levels of PAA may be present in the body
`
`if the dose of HPN-100, or other PAA prodrug, administered is too high. (Ex. 2001
`8
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`Case No. IPR2018-00459
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`¶¶ 37-38; Ex. 1001 at 3:22-34; Ex. 2017 at 2937; Ex. 2016 at 278.) He explains that
`
`elevated PAA levels in UCD patients cannot be ignored because, in prior studies
`
`involving cancer patients, high levels of PAA were shown to cause reversible side
`
`effects (PAA neurotoxicity). (Ex. 2001 ¶¶ 37-38; Ex. 1009 at 1694.) Because the
`
`signs and symptoms of PAA neurotoxicity are very similar to the signs and
`
`symptoms of ammonia-related neurotoxicity, Dr. Sutton notes it is difficult for a
`
`treating physician to know when a patient has been given too much PAA prodrug
`
`and has PAA toxicity, or not enough prodrug and is having episodes of
`
`hyperammonemia. (Ex. 2001 ¶ 39; Ex. 1001 at 10:50-55.)
`
`Accordingly, Dr. Sutton observes that PAA prodrug treatment requires
`
`ongoing monitoring and dose adjustment. (Ex. 2001 ¶ 40; Ex. 1018 at 3327-28; Ex.
`
`1017 at 1.) Even under a PAA prodrug regime, UCD patients remain at risk for life-
`
`threatening episodic hyperammonemia (due to under-treatment), or alternatively,
`
`risk of PAA toxicity (due to overtreatment). (Ex. 2001 ¶ 40; Ex. 1018 at 3327-28;
`
`Ex. 1017 at 1.) Therefore, Dr. Sutton notes that when evaluating PAA prodrug dose,
`
`the clinician must balance the elimination of ammonia while minimizing the risk of
`
`PAA toxicity. (Ex. 2001 ¶ 40.)
`
`According to Dr. Sutton, prior to the ’197 patent, clinicians did not use blood
`
`levels of PAA or PAGN to guide PAA prodrug dosing decisions. (Ex. 2001 ¶¶ 41-
`
`45; Ex. 1018; Ex. 1017.) This is because there was no understanding of the
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`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
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`relationship between PAA and/or PAGN plasma concentration and clinical efficacy
`
`or safety. (Ex. 2001 ¶ 45.) The predictive power of the PAA:PAGN ratio was
`
`entirely unknown as were the specific ranges of PAA:PAGN that defined a UCD
`
`patient group having an acceptable risk of both hyperammonemia and PAA toxicity.
`
`(Id.)
`
`Thus, Dr. Sutton observes, that prior to the ’197 patent, there was a need in
`
`the art for a simple test that could be administered to UCD patients in a clinical
`
`setting, at any time of the day, regardless of when the patient last ate a meal or took
`
`a dose of drug, that could provide useful information regarding the efficacy and
`
`safety of the PAA prodrug dose. (Id. ¶ 43.)
`
`Response to Lupin’s Technical Background
`2.
`The Petition’s description regarding the use of nitrogen-scavenging drugs in
`
`UCD treatments is oversimplified. (Pet. at 6.) Dr. Sutton notes that while a POSA
`
`would have understood that HPN-100 metabolizes into PBA, which in turn
`
`metabolizes into PAA, and which in turn metabolizes to PAGN, Lupin’s Petition
`
`overlooks the complexity and significant variability of these conversions between
`
`individuals and patient populations. (Ex. 2001 ¶¶ 46-47.) Dr. Sutton explains that
`
`little was known about the rate and extent of conversion of PAA prodrugs to PAA
`
`or the extent of conversion of PAA to PAGN in UCD patients. (Id.)
`
`10
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`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
`
`Dr. Sutton further notes that the Petitioner’s statement that “[HPN-100] is
`
`hydrolyzed … to release three molecules of PBA, which in turn are oxidized to form
`
`three molecules of PAA and, in turn, three molecules of PAGN” also ignores
`
`complexities in vivo. (Id.; Pet. at 9.) The human body has alternative reaction
`
`pathways for PBA and PAA that do not produce PAGN, so administering an oral
`
`dose of HPN-100 to a UCD patient would not simply convert stoichiometrically into
`
`PBA and then into PAA and PAGN. (Ex. 2001 ¶¶ 48-49.) As Dr. Sutton explains,
`
`it is this lack of understanding in the prior art that made the discovery of the utility
`
`of the PAA:PAGN ratio so significant. (Id.) Prior to the ’197 patent, the POSA had
`
`no understanding that the ratio of PAA:PAGN could effectively guide dosing. (Id.)
`
`Lupin’s Petition cites references relating to cancer patients and healthy
`
`subjects rather than UCD patients to support its arguments concerning PAA
`
`saturability and toxicity. (Pet. at 10-14; Ex. 2001 ¶ 50.) However, according to Dr.
`
`Sutton, different patient populations produce different and unknowable amounts of
`
`glutamine, so a POSA could not predict which patients would have saturable PAA
`
`conversion to PAGN. (Ex. 2001 ¶ 51.) According to Dr. Sutton, UCD patients are
`
`different because they cannot eliminate ammonia effectively, and thus have much
`
`higher amounts of ammonia and the related compound glutamine compared to other
`
`patient populations, making it impossible to predict how much PAA will be
`
`produced in a UCD subject treated with a PAA prodrug like HPN-100. (Id.) He
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`Case No. IPR2018-00459
`U.S. Patent No. 9,561,197
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`observes that one cannot draw conclusions regarding PAA saturability and toxicity
`
`from data collected in non-UCD patients and apply them to UCD patients. (Id. ¶¶
`
`52-53; Ex. 1004 at S73; Ex. 1005 at 1120.)
`
`Lupin’s Petition further cites references relating to intravenous administration
`
`of PAA or PBA, not HPN-100, to support its arguments concerning PAA saturability
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`and toxicity. (Pet. at 10-14; Ex. 2001 ¶¶ 54-55, 58-59.) However, as Dr. Sutton
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`explains, because the pharmacokinetics of intravenous PAA/PBA dosing differ from
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`oral PAA prodrug (e.g., HPN-100) dosing, information regarding a PAA:PAGN
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`ratio would not have utility in predicting PAA saturation or toxicity following PAA
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`prodrug administration. (Ex. 2001 ¶¶ 56-60.)
`
`Dr. Vaux does not address the above points.
`
`’197 Patent Prosecution History
`
`The ’197 patent issued from U.S. Patent Application No. 13/610,580 (“the
`
`’580 application”), filed on September 11, 2012, and claims priority to Provisional
`
`Application No. 61/636,256, filed on April 20, 2012. Drs. Scharschmidt and
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`Mokhtarani (“Applicants”) initially filed the ’580 application with method claims
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`directed to: (i) calculating a plasma PAA:PAGN ratio, (ii) determining whether the
`
`PAA prodrug dosage needs to be adjusted based on whether the PAA:PAGN ratio
`
`falls within a target range, where a PAA:PAGN ratio below the target range indicates
`
`that the dosage potentially needs to be increased and a PAA:PAGN ratio above the
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`U.S. Patent No. 9,561,197
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`target range indicates that the dosage needs to be decreased, and (iii) administering
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`a second dosage of the PAA prodrug based on the determination in (ii). (See Ex.
`
`1020 at 68.) In response to a Restriction Requirement, Applicants elected “urea
`
`cycle disorder” as the disorder and “glyceryl tri-[4-phenylbutyrate] (HPN-100)” as
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`the PAA prodrug. (Id. at 101.)
`
`On February 27, 2015, the Examiner rejected all claims as obvious over
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`Scharschmidt in view of McGuire. (See id. at 130-136.) The Examiner
`
`acknowledged Scharschmidt did not disclose “measuring PAA or PAGN levels in
`
`plasma,” “calculating a plasma PAA:PAGN ratio,” or a “PAA:PAGN ratio fall[ing]
`
`within a target range.” (Id. at 131-132.) Instead, the Examiner urged that McGuire
`
`taught a ratio, even though that ratio was comparing multiple samples from multiple
`
`patients on two different drugs. (Id. at 132, 157.)
`
`In response, the Applicants noted that McGuire did not disclose dose
`
`adjustment based on a measured ratio of PAA:PAGN “taken at the same time from
`
`the same patient” receiving HPN-100. (Id. at 158.) The Applicants argued that
`
`McGuire did not teach or suggest “measuring plasma levels of PAA and PAGN in a
`
`single patient following treatment with [HPN-100]” or “calculating the PAA/PAGN
`
`ratio and comparing to a target range.” (Id. at 158-159.) The Applicants also argued
`
`that “the PAA/PAGN ratio provides an unexpectedly accurate measure of PAA
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`prodrug metabolism in subjects with nitrogen retention disorders.” (Id. (citations
`
`omitted).)
`
`In a May 19, 2016, Office Action, the Examiner maintained her obviousness
`
`rejection. (See id. at 208-214.) In response, Applicants amended the claims to
`
`specify a target range for plasma PAA:PAGN of “1 to 2:5.” (See id. at 220-221.)
`
`The Applicants later corrected the typographical error “1 to 2:5” to “1 to 2.5.” (Id.
`
`at 239-242.) The Applicants again argued surprising and unexpected results from
`
`applying plasma PAA:PAGN ratios to evaluate and adjust PAA prodrug dosage. (Id.
`
`at 223.) The Applicants also explained that the cited art taught away from the use
`
`of measured plasma levels of PBA prodrugs or their metabolites for adjusting
`
`dosages, and failed to provide a motivation for calculating PAA:PAGN ratios,
`
`determining a target range for the PAA:PAGN ratio, or utilizing PAA:PAGN ratios
`
`for therapeutic purposes. (Id. at 225.)
`
`On August 24, 2016, the Examiner initiated an interview and “[a]greed that
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`the claimed steps of calculating a patient’s plasma PAA:PAGN ratio and adjusting
`
`the drug dosage if said ratio lies outside the target range of 1 to 2.5 are not
`
`specifically disclosed by the cited references.” (See id. at 251.) The Examiner also
`
`“[d]iscussed whether optimizing the dosage of a drug on the basis of metabolite
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`ratios is routine, in particular with respected to the claimed patient population, which
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`may be inherently limited to infants and children due to the nature of the disease.”
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`(Id.) The Examiner, however, maintained her rejection under 35 U.S.C. § 103 and
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`further cited Mayo Collaborative Servs. v. Prometheus Labs. Inc., 132 S.Ct. 1289
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`(2012). (Id. at 250.)
`
`The Applicants added new claims 14-22 in response. (Id. at 262-265.) The
`
`Examiner issued a Notice of Allowance and Allowability for claims 14 and 17, but
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`first redrafted claims 14 and 17 in an Examiner’s Amendment. (See id. at 270, 274,
`
`275.) The ’197 patent issued on February 7, 2017 with claims 1 and 2, which are
`
`identical to claims 14 and 17 as redrafted and allowed by the Examiner. (See id. at
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`288; Ex. 1001 at 32:8-20.)
`
` Overview of the ’197 Patent
`According to Dr. Sutton, the ’197 patent is generally directed to a clinically
`
`practical method of treating UCD patients with PAA prodrugs. (Ex. 1001 at 3:47-
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`55; Ex. 2001 ¶ 116.) The inventors of the ’197 patent recognized the need for
`
`improved methods of determining the appropriate dose of PAA prodrugs, such as
`
`HPN-100, to use in UCD patients that better achieve the dual goals of controlling
`
`plasma ammonia levels and avoiding toxic side effects. (Ex. 1001 at 10:4-10; Ex.
`
`2001 ¶ 117.)
`
`Dr. Sutton explains that in response to this need, the inventors investigated
`
`the previously unknown relationship between plasma levels of PAA and PAGN, the
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`plasma PAA:PAGN ratio. (Ex. 1001 at 10:11-44; Ex. 2001 ¶ 117.) They discovered
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`from their research that the plasma PAA:PAGN ratio “provide[s] an unexpectedly
`
`accurate measure of PAA prodrug metabolism in subjects with nitrogen retention
`
`disorders and/or hepatic impairment.” (Ex. 1001 at 10:11-44.) As Example 1
`
`describes, the inventors identified target ranges of PAA:PAGN ratios, i.e., 1 to 2 or
`
`1 to 2.5, that in their opinion reflected medically acceptable levels of risk of
`
`developing neurotoxicity resulting from either over-treatment (due to excess PAA
`
`levels) or under-treatment (due to insufficient ammonia removal). (Ex. 1001 at
`
`Example 1; Ex. 2001 ¶¶ 117-118.)
`
`The inventors further developed methods of UCD treatment based on the use
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`of the PAA:PAGN ratio as what Dr. Sutton calls a “predictive tool.” (Ex. 1001 at
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`23:27-26:60; Ex. 2001 ¶¶ 117-119.) Dr. Sutton explains that these methods involve
`
`(a) assessing whether the dose of PAA prodrug being administered to the UCD
`
`patient produces a PAA:PAGN ratio outside the acceptable target range and thus
`
`associated with a medically unacceptable risk of neurotoxicity, and then (b)
`
`adjusting the patient’s drug dose as needed to reduce the patient’s risk by shifting
`
`their PAA:PAGN ratio to a value falling inside the acceptable target range. (Ex.
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`1001 at 23:27-26:60; Ex. 2001 ¶¶ 120-121.) As stated by the inventors, such
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`methods “represent an improvement over previously developed methods for
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`evaluating PAA prodrug dosage and efficacy in that they allow more accurate
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`dosing, greater efficacy, and decreased risk of toxicity associated with PAA
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`accumulation.” (Ex. 1001 at 11:14-19.)
`
`The methods claimed by the ’197 patent are as follows:
`
`
`
`A method of treating a urea cycle disorder in a
`1.
`subject comprising administering to a subject having a
`plasma PAA to PAGN ratio outside the target range of 1
`to 2, a dosage of glyceryl tri-[4-phenylbutyrate] (HPN-
`100) effective to achieve a plasma PAA to PAGN ratio
`within the target range of 1 to 2.
`
`A method of treating a urea cycle disorder in a
`2.
`subject comprising administering to