Paper No. ___
`Filed: August 24, 2015
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`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
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`
`
`ALTAIRE PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`PARAGON BIOTECK, INC.,
`Patent Owner.
`_____________________________
`
`Case PGR2015-00011
`Patent 8,859,623
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`_____________________________
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`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.207
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`

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`TABLE OF CONTENTS
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`Case PGR2015-00011
`Patent 8,859,623
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`I.
`II.
`
`B.
`
`V.
`
`Page
`INTRODUCTION .......................................................................................... 1
`THE PETITION FAILS TO IDENTIFY SAWAYA AQUEBOGUE
`AS A REAL PARTY-IN-INTEREST ............................................................ 2
`A.
`Sawaya Aquebogue is a Real Party-In-Interest .................................... 3
`B.
`Correcting Real Party-in-Interest Would be Futile .............................. 6
`III. BACKGROUND OF THE ’623 PATENT AND PROSECUTION
`HISTORY ....................................................................................................... 7
`A.
`Paragon’s Identification of Phenylephrine Temperature
`Instability .............................................................................................. 9
`IV. THE PETITION RELIES UPON A FLAWED ANALYSIS ...................... 12
`A.
`The USP Standard HPLC Protocol Used by Petitioner Does Not
`Reliably Detect Chiral Impurity ......................................................... 12
`Petitioner’s Reliance on an Optical Rotation Comparison is
`Misplaced ........................................................................................... 16
`THE PETITION IS BASED ENTIRELY ON ATTORNEY
`ARGUMENT AND TESTIMONY FROM AN INTERESTED FACT
`WITNESS WHO LACKS EXPERTISE IN THE SUBJECT
`MATTER ...................................................................................................... 18
`VI. PETITIONER’S CLAIM CONSTRUCTION IGNORES KEY
`LIMITATIONS OF THE ’623 PATENT CLAIMS ..................................... 20
`A.
`“. . . the composition comprising R-phenylephrine
`hydrochloride having an initial chiral purity of at least 95%” ........... 21
`“. . . wherein the chiral purity of R-phenylephrine hydrochloride
`is at least 95% of the initial chiral purity after 6 months” ................. 22
`VII. PROPOSED GROUNDS OF CHALLENGE .............................................. 22
`A. Ground 1 Fails .................................................................................... 23
`1.
`“Altaire’s Product” Does Not Disclose “. . . the
`composition comprising R-phenylephrine hydrochloride
`having an initial chiral purity of at least 95%,” as Recited
`in Claim 1 ................................................................................. 24
`Ground 2 Fails .................................................................................... 28
`1.
`The Cited References Do Not Disclose “. . . the
`composition comprising R-phenylephrine hydrochloride
`
`B.
`
`B.
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`Case PGR2015-00011
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`having an initial chiral purity of at least 95%,” as Recited
`in Claim 1 ................................................................................. 30
`Ground 3 Fails .................................................................................... 34
`C.
`D. Ground 4 Fails .................................................................................... 35
`VIII. CONCLUSION ............................................................................................. 38
`IX. APPENDIX ................................................................................................... 39
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`Case PGR2015-00011
`Patent 8,859,623
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`I.
`
`INTRODUCTION
`
`The Board should not institute post grant review (PGR) of Claims 1-13 of
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`U.S. Patent No. 8,859,623 (“the ’623 patent”) because Petitioner, Altaire
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`Pharmaceuticals, Inc. (“Petitioner” or “Altaire”), has not met its burden of showing
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`the challenged claims are more likely than not unpatentable.
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`First, the petition should be dismissed for failing to identify Sawaya
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`Aquebogue as a real party-in-interest. Among other factors, Sawaya Aquebogue
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`and Altaire are related entities under common control, including control by the
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`same individual testifying as a fact witness in this PGR – Mr. Assad Sawaya.
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`Second, with regard to the asserted prior art, each of the stated grounds of
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`challenge can be denied for failing to meet the chiral purity limitations of the
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`claims, including at least the 95% initial chiral purity requirement of Claim 1.
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`Phenylephrine comprises two enantiomers, an R-form and an S-form, but the
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`petition relies entirely on methodologies incapable of reliably detecting S-form
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`chiral impurity. Paragon demonstrated that its chiral column chromatography
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`method uncovers degradation that was not detectible using methods pursuant to the
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`United States Pharmacopeia (USP) published guidelines, and that improvement of
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`testing methodology led to Paragon’s discovery regarding the unrecognized and
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`unappreciated effect of temperature conditions on degradation of the chiral purity
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`of phenylephrine. The petition relies on the faulty USP methodology, but omits
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`any discussion of the deficiencies in that method as addressed by Paragon in ex
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`parte prosecution. The petition instead attempts to remedy the defective nature of
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`its testing through faulty claim construction. In the end, Petitioner’s case in chief
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`collapses on itself once the claims are properly construed and petitioner’s
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`methodologies are scrutinized.
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`Finally, the challenge to the claims based on alleged indefiniteness is more
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`appropriately interpreted as an advancement of Petitioner’s preferred claim
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`construction position, but fails to provide a bona fide basis for unpatentability.
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`Accordingly, institution of post grant review should be denied.
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`II. THE PETITION FAILS TO IDENTIFY SAWAYA AQUEBOGUE AS
`A REAL PARTY-IN-INTEREST
`
`As a threshold matter, the petition should be dismissed for failing to identify
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`Sawaya Aquebogue, LLC (“Sawaya Aquebogue”) as a real party-in-interest as
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`required by 35 U.S.C. § 322(a)(2) and 37 C.F.R. § 42.8(b)(1).
`
` “A petition [for post grant review] may be considered only if . . . [it]
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`identifies all real parties in interest.” 35 U.S.C. § 322(a)(2); see also Trial Practice
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`Guide, 77 Fed. Reg. 48,759, (Aug. 14, 2012). “A common consideration is
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`whether the non-party exercised or could have exercised control over a party’s
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`participation in the proceeding.” Id. The non-party’s participation may be overt or
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`covert, and the evidence may be direct or circumstantial, but the evidence as a
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`whole must show that the non-party possessed control, or the ability to control,
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`from a practical standpoint. Gonzalez v. Banco Cent. Corp., 27 F.3d 751, 759 (1st
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`Cir. 1994). Indeed, the Board has recognized that it is sufficient to establish an
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`ability “to call the shots.” Galderma S.A. v. Allergan Indus., SAS, IPR2014-01422,
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`Paper 14 at 8, 12, (PTAB Mar. 5, 2015) (quoting Gonzalez, 27 F.3d at 758). As
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`discussed below, the evidence of record demonstrates that Sawaya Aquebogue has
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`a direct interest in this PGR and the ability to control this proceeding from a
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`petitioner’s perspective.
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`A.
`
`Sawaya Aquebogue is a Real Party-In-Interest
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`Sawaya Aquebogue possessed at least the ability to control this PGR
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`proceeding from a practical standpoint because both Sawaya Aquebogue and
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`Altaire are related companies under the common control, and are even run by the
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`same individual – Assad Sawaya.1 “[A person’s] presence at the helm of both [a
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`company] and [another company] strongly implies ‘an involved and controlling
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`parent corporation representing the unified interests of itself and Petitioner.’”
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`Galderma S.A. &Q-MED AB. v. Allergan Industrie, SAS, et al., IPR2014-01422,
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`Paper 15 at 8 (PTAB) at 12 (citing ZOLL Lifecor Corp. v.Philips Elec. N. Am.
`
`Corp., IPR2013-00606, slip op. at 10).
`
`First, Sawaya Aquebogue and Altaire are under common control by the
`
`same individual. Assad Sawaya is the “President of Altaire Pharmaceuticals, Inc.
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`(“Altaire”).” Ex. 2001, ¶1. Assad Sawaya is also the General Manager of Sawaya
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`Aquebogue, LLC. Id. (“I am President of Altaire Pharmaceuticals, Inc. (“Altaire”)
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`and General Manager of Sawaya Aquebogue, LLC (“Saw Aque”).”).
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`
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`In fact, Sawaya Aquebogue and Altaire are closely intertwined entities.
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`Ex. 2004 at 10 (“Sawaya Aquebogue [is] an affiliate of Altaire”). Both Altaire and
`
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`1 Petitioner submitted a declaration from Assad Sawaya testifying as the sole
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`witness in this proceeding. See Ex. 1003.
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`Sawaya Aquebogue share the same address, 311 West Lane, Aquebogue, NY
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`11931. See Exs. 2002, 2003, 2005. In addition, Michael Sawaya is General
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`Counsel of Altaire and accepts service of legal documents at the same address on
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`behalf of both Altaire and Sawaya Aquebogue. See Ex. 2002 at 1; see also Ex.
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`2003 at 1; see also Ex. 2007 at 2.2,3 Furthermore, on April 27, 2010, the New York
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`State Department of Environmental Conservation issued an Air State Facility
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`permit to Sawaya Aquebogue for the facility designated “Altaire Pharmaceuticals”.
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`Ex. 2005 at 1. Michael Sawaya is the corporate contact for both Sawaya
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`Aquebogue and the Altaire Pharmaceutical facility. Id. Michael Sawaya’s contact
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`information for both the “Permit Issued to: Sawaya Aquebogue LLC” and the
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`“Facility: Altaire Pharmaceuticals” is the same. Id.
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`Sawaya Aquebogue specifically has an interest in this PGR proceeding. In
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`particular, Sawaya Aquebogue is a third-party beneficiary to a contract agreement
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`(“Agreement”) between Altaire and Paragon, which involves, inter alia,
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`manufacturing, marketing, and distribution of a selection of products and subject
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`2 In the United States District Court of Oregon, Altaire and Sawaya Aquebogue
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`are named as co-defendants to Paragon’s suit for breach of the Agreement. See
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`Exs. 2001-2004, 2006, filed beginning on March 20, 2015.
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`3 Documents identify Assad Sawaya and Michael Sawaya as General Managers
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`of Altaire.
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`matter of the ’623 patent.4 Sawaya Aquebogue’s “designation as a third-party
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`beneficiary was made by Altaire alone. Paragon played no part in this
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`determination.” Ex. 2004 at 21. As stated in Altaire Pharmaceuticals, Inc. and
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`Sawaya Aquebogue LLC’s Motion to Dismiss or, in the Alternative, For Transfer
`
`of Venue “pursuant to the Agreement, Paragon agreed to provide certain
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`consideration to Saw Aque.” (emphasis added). Ex. 2006 at 9.5 Moreover, the
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`Agreement is signed by Assad Sawaya on behalf of Altaire.6
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`Such strategic interconnectedness creates a strong common interest and
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`makes an absence of control between Altaire and Sawaya Aquebogue almost
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`impossible. “Rather than maintaining well-defined corporate boundaries, [the
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`parent and its subsidiaries] are so intertwined that it is difficult for both insiders
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`4 The Agreement is the same Agreement cited at pages 9-10 in the Petition, and
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`the source of corresponding rhetoric. The Agreement has also been the subject of
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`litigation between Paragon and both Altaire and Sawaya Aquebogue. See United
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`States District Court For The District of Oregon, No. 3:15-CV-00189-PK; see also
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`United States District Court for the Eastern District of New York, No. 2:15-cv-
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`02416 LDW-AYS (Ex. 2015).
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`5 “Saw Aque” is short for Sawaya Aquebogue. “Saw Aque” and Sawaya
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`Aquebogue are the same entity.
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`6 There is little doubt that Assad Sawaya controlled negotiations on Altaire’s
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`behalf to ensure Sawaya Aquebogue was a third-party beneficiary.
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`and outsiders to determine precisely where one ends and another begins.” Atlanta
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`Gas Light Co. v. Bennett Regulator Guards, Inc., Case IPR2013-00453, slip op. at
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`11 (PTAB Jan.6, 2015) (Paper 88).
`
`Assad Sawaya’s testimony in related district court litigation7 further
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`underscores the interrelationship and common interests between Altaire and
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`Sawaya Aquebogue. Mr. Sawaya simultaneously testified as both President of
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`Altaire and General Manager of Sawaya Aquebogue on behalf of both parties in a
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`single declaration. See Ex. 2001. Throughout his declaration, Mr. Sawaya refers
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`to his knowledge regarding the business practices of Altaire and Sawaya
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`Aquebogue, often in the same sentence, “[n]either Altaire nor Saw Aque”. Id. at
`
`¶¶ 5-8.
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`Taken as a whole, the evidence of such relationships between Altaire and
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`Sawaya Aquebogue indicates Sawaya Aquebogue has a direct interest in this
`
`proceeding and has the motivation and ability to control this proceeding. Sawaya
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`Aquebogue should have been named as a real party-in-interest to Altaire’s Petition.
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`B. Correcting Real Party-in-Interest Would be Futile
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`Failure to name all real parties-in-interest renders a petition incomplete. See
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`Zoll, IPR2013-00609, Paper 15 at 16-17. Incomplete petitions are not accorded a
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`7 While the case in the United States District Court For The District of Oregon
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`has been dismissed, the case in the United States District Court for the Eastern
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`District of New York is still ongoing and involves nearly identical issues -
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`breaches of the parties’ May 30, 2011 agreement. See Ex. 2015.
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`filing date, and thus the petition is not entitled to its May 22, 2015 filing date. See
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`37 C.F.R. § 42.206(b). Moreover, correcting the omission through amendment
`
`would be futile because, even if corrected, the earliest filing date that could be
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`accorded to the petition would not fall within the nine-month period specified in 35
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`U.S.C. § 321(c).
`
`III. BACKGROUND OF THE ’623 PATENT AND PROSECUTION
`HISTORY
`
`The ’623 patent, titled “Methods and Compositions of Stable Phenylephrine
`
`Formulations,” was issued on October 14, 2014 from U.S. Patent Application No.
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`14/080,771 (“the ’771 application”) filed on November 14, 2013. A copy of the
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`’623 patent was submitted with the petition as Exhibit 1001.
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`The ’623 patent is based in part on Paragon’s development of an improved
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`chiral HPLC method allowing separate elution of the R-form and S-form of
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`phenylephrine hydrochloride. This led to the discovery of the previously
`
`unrecognized and unappreciated effect of temperature conditions on degradation of
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`the chiral purity of phenylephrine formulations.
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`As to chiral composition, it was known at the relevant time that
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`phenylephrine comprises two enantiomers, an R-form (also known as L-
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`Phenylephrine) and an S-form. See Ex. 1001 at 6:10-8:9. During the course of
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`developing a formulation of phenylephrine, Paragon discovered that the S-
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`enantiomer of phenylephrine has a negative effect on pupil dilation (rather than
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`mere inactivity). See Ex. 1001 at 7:8-15. Thus, Paragon sought to develop a
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`phenylephrine formulation that, when stored over long periods of time, maintained
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`high chiral purity of the R-enantiomer of phenylephrine so as to reduce the
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`negative effect on pupil dilation. See e.g., Id; see also Ex. 1002 at 113.
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`As for degradation of phenylephrine compositions, it was known that
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`phenylephrine was sensitive to light-induced deprotonation and should be stored
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`protected from light. See Ex. 1001 at 2:53-65. The conventional understanding in
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`the art at the time, however, was that temperature did not affect the chiral stability
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`of phenylephrine hydrochloride solutions. For example, a reference to Shibini
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`(Shibini et al., Arzneimettelforschung, 19(9), pp. 1613-14, 1969 ((“Shibini”))
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`reflects such conventional understanding and provides, inter alia, that “[n]o
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`noticeable changes in the optical rotation of [L-Phenylephrine] solutions could be
`
`detected after heating to 97ºC for several days.”8 Ex. 1002 at 104. Shibini goes on
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`to teach that phenylephrine can be subject to significant heating without concern
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`for purity degradation, even stating that “the [L-Phenylephrine] solution can be
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`safely sterilized by autoclaving.” Id. As a further reflection of the prevailing logic
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`at the time, the well-known and commercially-available Phenylephrine
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`Hydrochloride Ophthalmic Solution from Akorn, Inc. specifically instructed room
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`temperature storage, providing that the R-Phenylephrine solution should be stored
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`at 20º to 25º C. See Ex. 1001 at 2:60-64; see also Ex. 1002 at 109, 112.
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`8 As discussed in further detail below, optical rotation is a non-quantitative
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`method of detecting R- and S-enantiomers of a chiral compound.
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`Paragon’s Identification of Phenylephrine Temperature
`Instability
`
`A.
`
`The issue of temperature-based chiral instability, the conventional
`
`understanding at the time, and Paragon’s discovery to the contrary, were discussed
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`at length during ex parte prosecution of the ’771 application. See Ex.1002 at 100-
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`103. In particular, Paragon developed an improved HPLC-based method allowing
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`separate chromatographic elution and detection of the R-form and S-form of
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`phenylephrine hydrochloride that, in turn, allowed more accurate determination of
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`the chiral purity of phenylephrine hydrochloride solutions. Using these methods,
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`Paragon discovered that, contrary to the prevailing logic at the time, applied
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`temperature does in fact significantly affect the chiral stability of R-Phenylephrine
`
`hydrochloride solutions.
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`Paragon submitted evidence supporting its discovery of R-Phenylephrine’s
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`temperature-based chiral instability during ex parte prosecution, including the
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`Declaration of Patrick H. Witham. See Ex. 1002, pp. 97-113. As provided in the
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`Witham declaration and corresponding experimental results, an R-Phenylephrine
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`hydrochloride product of high chiral purity and subject to low temperature storage
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`showed surprisingly better preservation of R-Phenylephrine, when compared to a
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`commercially available R-Phenylephrine hydrochloride product subject to room
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`temperature storage.
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`Paragon analyzed the chiral purity of “a commercially available R-
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`Phenylephrine hydrochloride product [] stored at 20 to 25 ºC after 6 months.”
`
`Ex. 1002 at 110. Using Paragon’s chiral column chromatography method, Paragon
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`found that the R-Phenylephrine in the product stored at room temperature degraded
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`over time. Ex. 1002 at 113, top chromatogram reproduced below.
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`Paragon compared the above to a chiral column chromatogram of an R-
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`Phenylephrine hydrochloride formulation “stored at 2 to 8ºC after 6 months,”
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`analyzed using Paragon’s novel method. Id. at 110 and 113, bottom chromatogram
`
`reproduced below.
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`Thus, Paragon’s results demonstrated that, contrary to the conventional
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`understanding in the field at the relevant time, “low temperature storage shows
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`surprisingly better R-Phenylephrine preservation.” Id. at 109.
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`Additionally, Paragon demonstrated that its chiral column chromatography
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`method uncovered degradation that was not detectible using methods pursuant to
`
`the USP standard HPLC protocol. As Paragon explained during prosecution, the
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`“(currently published USP method) show[s] no or little chemical degradation of
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`R-Phenylephrine hydrochloride”, using Paragon’s chiral column chromatography
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`method and illustrated in the exemplary chromatograms. (emphasis added). Id at
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`110. As discussed in further detail below, this point is particularly important in this
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`PGR because Petitioner’s case-in-chief depends largely on its submitted data
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`purportedly generated using Altaire’s USP standard protocol procedure. See, e.g.,
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`Pet. at p. 36 (stating that Altaire acquired the submitted data using Altaire’s
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`“HPLC procedure” that has been “validated pursuant to established United States
`
`Pharmacopeia guidelines [(“USP”)].”)
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`In follow-up to Paragon’s discoveries, Paragon filed the ’771 patent
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`application which later issued as the ’623 patent having one independent claim and
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`12 dependent claims. Issued Claim 1 recites:
`
`
`1. A method of using an ophthalmic composition for pupil
`dilation, the composition comprising R-phenylephrine
`hydrochloride having an initial chiral purity of at least 95% and
`an aqueous buffer, wherein the chiral purity of R-phenylephrine
`hydrochloride is at least 95% of the initial chiral purity after 6
`months, the method comprising:
`administering the composition into an eye of an
`individual in need thereof,
`wherein the composition is stored between −10 to
`10 degree Celsius prior to administration, and
`wherein the composition comprises R-
`phenylephrine hydrochloride having a chiral purity of at least
`95% when administered after storage.
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`
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`-11-
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`Ex. 1001 at 12:39-50.
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`IV. THE PETITION RELIES UPON A FLAWED ANALYSIS
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`As a fundamental basis of its challenge, the petition identifies a purported
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`inability to detect chiral impurity of phenylephrine hydrochloride solutions of
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`“Altaire’s product.”9 The petition states “results relied upon by the Witham
`
`Declaration could not be duplicated.” (emphasis added). Pet. at p. 20. The
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`petition, however, relies on techniques different than those employed in the studies
`
`reported in the Witham Declaration. As explained in further detail below, the
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`techniques upon which the petition relies – i.e., (1) a USP standard HPLC protocol;
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`and (2) an optical rotation comparison – cannot reliably determine chiral purity.
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`A. The USP Standard HPLC Protocol Used by Petitioner Does Not
`Reliably Detect Chiral Impurity
`
`While the petition is sparse regarding the particular details of Petitioner’s
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`HPLC method, the petition is clear that its method conforms to the currently
`
`published USP standard HPLC protocol (and not those disclosed in the ’623
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`9 The petition identifies “Altaire’s Commercial Product” as “Lot 11578 and Lot
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`11581 and/or their accompanying Package Insert.” Pet. at p. 37. As explained in
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`further detail here, even assuming arguendo the “Altaire Product” was available as
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`alleged (a point not conceded here), such product fails to disclose the initial chiral
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`purity aspects recited in Claim 1. Mere labeling for cold storage for the purpose of
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`a user maintaining sterility in a multi-patient use ophthalmic applicator is not
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`dispositive of product purity or handling of the product during manufacture,
`
`shipping, etc. Indeed, Petitioner purports not to believe that temperature based
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`degradation occurs, so presumably would not have guarded against heat exposure.
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`patent). For example, the petition expressly indicates that “Altaire’s HPLC method
`
`for chiral purity testing was validated pursuant to established United States
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`Pharmacopeia guidelines (USP <1225> Validation of Compendial Procedures).”
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`Pet. at p. 36; see generally Ex. 2011.
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`Indeed, what details regarding Petitioner’s HPLC method are provided in the
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`petition materials indicate compliance with the currently published USP
`
`guidelines.
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`The column parameters identified in the petition compare with those listed in
`
`the USP guidelines. Compare Petitioner’s identified parameters of “HPLC using
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`Chiralpak 4.6x250mm, 5µm column at 270nm as per Altaire’s test method TMQC-
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`247” at page 1 of Ex. 1020, to parameters listed in the currently published USP
`
`guidelines. Ex. 2008, at p. 1 (listing “[t]he liquid chromatograph is equipped with a
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`280-nm detector and a 4.6-mm x 25-cm column that contains packing L1.”).
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`Moreover, according to the currently published USP method, the column should be
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`packed with L1 (octadecyl silane chemically bonded to porous silica or ceramic
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`micro-particles, 1.5 to 10µm in diameter, or a monolithic silica rod). Id. at 1, and
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`Ex. 2010 at 20. Petitioner’s column included Chiralpak at 5µm, the size of
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`microparticles within the range required by USP. See Ex. 1020 at 1; see also Ex.
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`2010 at 20.
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`Accordingly, based on Petitioner’s statement that their method was
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`“validated pursuant to established United States Pharmacopeia guidelines” and
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`indicia that their column conforms with the USP material and guidelines,
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`Petitioner’s methods are represented in the petition as providing resolution
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`comparable to the USP standard protocol. Pet. at p. 36; see Ex. 2008 and 2010; see
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`generally Ex. 2011.
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`Paragon, however, demonstrated that its chiral column chromatography
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`method uncovered S-form chiral impurity that was not reliably detectible using
`
`methods pursuant to the currently published USP standard HPLC protocol.
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`Ex.1002 at 110 ( “[n]on-chiral reverse phase column chromatographs (currently
`
`published USP HPLC method) show no or little chemical degradation of R-
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`Phenylephrine hydrochloride in both formulations (i) and (ii).”). This fact was
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`presented in the Witham declaration submitted during ex parte prosecution, and
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`further validated by Paragon.
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`In particular, Paragon conducted a study designed specifically to address
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`whether the currently published USP method could reliably detect S-
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`phenylephrine.10 See Ex. 2014. The tested samples included (1) an R-
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`phenylephrine ophthalmic solution, and (2) the same R-phenylephrine ophthalmic
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`solution spiked with S-phenylephrine. Paragon analyzed the spiked sample using
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`the currently published USP method and confirmed that the USP method failed to
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`detect the S-phenylephrine known to be present. See Ex. 2014 at 7, reproduced
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`below.
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`10 The study method is USP Monograph – Phenylephrine HCl Ophthalmic
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`Solution (Ex. 2008) and USP Monograph – Phenylephrine HCl Nasal Jelly (Ex.
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`2009). See Ex. 2014 at 1.
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`Case PGR2015-00011
`Patent 8,859,623
`
`The above figure illustrates a chromatograph of the R-form sample spiked
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`with S-phenylephrine. Only a single peak was detected. The S-form, known to be
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`present due to spiking the sample, co-eluted with the R-form as a single peak,
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`rather than elute separately. Paragon’s study was reviewed and the results were
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`corroborated by a third party. See Ex. 2013 at 1 (“S-isomer does indeed coelute
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`directly underneath the Phenylephrine”).
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`The petition never disputes the aspects of the Witham declaration providing
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`that S-form chiral impurity was not reliably detectible using methods pursuant to
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`the currently published USP standard HPLC protocol.11 See Ex. 1002 at 110.
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`11 As explained below, Petitioner attempts to remedy this technical flaw in its
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`case by advancing a strained claim construction – asserting that a composition is
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`chirally pure if Petitioner’s chosen test fails to detect the impurity.
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`

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`Case PGR2015-00011
`Patent 8,859,623
`Petitioner’s Reliance on an Optical Rotation Comparison is
`Misplaced
`
`B.
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`In addition to proffered data generated by testing according to the currently
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`published USP standard HPLC protocol, Petitioner relies upon an optical rotation
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`comparison study as evidence of the chiral purity of “Altaire’s Product.” For
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`example, Ex. 1012 is cited in the petition as a key study performed by Petitioner
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`allegedly showing “Altaire’s Commercial Product” in the form of Lot #11578 as
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`having a chiral purity of 101.5%.12 See e.g., Pet. at p. 10. Petitioner relies on the
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`same optical rotation comparison study throughout the petition in asserting the
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`chiral purity of Lot #11578. See e.g., Pet. at 35, 36, 38, 39, 43, 54 and 55. The
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`optical rotation comparison study, however, is of limited value because, rather than
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`quantitating chiral purity, it merely compares the Lot #11578 sample to a control
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`sample of unknown chiral purity.
`
`As a general matter, while optical rotation methods allow relative sample
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`comparison, they are not specific for quantitative analysis. Optical rotation relies
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`upon “[m]olecules with chiral centers caus[ing] the rotation of plane polarised light
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`and are ... optically active.” Ex. 1001 at 4:40-42 (internal quotation marks
`
`removed). Because “[a] non-racemic mixture of two enantiomers will have a net
`
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`12 The petition identifies “Altaire’s Commercial Product” as “Lot 11578 and
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`Lot 11581 and/or their accompanying Package Insert.” Pet. at p. 37. While Lot
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`#11578 was assessed in Petitioner’s optical rotation study, Lot #11581 was not.
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`See Ex. 1012.
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`
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`Case PGR2015-00011
`Patent 8,859,623
`
`optical rotation [i]t is possible to determine the specific rotation of the mixture.”
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`Ex. 1001 at 4:54-56.
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`Thus, optical rotation methods do not provide quantitative measurements but
`
`rather relative measurements because the calculation to determine the optical
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`purity of a sample relies upon the optical rotation of a control sample. This is
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`particularly relevant in this case because neither the cited study (i.e., Ex. 1012) nor
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`any other of the petition materials establish the chiral purity of the control sample
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`serving as the basis of comparison.
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`In particular, the study presented in Ex. 1012 relies on phenylephrine
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`hydrochloride obtained from Sigma Aldrich as a control. See Ex. 1012 at 3. With
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`respect to this control, the document indicates the “[p]urity factor is 1.00.” Id. No
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`testing is provided to establish the chiral purity of the control. The stated purity
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`characterization is nothing beyond an assumption based on having obtained a
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`control solution from a commercial vendor. Furthermore, no information is
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`provided regarding the handling of the control solution by the vendor, shipping
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`conditions, or handling by Petitioner after it was obtained, including, but not
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`limited to, certain incoming analytical testing. Moreover, there is no information
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`regarding whether the control solution was protected from light exposure, which is
`
`known to cause oxidation, or the thermal conditions to which it was exposed. In
`
`short, the chiral purity of the Sigma control used in study (Ex. 1012) is unknown.
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`Knowing the chiral purity of the Sigma control is critical to drawing any
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`conclusions from the study regarding the absolute chiral purity of Lot #11578. For
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`example, if the control was not pure R-phenylephrine hydrochloride, then the
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`Case PGR2015-00011
`Patent 8,859,623
`
`optical purity of the phenylephrine hydrochloride solution in Lot #11578 would be
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`relative to an impure control. Quite simply, the chiral purity of the Altaire Product
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`sample is unknown.
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`In fact, Petitioner’s data suggests that the R-Phenylephrine control is impure.
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`The “Phenylephrine Hydrochloride Ophthalmic Solution ... is in 101.5%
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`agreement with the Phenylephrine Hydrochloride R (-) control.” (emphasis added).
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`Ex. 1012 at 9. Given the calculations performed to determine optical purity, the
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`sample can only be of greater purity compared to the control when the control
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`itself is impure.13
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`Accordingly, Petitioner’s optical rotation analysis, at best, only provides a
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`relative comparison to a control of unknown chiral purity.
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`V. THE PETITION IS BASED ENTIRELY ON ATTORNEY
`ARGUMENT AND TESTIMONY FROM AN INTERESTED FACT
`WITNESS WHO LACKS EXPERTISE IN THE SUBJECT MATTER
`
`The petition materials include no expert witness testimony. Instead, the
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`petition relies on the testimony of Mr. Assad Sawaya, who is not an expert or even
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`one of ordinary skill in the art, but rather, a fact witness. By his own admission,
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`Mr. Sawaya testifies that he “makes this declaration based upon my personal
`
`knowledge of the facts stated herein.” Ex.1003 at ¶1. Indeed, nothing in the
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`petition claims or supports the notion that Mr. Sawaya is an expert witness or that
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`13 Petitioner appears to recognize that optical rotation is