UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`Altaire Pharmaceuticals, Inc.
`
`Petitioner
`
`v.
`
`Paragon Bioteck, Inc.
`
`Patent Owner
`
`U.S. Patent No. 8,859,623
`Issue Date: October 14, 2014
`Entitled: METHODS AND COMPOSITIONS OF STABLE PHENYLEPHRINE
`FORMULATIONS
`
`____________________
`
`Post-Grant Review No.: Unassigned
`____________________
`
`DECLARATION OF ASSAD SAWAYA
`
`Exhibit 1003- Page 1 of 30
`
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`Altaire Pharmaceuticals, Inc.
`
`Petitioner
`
`v.
`
`Paragon Bioteck, Inc.
`
`Patent Owner
`
`U.S. Patent No. 8,859,623
`Issue Date: October 14, 2014
`Entitled: METHODS AND COMPOSITIONS OF STABLE PHENYLEPHRINE
`FORMULATIONS
`
`____________________
`
`Post-Grant Review No.: Unassigned
`____________________
`
`DECLARATION OF ASSAD SAWAYA
`
`Exhibit 1003- Page 1 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`I, Assad Sawaya, declare as follows:
`
`1.
`
`I am President of Altaire Pharmaceutical, Inc. I make this
`
`declaration based upon my personal knowledge of the facts stated herein.
`
`2.
`
`Altaire manufactured the products that are the subject of the
`
`’623 patent (Phenylephrine HCl Ophthalmic Solution 2.5% and Phenylephrine
`
`HCl Ophthalmic Solution 10%) for various customers, for at least 8 years prior to
`
`the ’623 patent’s filing date. Altaire’s products have consistently had a label
`
`instructing storage in a refrigerator “at 2°-8° C (36°-46° F).” (See, e.g., Exhibits
`
`1004 and 1005 (excerpts reproduced and annotated below)).1
`
`1 Exhibits 1004 and 1005 are dated as approved for print in September 2005 and
`
`December 2004, respectively.
`
`1
`
`Exhibit 1003- Page 2 of 30
`
`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`3.
`
`Labels like those depicted above were provided on Altaire’s
`
`Phenylephrine Hydrochloride Ophthalmic Solution sold and distributed over one
`
`year prior to the ’623 patent’s filing. (See, e.g., Exhibit 1006 at 1 of 3 and 3 of 3
`
`(reproduced and annotated below).
`
`4.
`
`The above depicted product (Lot # 11578 (see id. at 2 of 3))
`
`was sold and distributed over a year prior to the ’623 patent’s earliest filing date.
`
`(See Exhibit 1007). Lot # 11578 was manufactured in December 2011 as a 2.5%
`
`Phenylephrine Hydrochloride Ophthalmic Solution. Lot #11578 had an expiration
`
`2
`
`Exhibit 1003- Page 3 of 30
`
`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`date of December 2013, which means that it would maintain its chirality for
`
`application to the eye when stored at 2°-8° C low temperature storage until that
`
`date. (See Exhibit 1006 at 2 of 3 (noting a date of “12/13” indicating its
`
`expiration date)).
`
`5.
`
`Altaire also sold and distributed a 10% Phenylephrine
`
`Hydrochloride Ophthalmic Solution. (See, e.g., Exhibit 1008 at 1 of 3 and 3 of 3
`
`(reproduced below)).
`
`6.
`
`Lot # 11581 (see id. at 2 of 3)) was sold and distributed over a
`
`year prior to the ’623 patent’s earliest filing date. (See Exhibit 1009). Lot #
`
`11581 was manufactured in January 2012 and had an expiration date of December
`
`3
`
`Exhibit 1003- Page 4 of 30
`
`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`2013, which means that it would maintain its chirality for application to the eye
`
`when stored at 2°-8° C low temperature storage until that date. (See Exhibit 1008
`
`at 2 of 3 (noting a date of “12/13” indicating its expiration date)).
`
`7.
`
`After years of selling its Phenylephrine Hydrochloride
`
`Ophthalmic Solution, Altaire was approached by Paragon’s CEO, Mr. Patrick
`
`Witham, to enter into an agreement dated May 15, 2011 (“Agreement”) whereby
`
`Altaire would provide the Chemistry, Manufacturing and Controls (or CMC)
`
`sections regarding Altaire’s Phenylephrine HCl Ophthalmic Solution product for
`
`the limited purposes of supporting a New Drug Application (or NDA) to be
`
`submitted by Paragon to the Federal Food & Drug Administration (“FDA”).
`
`8.
`
`The Agreement specified that:
`
`a. Altaire’s CMC sections are provided for the limited
`
`purposes of obtaining the NDAs contemplated by the
`
`Agreement;
`
`b. the Altaire information may not be used for any other
`
`purpose; and
`
`c.
`
`it is the specific intent of the parties that the Altaire
`
`information is the proprietary and confidential information
`
`of Altaire,
`
`4
`
`Exhibit 1003- Page 5 of 30
`
`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`9.
`
`Also, as part of the Agreement, Altaire would be Paragon’s
`
`exclusive manufacturer and supplier, and Paragon would purchase Altaire’s
`
`phenylephrine hydrochloride ophthalmic solution at a recited price and be its
`
`exclusive distributor. Paragon submitted its NDA on September 21, 2012. In a
`
`December 2012 Information Request, the FDA requested that the NDA sponsor
`
`“[c]onsider adding a chiral purity test to the drug product specification or provide
`
`a justification for not doing so.” See Exhibit 1010 at 2 of 2. Apparently, the FDA
`
`requested this information knowing that the R-isomer was the biologically active
`
`isomer whereas the S-isomer was not biologically active. In fact, it was known
`
`for decades that the R-isomer of phenylephrine hydrochloride was active while the
`
`S-isomer of phenylephrine hydrochloride was not. (See Exhibit 1011 (U.S. Patent
`
`No. 3,966,749) at 6:21 and 1:28-33 (“R-Phenylephrine is used to dilate the iris . . .
`
`.” and that in “a racemic mixture (a mixture containing both the biologically active
`
`and the biologically non-active isomer) . . . the R isomer is the only isomer
`
`exhibiting therapeutic activity . . . .”)).
`
`10.
`
`In February 2013, Altaire performed a study to assess the chiral
`
`purity of its products after low temperature (2° C to 8° C) storage. Since Altaire
`
`manufactured two products – containing 2.5% (Altaire formula # A0358) and 10%
`
`(Altaire formula # A0359) – Altaire subjected one lot of each formulation to chiral
`
`purity testing. Lot # 11578 (2.5% formula # A0358) and 11582 (10% formula #
`
`5
`
`Exhibit 1003- Page 6 of 30
`
`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`A0359)2, both manufactured in January 2012, and stored under refrigeration (2 C
`
`to 8 C) were tested in Altaire’s cGLP laboratories, and found to have had a chiral
`
`purity of 101.5% and 97.8%, respectively. (See Exhibit 1012 at 8 of 9 (showing
`
`that 2.5% formula A0358 had a chiral purity percentage of 101.5 and showing that
`
`10% formula A0359 had a chiral purity percentage of 97.8); see also id. at 3 of 9
`
`(showing formulation A0358 having R-phenylephrine hydrochloride from
`
`finished product Lot # 11578 and showing formulation A0359 having R-
`
`phenylephrine hydrochloride from finished product Lot 11582)). Altaire
`
`summarized its findings in a report bearing Altaire study number STU0328. (See
`
`generally Exhibit 1012.)
`
`11.
`
`The chiral purity of the samples was tested by obtaining their
`
`specific rotation. (See id. at 3 of 9). Lot # 11578 was found to have a specific
`
`rotation of -47.0. (See id. at 7 of 9). Lot # 11578’s specific rotation was divided
`
`by a control, which had a specific rotation of -46.3, and found to have a chiral
`
`purity of 101.5%. (See id. at 8 of 9). Lot # 11582 was found to have a specific
`
`rotation of -45.5°. (See id.). Lot # 11582’s specific rotation was divided by a
`
`control, which had a specific rotation of -46.5°, and found to have a chiral purity
`
`of 97.8%. (See id.).
`
`2 Lot # 11582 and lot # 11581 are the same formulation, i.e., A0359.
`
`6
`
`Exhibit 1003- Page 7 of 30
`
`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`12.
`
`Prior to testing, Altaire sold and distributed 6,024 units of Lot
`
`11578 of its 2.5% Phenylephrine Hydrochloride Ophthalmic Solution to OcuSoft,
`
`Inc. (Rosenberg, Texas) on October 18, 2012 – more than 1 year prior to the ’623
`
`patent’s filing date. (See Exhibit 1007). Similarly, Altaire sold and distributed
`
`3996 units of Lot # 11581 – the same formulation as Lot # 11582 – of its 10%
`
`Phenylephrine Hydrochloride Ophthalmic Solution to Hub Pharmaceuticals
`
`(Livonia, Michigan) on October 16, 2012 – more than 1 year prior to the ’623
`
`patent’s filing date. (See Exhibit 1009).
`
`13.
`
`Pursuant to the limitations in the Agreement, a confidential
`
`copy of STU0328 (see generally Exhibit 1012) summarizing the chiral purity of
`
`these two lots was provided to Paragon, which submitted a supplementary NDA
`
`filing with the FDA. On March 21, 2013, the FDA granted Paragon’s NDA.
`
`14. On or about April 10, 2013, Altaire received a purchase order
`
`from Paragon, signed by Patrick Witham, for the FDA approved phenylephrine
`
`hydrochloride ophthalmic solution. (See Exhibit 1013 (a purchase order from
`
`Paragon to Altaire).) Paragon issued a second purchase order on or about July 25,
`
`2013 to Altaire for the FDA approved phenylephrine hydrochloride ophthalmic
`
`solution. (See Exhibit 1014 (purchase order from Paragon to Altaire)).
`
`15. On November 14, 2013, Paragon filed the ’711 application
`
`naming Patrick H. Witham, Sailaja Machiraju and Lauren Mackensie-Clark Bluett
`
`7
`
`Exhibit 1003- Page 8 of 30
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`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`as joint inventors. (See Exhibit 1001). On October 14, 2014, the ’623 patent
`
`issued. (Id.) To Altaire’s surprise, Example 1 of the ’623 patent included
`
`Altaire’s confidential and proprietary formulation of its Phenylephrine
`
`Hydrochloride Ophthalmic Solution, including product subject to chiral testing.
`
`16.
`
`It is my understanding that Paragon has listed the ’623 patent in
`
`the FDA publication generally known as the “Orange Book” in connection with
`
`the NDA discussed above, which encompasses Altaire’s Phenylephrine
`
`Hydrochloride Ophthalmic Solution that was previously sold and distributed to
`
`third parties years prior to the ’623 patent’s filing.
`
`17.
`
`The Witham Declaration, which I have reviewed and
`
`understand, purports to compare a room temperature-stored formulation identified
`
`as that described in an Akorn package insert with a low temperature-stored
`
`formulation. (See Exhibit 1002 at 109-110 of 617). Neither the initial chiral
`
`purity of the Akorn formulation nor a chromatogram of the initial formulation was
`
`shown. (See id. at 108-113 of 617).
`
`18.
`
`The chromatogram of the Akorn formulation set forth at the top
`
`of Exhibit 3 of the Witham Declaration shows two unresolved “peaks” having
`
`retention times of 5.222 minutes and 5.481 minutes, respectively, and being
`
`completely eluted at about 5.9 minutes. (See id. at 113 of 617). Both of these
`
`unresolved peaks fall squarely within the range of retention time applicable to the
`
`8
`
`Exhibit 1003- Page 9 of 30
`
`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`R-phenylephrine hydrochloride (5.1-5.5 minutes) and are prior to the retention
`
`time applicable to the S-phenylephrine hydrochloride (6.3-6.4 minutes). (Exhibit
`
`1001 at 2:23-34). Since there is no peak at 6.3-6.4 minutes for the Akorn
`
`formulation (Exhibit 3 of the Witham Declaration), the composition does not
`
`contain any S-phenylephrine, and consequently the chiral purity of the R-
`
`phenylephrine in the Akorn formulation after storage at room temperature is
`
`100%.
`
`19. Mr. Witham asserted that “low temperature storage shows
`
`surprisingly better R-Phenylephrine preservation, when compared to chiral
`
`chromatogram of a commercially available R-Phenylephrine hydrochloride
`
`product and subject to room temperature storage.” (Exhibit 1002 at 109 of 617
`
`(emphasis added)). Contrary to the Examiner’s statement upon allowance, Mr.
`
`Witham did not conclude that the chiral purity of R-Phenylephrine hydrochloride
`
`is better preserved by virtue of low temperature storage. (Id. at 109-110 of 617).
`
`Mr. Witham acknowledged that the “chromatograms . . . show little or no
`
`degradation of R-phenylephrine hydrochloride in both the (i) [Akorn formulation
`
`at room temperature storage] and (ii) [the ’623 patent’s formulation at low
`
`temperature storage].” (Id. at 110 of 617). Since there was no chromatogram of
`
`the Akorn formulation subject to room temperature storage prior to storage, there
`
`is no basis for even asserting that the product after storage exhibited any type of
`
`9
`
`Exhibit 1003- Page 10 of 30
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`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`degradation after storage. (Id. at 109-110, 113 of 617). The two chromatograms
`
`merely show that the products being compared have different formulations.
`
`20.
`
`In addition, the Exhibit 3 chromatogram of the Witham
`
`Declaration is not resolved as required by current Good Laboratory Practice
`
`(cGLP). The chromatogram demonstrates an unresolved doublet peak (or peak-
`
`overlap-with-shoulder), which could be ascribed to a void in the HPLC column.
`
`Alternatively, the cause of the unresolved peak could also be use of an unreliable
`
`HPLC procedure to perform the analysis (i.e. a procedure that does not meet the
`
`required criteria for validation pursuant to USP and ICH guidelines). Therefore,
`
`the doublet peak cannot be relied upon to demonstrate the detection of any S-form
`
`Phenylephrine in the Phenylephrine HCl Ophthalmic Solution drug product
`
`manufactured with R-form Phenylephrine (i.e. the Akorn product) following
`
`storage of such drug product under room temperature conditions. The defects
`
`noted above in the peak shape relied upon by Witham lead one to question
`
`whether the HPLC procedure utilized to support the patent application was
`
`actually validated pursuant to established cGLP. Only results obtained from a
`
`properly validated method can be reasonably relied upon.
`
`21.
`
`In fact, Altaire could not duplicate the results relied upon by the
`
`Witham Declaration. Altaire performed Chiral HPLC studies using its proprietary
`
`and validated HPLC procedure <TMQC-247> (ref.: Validation Report STU0346)
`
`10
`
`Exhibit 1003- Page 11 of 30
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`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`to determine the impact of storage at room temperature upon the Phenylephrine
`
`HCl Ophthalmic Solution drug product manufactured with R-form Phenylephrine.
`
`The studies demonstrated that following storage of such drug product under room
`
`temperature conditions does not result in the subsequent presence of any S-form
`
`Phenylephrine in the Phenylephrine HCl Ophthalmic Solution drug product
`
`manufactured with R-form Phenylephrine.
`
`22.
`
`Exhibit 1015 illustrates the results of a Chiral HPLC study on
`
`the Akorn Phenylephrine HCl 2.5% and 10% Ophthalmic Solution (the same
`
`commercial product as referenced and tested in Witham’s patent application),
`
`compared side-by-side with a chromatogram of the USP reference standard for the
`
`Phenylephrine drug substance (containing both R-form and S-form
`
`Phenylephrine).
`
`23.
`
`The Akorn sample was prepared at 1000 µg/mL and the USP
`
`standard at 100 µg/mL. The chromatography for the USP standard shows the R-
`
`Phenylephrine peak appearing at a retention time of 7.8 minutes and the S-
`
`Phenylephrine peak appearing at a retention time of 9.2 minutes. The S-
`
`Phenylephrine peak is well-resolved with respect to the R-Phenylephrine peak,
`
`with a resolution of 2.5. By comparison, the chromatography for the Akorn
`
`samples shows the R-form Phenylephrine presenting in abundance, while the S-
`
`Phenylephrine peak is Not Detected in Akorn’s Phenylephrine HCl Ophthalmic
`
`11
`
`Exhibit 1003- Page 12 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`Solution 2.5% and 10% following storage for 40 months under room temperature
`
`conditions (20° C to 25° C). (See id.; see also Table 1 below). Given that the
`
`expiry period for the product is 24 months, this is a truly rugged challenge. From
`
`this data one can conclude that, contrary to the data presented by the Witham
`
`Declaration, storage of Phenylephrine HCl Ophthalmic Solution drug product
`
`manufactured with R-form Phenylephrine (i.e. the Akorn product) under room
`
`temperature conditions does not result in subsequent presence of the S-form
`
`Phenylephrine in the drug product.
`
`Table 1: Summary of Chiral Analysis
`
`(Average of Two Injections)
`
`Akorn Phenylephrine HCl Ophthalmic Solution
`
`Product
`
`Akorn Lot#
`
`Phenylephrine 2.5%
`
`Phenylephrine 10%
`
`091281
`
`081431
`
`Stability Condition
`
`40 mos Room Temp
`
`40 mos Room Temp
`
`R-form Peak Area
`
`10098269
`
`R-form Percentage
`
`S-form Peak Area
`
`S-form Percentage
`
`100%
`
`N/D
`
`0%
`
`12
`
`7774604
`
`100%
`
`N/D
`
`0%
`
`Exhibit 1003- Page 13 of 30
`
`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`24.
`
`Exhibit 1016 illustrates the results of a Chiral HPLC study on
`
`Altaire’s proprietary formulation for Phenylephrine HCl Ophthalmic Solution
`
`2.5% & 10%3 after being held under room temperature storage conditions for 37
`
`to 42 months, compared side-by-side with a chromatogram of the USP reference
`
`standard for the Phenylephrine drug substance (containing both R-form and S-
`
`form Phenylephrine).
`
`25.
`
`The Altaire sample was prepared at 100 µg/mL, as was the USP
`
`standard. In the Altaire product the R-Phenylephrine peak appears at a retention
`
`time of 7.7 minutes and S-Phenylephrine peak appears at a retention time of 9.1
`
`minutes, which is substantially similar to the retention times in the Akorn product.
`
`(Compare Exhibits 1015 and 1016). In the Altaire product analysis, the R-
`
`Phenylephrine was found to occupy the Total Area (100%) and S-Phenylephrine
`
`is Not Detected in all challenged stability samples. (See Exhibit 1016). Given
`
`that the expiry period for the product is 24 months, this is a truly rugged
`
`challenge. As shown in Exhibit 1016 (and Tables 2 and 3 below) storage of
`
`Phenylephrine HCl Ophthalmic Solution drug product manufactured with R-form
`
`Phenylephrine (i.e. the Altaire product formulation) under room temperature
`
`3 This is the same formulation improperly appropriated by and disclosed in the
`
`’623 patent.
`
`13
`
`Exhibit 1003- Page 14 of 30
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`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`conditions does not result in subsequent presence of the S-form Phenylephrine in
`
`the drug product.
`
`Table 2: Summary of Chiral Analysis
`
`(Average of Two Injections)
`
`Altaire Phenylephrine HCl Ophthalmic Solution 2.5%
`
`Lot#
`
`11302
`
`11577
`
`11578
`
`42 mos Room
`
`37 mos Room
`
`37 mos Room
`
`Temp
`
`1022912
`
`100%
`
`N/D
`
`0%
`
`Temp
`
`1022568
`
`100%
`
`N/D
`
`0%
`
`Stability Condition
`
`Temp
`
`R-form Peak Area
`
`1012144
`
`R-form Percentage
`
`S-form Peak Area
`
`S-form Percentage
`
`100%
`
`N/D
`
`0%
`
`Table 3: Summary of Chiral Analysis
`
`(Average of Two Injections)
`
`Altaire Phenylephrine HCl Ophthalmic Solution 10%
`
`Lot#
`
`11323
`
`11581
`
`11582
`
`Stability Condition
`
`R-form Peak Area
`
`42 mos Room
`
`37 mos Room
`
`37 mos Room
`
`Temp
`
`974762
`
`Temp
`
`982172
`
`Temp
`
`1006006
`
`14
`
`Exhibit 1003- Page 15 of 30
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`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`R-form Percentage
`
`S-form Peak Area
`
`S-form Percentage
`
`100%
`
`N/D
`
`0%
`
`100%
`
`N/D
`
`0%
`
`100%
`
`N/D
`
`0%
`
`26.
`
`Exhibit 1017 illustrates the results of a further Chiral HPLC
`
`study on Altaire’s proprietary formulation for Phenylephrine HCl Ophthalmic
`
`Solution 2.5%. Specifically, a fresh preparation of the formula was manufactured
`
`under commercial conditions, then challenged with various heat exposures as
`
`follows: exposed to 40°C, 55°C, 80°C, and 122°C.
`
`27.
`
`The Altaire samples were again prepared at 100 µg/mL, as was
`
`the USP standard. The R-Phenylephrine peak appears at a retention time of 7.6
`
`minutes (which is substantially similar to the retention time found for the Altaire
`
`stability samples) and the S-Phenylephrine peak appears again at a retention time
`
`of 9.1 minutes. (See Exhibit 1017). A summary of all the treated samples studied
`
`is shown in Table 4 below.
`
`Table 4: Summary of Chiral Analysis
`
`(Average of Two Injections)
`
`Altaire Phenylephrine HCl Ophthalmic Solution 2.5%
`
`Product
`
`Phenylephrine 2.5%
`
`15
`
`Exhibit 1003- Page 16 of 30
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`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`Lot#
`
`Heat
`
`(exposure
`
`temp)
`
`Duration
`
`R-form
`
`Peak Area
`
`R-form
`
`Percentage
`
`S-form
`
`Peak Area
`
`S-form
`
`Percentage
`
`15040, fresh prepared
`
`Control
`
`(no
`
`exp.)
`
`40°C
`
`55°C
`
`80°C
`
`80°C
`
`80°C
`
`122°C
`
`4 Days
`
`4 Days
`
`1 Day
`
`2 Days
`
`3 Days
`
`35 min.
`
`1001298 1007044 1003124 1013856 1008655 997326 1007865
`
`99.86% 99.86% 99.86% 99.85% 99.85% 99.84% 99.84%
`
`1356
`
`1422
`
`1437
`
`1576
`
`1525
`
`1643
`
`1640
`
`0.14%
`
`0.15%
`
`0.15%
`
`0.16%
`
`0.15% 0.17% 0.17%
`
`28. As shown above and in Exhibit 1017, the peak area is
`
`dominantly composed of R-form Phenylephrine, i.e., from 99.84% to 99.86% for
`
`all Heat exposed samples (challenge samples) and Control (without heat exposure)
`
`samples. A small amount of S-form Phenylephrine was recovered from both the
`
`Heat exposed and Control samples, ranging from 0.14% (Control) to 0.17% (80°C
`
`for 3 Days and the maximum exposure of 122°C for 35 minutes). Upon review,
`
`16
`
`Exhibit 1003- Page 17 of 30
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`
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`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
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`the S-Phenylephrine peak areas are most probably attributable to the initial carry-
`
`over of the small amount of S-form found in the Phenylephrine HCl active
`
`pharmaceutical ingredient (or raw material). Accordingly, the data demonstrates
`
`that heat exposure is not a significant factor for converting R-Phenylephrine to S-
`
`Phenylephrine in the drug product. Therefore, the stability of the R-form
`
`Phenylephrine within the Phenylephrine HCl Ophthalmic Solution drug product
`
`manufactured with R-form Phenylephrine is not reliant on storage under
`
`refrigerated conditions (2° C-8° C).
`
`29.
`
`The ’623 patent claims that the inventors “surprisingly”
`
`discovered that S-Phenylephrine dilated the eye only slightly more than an
`
`untreated eye. (See the ’623 patent at 6:28-33.) The named inventors claim that
`
`an eye drop for pupil dilation need contain predominantly R-isomer Phenylephrine
`
`hydrochloride to maximize “efficacy of the ophthalmic solution.” (Id.) It had
`
`been known for decades that the R enantiomer of phenylephrine hydrochloride
`
`was active while the S enantiomer of phenylephrine hydrochloride was not. (See
`
`Exhibit 1011 (U.S. Patent No. 3,966,749) at 6:21 and 1:28-33(“R-Phenylephrine
`
`is used to dilate the iris . . . .” and that in “a racemic mixture (a mixture containing
`
`both the biologically active and the biologically non-active isomer) . . . the R
`
`isomer is the only isomer exhibiting therapeutic activity . . . .”)).
`
`17
`
`Exhibit 1003- Page 18 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`30. At the effective filing date of the ’623 patent, one of ordinary
`
`skill in the art would possess at least three years of experience in the
`
`pharmaceutical arts, or a bachelor’s degree in pharmaceutically related arts.
`
`31.
`
`I understand that the PTO interprets terms of a claim under their
`
`broadest reasonable interpretation in light of the specification, as understood by
`
`one of ordinary skill in the art. I understand that I am providing what I believe are
`
`the broadest reasonable interpretations in light of the specification, as understood
`
`by one of ordinary skill in the art for the following terms and phrases for purposes
`
`of these proceedings only.
`
`32. Chiral purity is the amount of a particular enantiomer expressed
`
`as a percentage of all enantiomers present. (See the ’623 patent at 2:18-32.) If
`
`there are two enantiomers and the presence of only one can be detected, the chiral
`
`purity of the present enantiomer is 100%. The ’623 patent describes that the
`
`buffer is responsible for “maintaining the chiral purity of R-phenylephrine
`
`hydrochloride for at least 6 months . . . .” (Exhibit 1001 at 3:8-17). Further, claim
`
`1 recites, “wherein the chiral purity of R-phenylephrine hydrochloride is at least
`
`95% of the initial chiral purity after 6 months.” Thus, in light of the ’623 patent
`
`specification and claim language, one skilled in the art would understand “initial
`
`chiral purity” to be the chiral purity of a composition prior to any storage.
`
`18
`
`Exhibit 1003- Page 19 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`33.
`
`The broadest reasonable interpretation of the phrase “wherein
`
`the chiral purity of R-phenylephrine hydrochloride is at least 95% of the initial
`
`chiral purity after 6 months” is that the chiral purity of the composition after six
`
`months of storage was at least 95% of the chiral purity prior to storage. Any
`
`chiral purity obtained after more than six months of storage which is at least 95%
`
`of the chiral purity obtained prior to storage will satisfy this limitation given the
`
`fact that the specification includes descriptions of purity after longer periods of
`
`time.
`
`34.
`
`The broadest reasonable interpretation of the above clause is
`
`applying the claimed composition into an eye, wherein prior to applying the
`
`composition, it is stored at any time, and for any duration at between -10 to 10 °C.
`
`35. As discussed above, Altaire had been manufacturing, selling
`
`and distributing phenylephrine hydrochloride ophthalmic solution for several
`
`years prior to the filing of the ’711 application that eventually issued as the ’623
`
`patent. (See, e.g., Exhibits 1004, 1005, 1006, 1007, 1008 and 1009).
`
`36.
`
`Two of those lots included Lot # 11578 (manufactured in
`
`December 2011) and Lot # 11581 (manufactured in January 2012). Lot # 11578
`
`was sold and distributed to Altaire’s customer, OcuSoft Inc. (Rosenberg, Texas)
`
`on or about October 18, 2012. (See Exhibit 1007). Lot # 11581 was sold and
`
`distributed to Altaire’s customer Hub Pharmaceuticals (Livonia, Michigan) on
`
`19
`
`Exhibit 1003- Page 20 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`October 16, 2012. Each unit of these two lots shipped to either OcuSoft or Hub
`
`Pharmaceuticals included a package insert (“Package Insert”) indicating its
`
`intended use, reading in relevant part:
`
`(See Exhibit 1018 (Package Insert) at 1 of 2 (emphasis added)). The Package
`
`Insert also provided the contents of each unit, which read in relevant part:
`
`(Id.) The Package Insert further instructed storage at 2° C to 8° C. (Id. at 2 of 2
`(reproduced below)).
`
`37.
`
`Lot # 11578 had a chiral purity of R-phenylephrine of
`
`essentially 100%.4 (See Exhibit 1012 at 8 of 9). Because the R-form chiral purity
`
`4 As discussed above, the cited Study actually states that the chiral purity of the
`
`sample of Lot 11578 was over 100% based on a specific rotation value of -47.0° as
`
`20
`
`Exhibit 1003- Page 21 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`after cold storage of at least 6 months (in fact, over 13 months) was found to be
`
`essentially 100%, it is my opinion that the initial R-form chirality was also
`
`essentially 100%. Further, even after storage at room temperature for 37 months,
`
`there was no S-phenylephrine detected in Lot # 11578. (See Table 2 above).
`
`HPLC analysis of lot # 11578 for chiral purity after 37 months reported an R-form
`
`chiral purity of essentially 100% and did not detect the S-form.5 (Id.) This is
`
`consistent with chiral tests conducted on a freshly prepared lot (Lot 15040), which
`
`had an initial (prior to any storage) chiral purity of 99.86%. (See Exhibit 1017).
`
`Lot # 15040 was then subjected to various heat exposures (see id) and analyzed by
`
`HPLC for chiral purity. In all cases the chiral purity results demonstrated that
`
`heat exposure does not convert the R-form phenylephrine to the S-form; the
`
`stability of the R-form phenylephrine within the Phenylephrine HCl Ophthalmic
`
`Solution drug product is not reliant on storage under low temperature/refrigerated
`
`compared with a specific rotation value of -46.3° of a 25 mg/mL control sample.
`
`(See Exhibit 1012 at 4 of 9)
`
`5 Altaire’s HPLC method for chiral purity testing was validated pursuant to
`
`established United States Pharmacopeia guidelines (USP <1225> Validation of
`
`Compendial Procedures) and ICH guidelines (Q2B ‘Validation of Analytical
`
`Procedures – Methodology.)
`
`21
`
`Exhibit 1003- Page 22 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`conditions (2° C - 8° C). The above summarized chiral data demonstrates that the
`
`storage conditions to which the drug product is subjected do not impact on the
`
`chiral purity of the drug product.
`
`38.
`
`Lot # 11581 similarly had a chiral purity of R-phenylephrine of
`
`essentially 100%.6 (See Exhibit 1019). Because the R-form chiral purity after
`
`cold storage of at least 6 months (in fact, over 12 months) was found to be
`
`essentially 100% (“ND” meaning none detected), it is my opinion that the initial
`
`R-form chirality was also essentially 100%. Further, even after storage at room
`
`temperature for 37 months, there was no S-phenylephrine detected in Lot # 11581.
`
`(See Table 3 above).
`
`39. Altaire’s Package Insert states:
`
`(Exhibit 1018 at 2 of 2.)
`
`6 As discussed above, the cited Study actually states that the chiral purity of the
`
`sample of Lot 11578 was over 100% based on a specific rotation value of -47.0° as
`
`compared with a specific rotation value of -46.3° of a 25 mg/mL control sample.
`
`(See Exhibit 1012 at 4 of 9)
`
`22
`
`Exhibit 1003- Page 23 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`40. Altaire’s Commercial Product disclosed storage of R-
`
`phenylephrine hydrochloride in an aqueous buffer at a temperature in the range of
`
`2° C to 8° C. (Exhibit 1018 at 2 of 2 (reproduced below, in part).)
`
`41.
`
`In addition, Altaire’s Commercial Product Lot # 11578 and Lot
`
`# 11581 sold and distributed prior to the ’623 patent’s earliest filing date had an
`
`approximately 24-month expiration date from the date of manufacture (or
`
`December 2013 expiration date). Accordingly, Altaire’s Commercial Product
`
`would maintain its chiral purity for application to the eye after being stored at 2°-
`
`8° C for nearly two years.
`
`42. Altaire’s Package Insert included R-phenylephrine
`
`hydrochloride in 2.5% w/v and 10% w/v. (See Exhibit 1018 at 2 of 2 (reproduced
`
`below, in part)).
`
`23
`
`Exhibit 1003- Page 24 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`43. Altaire’s Commercial Product was available in 5 mL and 15
`
`mL plastic opaque bottles. (See Exhibit 1018 at 2 of 2 (reproduced below, in
`
`part); see also Exhibits 1006 and 1008 above)).
`
`44. Altaire’s Package Insert was publicly available by August 2010.
`
`(See Exhibit 1018 at 2 of 2 (showing a “Revised” date of “August 2010”)).
`
`Altaire’s Package Insert includes a description of its ingredient:
`
`(Id. at 1 of 2.) (-) m-Hydroxy-α-[(methylamino)methyl] benzyl alcohol
`hydrochloride is the same chemical as R-phenylephrine hydrochloride. S-
`phenylephrine hydrochloride (which would have a (+) designation) is not listed in
`the Package Insert.
`
`24
`
`Exhibit 1003- Page 25 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`45. One of ordinary skill in the art would have known that since the
`
`Altaire Phenylephrine HCl Ophthalmic Solution Package Insert does not list the
`
`S-enantiomer of phenylephrine hydrochloride as an ingredient, that the Package
`
`Insert contained only the R enantiomer, corresponding to essentially a 100%
`
`purity.
`
`46.
`
`In addition, one of ordinary skill in the art would have had
`
`known for decades before the filing date of the ’623 patent that the R-enantiomer
`
`of phenylephrine hydrochloride was active while the S-enantiomer of
`
`phenylephrine hydrochloride was not. For example, U.S. Patent No. 3,966,749
`
`(the ’749 patent), filed in 1975, explains that “a racemic mixture” is “a mixture
`
`containing both the biologically active and the biologically non-active isomer.”
`
`(Exhibit 1011 at 1:29-31 (emphasis added).) The ’749 patent continues that the
`
`“R isomer is the only isomer exhibiting therapeutic activity.” (Id. at 1:31-33
`
`(emphasis added).) Accordingly, whenever the detailed description of an
`
`ophthalmic formulation stated the R-phenylephrine hydrochloride was present,
`
`one of ordinary skill in the art would have recognized that the S-enantiomer was
`
`absent, and that the chiral purity was essentially 100%.
`
`47. One of ordinary skill in the art would have been motivated to
`
`obtain an ophthalmic solution for pupil dilation from raw material (or active
`
`pharmaceutical ingredient (or API)) comprising an essentially pure R-form
`
`25
`
`Exhibit 1003- Page 26 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`phenylephrine hydrochloride. An essentially pure R-phenylephrine hydrochloride
`
`starting material was commercially available through, for example, Syn-Tech
`
`Chem. & Pharm. Co., Ltd. Altaire tested five lots of the API manufactured by
`
`Syn-Tech – including one lot used to manufacture both Lot # 11578 and Lot #
`
`11581 discussed above – using Altaire’s HPLC method (Altaire test method
`
`TMQC-247)7 which returned R-form phenylephrine ranging from 99.17% to
`
`100%. (See Exhibit 1020 (reproduced below, in part)). Altaire’s data
`
`demonstrates that the Syn-Tech API’s R-form chiral purity is greater than 99% for
`
`each lot. Therefore, the Syn-Tech API utilized by Altaire to manufacture its drug
`
`product has been confirmed to be a pure R-form Phenylephrine HCl starting
`
`material.
`
`7 Altaire’s HPLC method can detect the S-isomer at concentrations of less that
`
`0.1%.
`
`26
`
`Exhibit 1003- Page 27 of 30
`
`
`
`U.S. Patent No. 8,859,623
`Petition for Post Grant Review
`
`48. One of ordinary skill in the art would have understood that the
`
`chiral purity of the composition
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