throbber
UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`ALTAIRE PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`PARAGON BIOTECK, INC.,
`Patent Owner.
`
`_____________________________
`
`Case PGR2015-00011
`Patent No. 8,859,623
`
`_____________________________
`
`
`
`DECLARATION OF GOJKO LALIC, PH.D.
`
`
`
`
`PARAGON - EXHIBIT 2016
`
`

`
`
`
`
`
`TABLE OF CONTENTS
`TABLE OF CONTENTS
`
`I.
`
`QUALIFICATIONS ........................................................................................... 1
`QUALIFICATIONS ......................................................................................... .. 1
`
`II.
`
`SCOPE OF WORK ............................................................................................ 2
`SCOPE OF WORK .......................................................................................... ..2
`
`III.
`III.
`
`SUMMARY OF OPINIONS ................................................................................. 2
`SUMMARY OF OPINIONS ............................................................................... ..2
`
`IV. PERSON OF ORDINARY SKILL IN THE ART ....................................................... 4
`IV.
`PERSON OF ORDINARY SKILL IN THE ART ..................................................... ..4
`
`V. ALTAIRE HAS NOT ESTABLISHED THE ENANTIOMERIC PURITY OF THE
`ALTAIRE HAS NOT ESTABLISHED THE ENANTIOMERIC PURITY OF THE
`ALTAIRE PRODUCT ........................................................................................ 5
`ALTAIRE PRODUCT ...................................................................................... ..5
`
`VI. THE USP METHOD IS INCAPABLE OF SEPARATING PHENYLEPHRINE
`VI.
`THE USP METHOD IS INCAPABLE OF SEPARATING PHENYLEPHRINE
`ENANTIOMERS ............................................................................................. 15
`ENANTIOMERS ........................................................................................... .. 15
`
`VII. CONCLUDING STATEMENTS .......................................................................... 18
`VII.
`CONCLUDING STATEMENTS ........................................................................ .. 18
`
`VIII. APPENDIX – LIST OF EXHIBITS ..................................................................... 19
`VIII.
`APPENDIX — LIST OF EXHIBITS ................................................................... .. 19
`
`
`-i-
`
`

`
`
`
`I, Gojko Lalic, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1. My name is Gojko Lalic. I am an Assistant Professor at the
`
`University of Washington (“UW”). I received my B.S. in Chemistry from the
`
`University of Belgrade in 1998 and my Ph.D. in Organic Chemistry from Harvard
`
`University in 2004.
`
`2.
`
`Following completion of my Ph.D. thesis, I was a post-doctoral
`
`research fellow for two years at the University of California, Berkeley and an
`
`additional two years at Harvard University. During this time, I was heavily
`
`involved in the development of enantioselective synthetic methods.
`
`3.
`
`In 1998 I joined UW as an Assistant Professor. At UW I lead a
`
`research group devoted to the development of new methods for the synthesis of
`
`organic molecules, including the synthesis of enantioenriched chiral molecules. I
`
`have supervised numerous Ph.D. and post-doctoral research fellows in my
`
`laboratory.
`
`4.
`
`I am the author or co-author of 30 peer-reviewed publications in
`
`synthetic organic chemistry and enantioselective synthesis. I have presented
`
`lectures on the development of new reactions for the synthesis of organic
`
`molecules at academic conferences and been an invited lecturer at universities and
`
`pharmaceutical companies.
`
`5.
`
`I have received awards based on the high quality of my scientific
`
`research, including a Career Award from the National Science Foundation.
`
`6.
`
`A copy of my curriculum vitae is attached as Exhibit 2017.
`
`1
`
`

`
`
`
`II.
`
`SCOPE OF WORK
`
`7.
`
`I understand that a petition was filed with the United States Patent and
`
`Trademark Office for post-grant review of U.S. Patent No. 8,859,623 (“the ’623
`
`patent,” Ex. 1001).
`
`8.
`
`I further understand that the Patent Trial and Appeal Board (“PTAB”
`
`or the “Board”) has decided to institute post-grant review of claims 1-13 of the
`
`’623 patent under 35 U.S.C. § 103 based on Lot #11578 and #11581 of
`
`phenylephrine hydrochloride ophthalmic solution allegedly produced and sold by
`
`Altaire (“the Altaire Product”).
`
`9.
`
`I have been specifically asked to provide my expert opinion on the
`
`experiments that purport to establish the chiral purity of the Altaire Product. (Exs.
`
`1012, 1015-1017, 1019, 1020). I have further been asked to provide my opinion
`
`on the HPLC experiments presented by Paragon in support of their Patent Owner
`
`Response. In connection with this analysis, I have also been asked to review the
`
`’623 patent as well as the declaration of Altaire’s President, Mr. Sawaya. (Ex.
`
`1001, 1003).
`
`III. SUMMARY OF OPINIONS
`
`10.
`
`In my opinion the HPLC data submitted by Altaire in the Petition
`
`(including what is shown in Ex. 1016) is insufficient to establish the chiral purity
`
`of the Altaire Product in terms of both initial purity and purity following storage.
`
`Exhibit 1016 is the only exhibit that presents chromatograms for samples of the
`
`Altaire Product.
`
`-2-
`
`

`
`
`
`11. There are numerous deficiencies with the HPLC data presented,
`
`including a lack of any accompanying experimental and methodological detail;
`
`however, in my analysis I have focused primarily on the lack of controls. The lack
`
`of experimental controls presented with the HPLC data regarding the purity of the
`
`Altaire Product renders the submitted experiments incapable of supporting an
`
`assertion of at least 95% optical purity of the tested Altaire Product.
`
`12.
`
`I have also reviewed the optical rotation analysis provided by Altaire
`
`and the corresponding exhibits. In my opinion, those materials provided by Altaire
`
`fail to establish the chiral purity of the Altaire Product in terms of both initial
`
`purity and purity following storage.
`
`13.
`
`In my experience and opinion, optical rotation measurements are
`
`highly variable, and as a result, are generally not used to accurately determine
`
`chiral purity of a sample. In agreement with this general limitation of the optical
`
`rotation measurement is the stated accuracy limitation of the optical rotation assay
`
`reported in Exhibit 1012. According to Altaire’s statement this assay only allows
`
`estimation of optical purity within ±6%. Thus, Altaire’s optical rotation
`
`measurements cannot establish that the chiral purity of the Altaire Product is at
`
`least 95%. The second problem with the polarimetry data submitted by Altaire is
`
`the purity of the phenylephrine control used in calculating optical purity of the
`
`Altaire Product. The optical purity if the control sample is either unknown or not
`
`specified. The basis for my opinions is discussed in detail below.
`
`-3-
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`

`
`
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`
`14.
`
`I understand that the application that led to the ’623 patent was filed
`
`on November 14, 2013.
`
`15.
`
`I have been advised that “a person of ordinary skill in the relevant
`
`field” is a hypothetical person to whom one could assign a routine task with
`
`reasonable confidence that the task would be successfully carried out. I have been
`
`advised that the relevant timeframe is prior to November 14, 2013.
`
`16. By virtue of my education, experience, and training, I am familiar
`
`with the level of skill in the art of the ’623 patent prior to November 14, 2013.
`
`17.
`
`In my opinion, a person of ordinary skill in the relevant field prior to
`
`November 14, 2013 would include someone who had a Master of Science degree
`
`in Chemistry and had at least two years of experience in analytical chemistry
`
`techniques.
`
`18. A person of ordinary skill in the relevant field would further have a
`
`working knowledge of analytical chemistry techniques for determining purity of
`
`pharmaceutical compounds, including techniques useful for establishing chiral
`
`purity.
`
`
`
`-4-
`
`

`
`
`
`V. ALTAIRE HAS NOT ESTABLISHED THE ENANTIOMERIC PURITY OF THE
`
`ALTAIRE PRODUCT
`A.
`
`Phenylephrine stereochemistry
`
`19. Phenylephrine contains one chiral center. Because the molecule
`
`contains one chiral center, it has two stereochemical forms, called enantiomers,
`
`designated as R- or S-form.
`
`20. The two enantiomeric forms of phenylephrine, in standard chemical
`
`nomenclature, may be referred to as (R)-3-(1-hydroxy-2-
`
`(methylamino)ethyl)phenol and (S)-3-(1-hydroxy-2-(methylamino)ethyl)phenol.
`
`The compounds may be drawn as shown below.
`
`
`
`
`
`The two forms have the same physical properties (UV spectrum, Nuclear
`
`Magnetic Resonance (NMR) spectrum, melting point, etc). However, they have
`
`-5-
`
`

`
`
`
`different chiroptical properties and they may interact differently with other chiral
`
`compounds.
`
`21. Racemic mixtures contain an equal amount of R and S enantiomers of
`
`a compound.
`
`22. Chemical compounds may also be referred to by Chemical Abstract
`
`Service (CAS) registry number which allows for the unique identification of
`
`compounds, as well as their different forms, including both enantiomers and
`
`racemic mixtures. The CAS registry numbers for the hydrochloride salts of the R-
`
`and S- forms of phenylephrine are 61-76-7 and 939-38-8, respectively.
`
`23. According to the ’623 patent and the Witham declaration, submitted
`
`during prosecution of the ’623 patent (Ex. 1002, pp. 108-113), the R-form
`
`phenylephrine is much more pharmacologically active than the S-form of
`
`phenylephrine. Ex. 1001, 7:1-7; Ex. 1002, p. 111
`
`24. The R-form of phenylephrine hydrochloride obtained by Altaire from
`
`Sigma-Aldrich and used in the polarimetry experiment (Ex. 1012) was designated
`
`as lot P6126. P6126 is actually a product number. (Ex. 2019). The Sigma-Aldrich
`
`catalog indicates that this product is ≥99% pure. (Ex. 2019). The Sigma-Aldrich
`
`catalog does not indicate how purity of this product was determined or the
`
`chemical form of the impurities. Altaire does not describe storage conditions of
`
`the Sigma-Aldrich product after it was obtained. Altaire reports no testing of the
`
`Sigma-Aldrich product to assess purity.
`
`
`
`-6-
`
`

`
`
`
`B. HPLC-based analytic methods
`
`25. A mixture of chemicals may be analyzed using a technique known as
`
`high-performance liquid chromatography (HPLC). HPLC uses pumps to create a
`
`pressurized flow of solvent over a column filled with a solid packing material.
`
`Samples are injected onto the column and compounds within the sample are
`
`separated based on differences in their adsorption1 properties. Differences in
`
`adsorption properties manifest as differences in elution time from a column. The
`
`elution of compounds from a column may be monitored using absorption of UV
`
`light. UV absorption over time produces a chromatogram with peaks that may
`
`correspond to individual compounds within the mixture.
`
`26. The elution profile for a given sample is dependent on experimental
`
`conditions. The solid packing material in the column, mobile phase (solvent), flow
`
`rate, and temperature are factors that influence adsorption of compounds onto the
`
`column and hence elution time.
`
`27. Assignment of chromatogram peaks to individual compounds within a
`
`sample typically involves either upstream HPLC validation experiments employing
`
`known compound controls or downstream specific identification methods.
`
`Experiments that employ neither upstream validation methods nor downstream
`
`specific identification methods cannot reliably assign compounds to peaks.
`
`28. A validation experiment may take the form of a series of three HPLC
`
`runs. If the validation experiment was done in order to demonstrate separation of
`
`
`1 Adsorption refers to the adhesion of molecules to a solid surface.
`
`-7-
`
`

`
`
`
`enantiomers it may be performed as follows. In the first run, a highly enriched
`
`sample of S-form is injected onto a column. The elution profile of the highly
`
`enriched S-form would then be obtained. In the second run, a highly enriched
`
`sample of R-form is injected onto a column. The elution profile of the highly
`
`enriched R-form would then be obtained. A third HPLC run would then be
`
`performed with a racemic mixture of the compound (i.e. one containing an equal
`
`amount of enantiomers of a compound). By performing these three HPLC runs,
`
`the elution time of each enantiomer would be determined. The final chromatogram
`
`for the racemic mixture should have two elution peaks at the elution times for each
`
`enantiomer. Proper assignment is confirmed by assessing whether the area under
`
`each peak is proportional to the concentration of the enantiomer in the sample.
`
`29. The USP Monograph describes methods for determining the chiral
`
`purity of phenylephrine samples, including an HPLC method. (Exs. 2009; 2010).
`
`In brief, the method uses a non-polar achiral column packing material, octadecyl
`
`silane, commonly referred to as C-18. The mobile phase is a 1:1 mixture of
`
`methanol and water and contains 1.1 g of sodium 1-octanesulfonate per liter. The
`
`pH of the mobile phase is adjusted to a pH of 3.0 with phosphoric acid. The flow
`
`rate is about 1 mL per minute.
`C. Altaire HPLC chromatograms
`
`30.
`
`I have reviewed the HPLC chromatograms Altaire submitted with
`
`their Petition for post-grant review as well as the declaration of Mr. Sawaya that
`
`describes the experiments. (Ex. 1003; 1015-1017).
`
`-8-
`
`

`
`
`
`31. The experiments aimed at determining optical purity of the Altaire
`
`Product described in Exhibit 1003 and displayed in Exhibits 1015-1017 do not
`
`contain sufficient experimental details to draw any meaningful information or
`
`conclusions. For example, it lacks description of even the most basic details of the
`
`method employed in generating the data.
`
`32.
`
` Altaire indicates that some of the HPLC experiments were done using
`
`HPLC procedure “<TMQC-247> (ref.: Validation Report STU0346).” (Ex. 1003 ¶
`
`20). I do not know what this procedure entails because it is apparently
`
`“proprietary” and the details were not included in the materials available to me.
`
`(Exs. 1003, 1020). Furthermore, there is no indication that all HPLC runs were
`
`performed using “<TMQC-247> (ref.: Validation Report STU0346).”
`
`33. Where Altaire does provide further information regarding their HPLC
`
`method, they reference USP guidelines. For example, Altaire indicates that their
`
`“HPLC method for chiral purity testing was validated pursuant to established
`
`United States Pharmacopeia [USP] guidelines.” (Ex. 1003, pg. 21, footnote 5). As
`
`shown in the section below this method is not capable of separating enantiomers of
`
`phenylephrine.
`
`34. Reproducibility of HPLC experiments is dependent on the procedural
`
`details. Among other variables, column packing material and mobile phase
`
`influence the elution profile of compounds from an HPLC column. Because the
`
`details of the HPLC procedure were not provided, I am not able to assign any
`
`significance to Altaire’s reported results or draw any meaningful conclusions. (Ex.
`
`1003 ¶ 21).
`
`-9-
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`

`
`
`
`35. The ability to interpret phenylephrine chromatograms is dependent on
`
`proper assignment of a peak to an enantiomer and requires either control
`
`experiments, such as the experiments with authentic samples of individual
`
`enantiomers and the racemic mixture I described above, or downstream analytical
`
`techniques that unambiguously identify the compound(s) present in a
`
`chromatogram peak. Neither type of control was present in the materials I
`
`reviewed. (Exs. 1015-1017). Without experimental controls, it is impossible to
`
`determine if an HPLC method is capable of separating R- and S-forms of
`
`phenylephrine.
`
`36. Control experiments performed by Altaire do not provide sufficient
`
`validation for the method used. The problem is that samples with independently
`
`verified content of R and S enantiomers of a compound have not been used.
`
`Considering reliable access to pure samples of both enantiomers and the racemic
`
`mixture of the compound, the control experiments necessary for method validation,
`
`such as the one described in above, are straightforward and their absence is
`
`confusing.
`
`37.
`
`In summary, neither Exhibits 1015-1017 nor the declaration of Mr.
`
`Sawaya describe the experimental conditions. They also do not describe the use of
`
`adequate positive controls or downstream analytical techniques to assign peaks to
`
`the R- and S-forms of phenylephrine. As a result, Altaire’s HPLC experiments do
`
`not establish the chiral purity of the Altaire Product.
`
`38. The summary of HPLC experiments in Exhibits 1019 and 1020
`
`similarly do not describe the experimental conditions nor do they describe the use
`
`-10-
`
`

`
`
`
`of any positive controls or downstream analytical techniques to assign peaks to the
`
`R- and S-forms of phenylephrine. Furthermore, the raw data was not provided for
`
`these sample HPLC runs. Exhibit 1020 does indicate that the “S(+) isomer
`
`concentration was determined by HPLC using a Chiralpak 4.6x250mm 5 µ m
`
`column.” However, there are many Chiralpak columns and I cannot determine
`
`which column was used from this description. Furthermore, results are likely to
`
`vary depending on the specific chiral support used. As a result, in my opinion,
`
`Exhibits 1019 and 1020 fail to establish the initial chiral purity of the Altaire
`
`Product.
`
`
`D.
`
`Polarimetry of chiral molecules
`
`39. Altaire provides some information purportedly produced using
`
`polarimetry analysis. (Ex. 1012). As explained in further detail below, the
`
`conclusion that Lot #11578 of the Altaire Product has a chiral purity of 101.5% is
`
`not valid.
`
`40. Polarimetry is used to measure the rotation of plane polarized light by
`
`chiral compounds. Each enantiomer rotates light to the same degree in opposite
`
`directions. As a result, racemic mixtures have a net optical rotation of zero.
`
`41. Specific rotation is a normalized value and is calculated using the
`
`(cid:5), is
`optical rotation of a sample measured by a polarimeter. Specific rotation, (cid:1)(cid:2)(cid:3)(cid:4)
`
`calculated according to the equation
`
`(cid:5) =
`(cid:1)(cid:2)(cid:3)(cid:4)
`
`100(cid:11)
`
`(cid:12)(cid:13)
`
`
`
`-11-
`
`

`
`
`
`where (cid:11) is the measured optical rotation, (cid:12) is the path length of the sample chamber
`
`and (cid:13) is the concentration of the solution. Specific rotation is dependent on
`
`temperature ((cid:14)), wavelength of light ((cid:16)), and solvent.
`
`42. To obtain an estimate of optical purity, the specific rotation must first
`
`be calculated for the control and the sample. These values are then used to
`
`calculate percent purity as shown below.
`
`(cid:5)(cid:17)(cid:11)(cid:18)(cid:19)(cid:12)(cid:20)
`(cid:1)(cid:2)(cid:3)(cid:4)
`(cid:5)(cid:21)(cid:22)(cid:23)(cid:24)(cid:25)(cid:22)(cid:12)
`(cid:1)(cid:2)(cid:3)(cid:4)
`
`× 100 = (cid:27)(cid:20)(cid:12)(cid:11)(cid:24)(cid:28)(cid:29)(cid:20) (cid:30)(cid:31)(cid:25)(cid:28)(cid:24)
`
`The above equation calculates chiral purity relative to the control sample.
`
`Therefore, the purity of the control must be known and deviation from 100% purity
`
`must be accounted for in order to estimate chiral purity.
`
`43. Because specific rotation of a racemic mixture is zero, but a sample of
`
`pure enantiomer has a characteristic positive or negative value, this measurement
`
`has been used in the past to estimate purity. However, the estimate of purity is
`
`dependent on the purity of a control specimen as well as all of the variables
`
`indicated in the above paragraph. For instance, small inaccuracies in the
`
`concentration of the sample and/or the control directly impact the estimate of
`
`purity.
`
`44. Polarimetry is not an analytical chemistry technique typically used to
`
`determine optical purity of a sample.
`
`45. Optical rotation ((cid:11)) depends on the variables I discussed above and is
`
`also sensitive to the presence of impurities. Because of the dependence of optical
`
`rotation on multiple variables, there tends to be considerable variation in optical
`
`-12-
`
`

`
`
`
`rotation measurements. (See, e.g. Ex. 2022, p. 1073(“Values of (cid:11) are affected by
`
`many variables, among which are wavelength, solvent, concentration, temperature,
`
`and presence of soluble impurities. . .. The cumulative effect of the above-
`
`mentioned variables on [(cid:11)] . . . is potentially very large. A practical consequence
`
`is that precise reproduction of published rotation values, from laboratory to
`
`laboratory, or even from day to day in the same laboratory, is difficult to
`
`achieve.”)).
`E. Altaire optical purity measurements
`
`46. As indicated above, among other variables, estimates of optical purity
`
`are measured relative to a control. Altaire’s polarimetry experiment (Ex. 1012) is
`
`deficient at least in lacking a control of known purity.
`
`47. Altaire indicates that the control used was phenylephrine
`
`hydrochloride purchased from Sigma-Aldrich (Catalog No. P6126). Altaire
`
`assigned a purity factor of 1.00 (meaning 100% pure) to this control (Ex. 1012, pg.
`
`3). The assignment of a purity factor of 1.00 to the control appears to be an
`
`assumption rather than based on any testing or validation. The product used by
`
`Altaire is listed as ≥99% pure in the Sigma-Aldrich catalog. (Ex. 2019). Altaire
`
`does not indicate what testing was performed by Sigma-Aldrich to assess chiral
`
`purity (e.g., USP HPLC protocol), whether purity was ever validated by Altaire, or
`
`how the control was stored or handled by Altaire after it was obtained. In addition
`
`to not knowing the purity of the control, the confidence interval supported by the
`
`experimental conditions is insufficient for establishing at least 95% chiral purity of
`
`-13-
`
`

`
`
`
`the Altaire Product. As explained below, confidence interval is calculated based
`
`on the uncertainty associated with the specific rotation value of a control sample.
`
`48. The USP Monograph reports that a 50 mg/mL sample of the pure R-
`
`form of phenylephrine in water is identified by a specific rotation between −42°
`
`and −47.5°. (Ex. 2020). This range represents the uncertainty in the specific
`
`rotation for a pure R-form phenylephrine control. This is the same range as
`
`indicated on page three of Exhibit 1012 for the “limit” of the polarimetry test
`
`performed by Altaire, as shown below.
`
`49. The wide range for the specific rotation value listed for the R-form of
`
`phenylephrine is consistent with the variability in optical rotation measurements
`
`that I discussed above.
`
`50. The wide range for the specific rotation value listed for the R-form of
`
`phenylephrine is inconsistent with its use as a method for accurately determining
`
`optical purity. The expected range of optical rotation ((cid:11)) for the R-form of
`
`phenylephrine encompasses 5.5°. If any value between −42° and −47.5° indicates
`
`that the sample is the pure R-form of phenylephrine, the implicit uncertainty of the
`
`measurement is ±6% (from the middle of the interval −44.75° it is +6% to −47.5°
`
`and -6% to −42°). Considering that the optical purity is directly related to the
`
`optical rotation (see the formula above), the uncertainty of the calculated optical
`
`purity is no less than the uncertainty for the optical rotation measurement or ±6%.
`
`-14-
`
`

`
`
`
`51. The ±6% value can also be calculated using the formula I described
`
`above.
`
`(cid:5)(cid:17)(cid:11)(cid:18)(cid:19)(cid:12)(cid:20)
`(cid:1)(cid:2)(cid:3)(cid:4)
`(cid:5)(cid:21)(cid:22)(cid:23)(cid:24)(cid:25)(cid:22)(cid:12)
`(cid:1)(cid:2)(cid:3)(cid:4)
`
`× 100 = (cid:27)(cid:20)(cid:12)(cid:11)(cid:24)(cid:28)(cid:29)(cid:20) (cid:30)(cid:31)(cid:25)(cid:28)(cid:24)
`
`I determined the average optical rotation value for R-form phenylephrine (i.e. the
`
`(cid:5)(cid:21)(cid:22)(cid:23)(cid:24)(cid:25)(cid:22)(cid:12).
`average of −42° and −47° which is −44.75°) and used this value for (cid:1)(cid:2)(cid:3)(cid:4)
`(cid:5)(cid:17)(cid:11)(cid:18)(cid:19)(cid:12)(cid:20) equal to either −42° or
`I then calculated percent purity by setting (cid:1)(cid:2)(cid:3)(cid:4)
`
`−47°.
`
`52. The confidence interval of the Altaire’s measurement has to be greater
`
`than the one described by USP, because Altaire’s samples were prepared from a
`
`solution of a unknown purity and not from a pure sample of R-form phenylephrine.
`
`This introduces further uncertainty into the final concentration of the sample, and
`
`therefore further uncertainty into the estimate of optical purity of the Altaire
`
`Product. Based on the data provided by Altaire, it is not possible to establish the
`
`actual confidence interval of the measurement.
`
`53. A confidence interval of greater than ±6% prevents one from
`
`concluding that the Altaire Product is at least 95% optically pure by polarimetry.
`
`VI. THE USP METHOD IS INCAPABLE OF SEPARATING PHENYLEPHRINE
`
`ENANTIOMERS
`
`54.
`
`I have reviewed the declaration of Sailaja Machiraju (Ex. 2021) which
`
`contains the experimental method used in the following HPLC runs. The method
`
`described by Sailaja Machiraju is identical to that published in the USP
`
`Monograph for phenylephrine hydrochloride. (Ex. 2009). I have reviewed the
`
`-15-
`
`

`
`
`
`results of the HPLC runs. Ex. 2040. In my opinion, the materials provided in the
`
`Machiraju declaration and corresponding experimental results indicate that the
`
`HPLC procedure published in the USP Monograph (Ex. 2009) does not separate
`
`phenylephrine enantiomers.
`
`55. Paragon ran a sample that was highly enriched in the R-form of
`
`phenylephrine according to the USP method. Ex. 2040, p. 3. The chromatogram is
`
`reproduced below. As can be seen from the chromatogram the USP method yields
`
`a single peak at 6.0 minutes.
`
`Enantiomerically
`Enriched
`R-form
`
`56. Paragon ran a sample that was highly enriched in the S-form of
`
`phenylephrine according to the USP method. Ex. 2040, p. 4. The chromatogram is
`
`reproduced below. As can be seen from the chromatograms the USP method
`
`yields a single peak at 6.0 minutes.
`
`-16-
`
`

`
`
`
`Enantiomerically
`Enriched
`S-form
`
`57. Paragon ran a racemic sample of phenylephrine according to the USP
`
`method. Ex. 2040, p. 5. The chromatogram is reproduced below. As can be seen
`
`from the chromatogram the USP method yields a single peak at 6.0 minutes.
`
`Racemic
`Mixture
`
`58. The above experiment demonstrates that the USP method does not
`
`separate the enantiomeric forms of phenylephrine. R- and S-form elute at 6.0
`
`minutes, therefore it is not possible to determine chiral purity of a phenylephrine
`
`sample using the USP method.
`
`-17-
`
`

`
`
`
`VII. CONCLUDING STATEMENTS
`
`59.
`
`In signing this declaration, I understand that the declaration will be
`
`filed as evidence in a contested case before the Patent Trial and Appeal Board of
`
`the United States Patent and Trademark Office. I acknowledge that I may be
`
`subject to cross-examination in this case and that cross-examination will take place
`
`within the United States. If cross-examination is required of me, I will appear for
`
`cross-examination within the United States during the time allotted for cross-
`
`examination.
`
`60.
`
`I declare that all statements made herein of my knowledge are true,
`
`and that all statements made on information and belief are believed to be true, and
`
`that these statements were made with the knowledge that willful false statements
`
`and the like so made are punishable by fine or imprisonment, or both, under
`
`Section 1001 of Title 18 of the United States Code.
`
`
`
`Dated: February 10, 2016
`
`
`
`
`
`By: / Gojko Lalic /
`
`Gojko Lalic
`
`
`
`-18-
`
`

`
`
`
`
`
`VIII. APPENDIX – LIST OF EXHIBITS
`
`
`Exhibit
`No.
`
`Description
`
`1001
`
`1002
`
`1003
`
`1012
`
`1015
`
`1016
`
`1017
`
`1019
`
`1020
`
`2009
`
`2010
`
`U.S. Patent No. 8,859,623 to Witham et al.
`
`File History of 8,859,623 pages 108 to 113
`
`Declaration of Assad Sawaya
`
`Identification study for the racemic (-) form of phenylephrine
`hydrochloride
`
`Akorn Phenylephrine 2.5% (Lot 091281) and 10 % (Lot 081431)
`Chromatograms
`
`Altaire Pharmaceuticals, Inc. Phenylephrine 2.5% (Lots 11302,
`11577, 11578) and 10 %
`(Lots 11323, 11581, 11582)
`Chromatograms
`
`Altaire Pharmaceuticals, Inc. Phenylephrine 2.5% (Lot 15040)
`Elevated Temperature Storage Chromatograms
`
`Summary of Chiral Purity Testing by HPLC of Phenylephrine HCl
`Ophthalmic Solution USP (2.5% and 10%) (4/15)
`
`Drug Substances used in the Manufacture of Phenylephrine HCL
`Ophthalmic Solution (4/15)
`
`USP Monographs: Phenylephrine Hydrochloride Nasal Jelly,
`Pharmacopdeia online,
`http://uspbpep.com/usp031/v31261/usp31nf26s1_m64180.asp (last
`visited August 11, 2015)
`
`USP: General Chapters: <621> Chromatography, U.S. Pharmacopeia,
`http://www.pharmacopeia.cn/v29240/usp29nf24s0_c621_viewall.ht
`ml (last visited August 24, 2015)
`
`2018
`
`USP reference standard certificate for phenylephrine Lot M0L504
`(2012)
`
`-19-
`
`

`
`Sigma-Aldrich Product Specification for phenylephrine product
`number P6126
`
`USP Monographs: Phenylephrine Hydrochloride U.S. Pharmacopeia,
`http://www.pharmacopeia.cn/v29240/usp29nf24s0_m64160.html
`(last visited January 4, 2016)
`
`Declaration of Sailaja Machiraju
`
`Ernest L. Eliel et al., Stereochemistry of Organic Compounds (1994)
`
`HPLC chromatograms obtained by Paragon for phenylephrine
`hydrochloride enantiomers and controls run under the USP
`Compendium method, Project Name:
`PPHcl_NasalJ_Sys4_160118_NJ (2016)
`
`2019
`
`2020
`
`2021
`
`2022
`
`2040
`
`
`
`
`
`-20-

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