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 SAILAJA MACHIRAJU
`
`
`
`
`PARAGON - EXHIBIT 2021
`
`
`_____________________________
`
`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 SAILAJA MACHIRAJU
`
`
`
`
`PARAGON - EXHIBIT 2021
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`TABLE OF CONTENTS
`
`I.
`I.
`
`QUALIFICATIONS ........................................................................................... 1
`QUALIFICATIONS ......................................................................................... .. 1
`
`II.
`II.
`
`HPLC EXPERIMENTS ..................................................................................... 2
`HPLC EXPERIMENTS ................................................................................... ..2
`
`III. CONCLUDING STATEMENTS ............................................................................ 5
`III.
`CONCLUDING STATEMENTS .......................................................................... ..5
`
`
`-i-
`
`
`
`
`
`I, Sailaja Machiraju, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1. My name is Sailaja Machiraju. I am a Senior Research Associate at
`
`Paragon BioTeck, Inc (“Paragon”). I have been employed by Paragon since June,
`
`2013.
`
`2.
`
`I am a named inventor on U.S. Patent No. 8,859,623 (“the ’623
`
`patent,” Ex. 1001).
`
`3.
`
`I have a Master of Science degree in Organic Chemistry from BAM
`
`University in India.
`
`4.
`
`industry.
`
`I have about eight and a half years of experience in the pharmaceutical
`
`5. My primary duties at Paragon include leading research on ophthalmic
`
`pharmacology, clinical biology, organic and analytical chemistry.
`
`6.
`
`A major focus of my current and past research is synthesis,
`
`characterization, and separation of chiral molecules. As a result, I am familiar with
`
`a variety of analytical techniques for confirming chiral purity including high-
`
`performance liquid chromatography (HPLC).
`
`7.
`
`I am the lead scientist with respect to research and development
`
`performed in-house at Paragon. I also direct experiments performed by contract
`
`research organizations on Paragon’s behalf.
`
`1
`
`
`
`
`
`II. HPLC EXPERIMENTS
`
`8.
`
`I was responsible for overseeing the performance of the HPLC
`
`experiments, described herein, by Encompass Pharmaceutical Services, Inc.
`
`(“Encompass”).
`
`9.
`
`Encompass provides analytical chemistry services to the
`
`pharmaceutical industry, as such, the analytical methods performed in their
`
`laboratories conform to Good Manufacturing Practice (GMP), International
`
`Conference on Harmonisation of Technical Requirements for Registration of
`
`Pharmaceuticals for Human Use (ICH), and United States Pharmacopeial
`
`Convention (USP) guidelines. We have used Encompass in the past and are
`
`confident in the quality of analytical chemistry services they provide.
`
`10. The purpose of the experiment was to determine whether the HPLC
`
`method described in the USP Monograph for identification of R-form
`
`phenylephrine was capable of separating phenylephrine enantiomers.
`
`11.
`
`I directed Encompass to perform certain HPLC experiments on
`
`phenylephrine using the experimental conditions described in the USP Monograph.
`
`(Ex. 2009; Ex. 2010). These experiments were performed using a L1 HPLC
`
`column which contains octyl decyl silane (“C-18”) solid packing material. The
`
`specific HPLC column used was a Zorbax C18 (2) 250 x 4.6mm HPLC column, 5
`
`µm, part number 880975-902.
`
`12. The mobile phase was methanol and water (1:1) containing 1.1 g of
`
`sodium 1-octanesulfonate per liter, adjusted with phosphoric acid to a pH of 3.0,
`
`-2-
`
`
`
`
`
`filter, and de-gassed. The diluent for all samples was a mixture of methanol and
`
`water (1:1), adjusted with phosphoric acid to a pH of 3.0.
`
`13. The flow rate for all HPLC runs was 1 mL per minute and the
`
`injection volume was 20 µL. Peaks were detected at 270 nm.
`
`14.
`
`I directed the following samples to be injected onto the C-18 column:
`
`• A blank, which comprises injection of the diluent for the samples;
`
`• A resolution control, which comprises a mixture of epinephrine
`
`bitartrate and R-form phenylephrine;
`
`• 2.5% w/v enantiomerically enriched R-form phenylephrine;
`
`• 2.5% w/v enantiomerically enriched S-form phenylephrine; and
`
`• A racemic mixture (2.5% w/v with respect to each enantiomer) of
`
`phenylephrine.
`
`15. The R-form of phenylephrine was purchased from USP and is from
`
`Lot M0L504. The S-form of phenylephrine was purchased from Toronto Research
`
`Chemicals and is from Lot 10-XAL-77-1. Epinephrine bitartrate was purchased
`
`from USP and is from Lot PIL 152.
`
`16. Encompass confirmed that they ran the three phenylephrine samples
`
`according to the method I directed.
`
`17.
`
`I have reviewed the data acquired by Encompass and I include it as
`
`Exhibit 2040.
`
`18. Page 1 of Exhibit 2040 shows the HPLC chromatogram for the
`
`diluent-only injection in which no peaks are visible. This is the expected result
`
`-3-
`
`
`
`
`
`19. Page 2 of Exhibit 2040 shows the HPLC chromatogram of the
`
`resolution control which shows two peaks, as expected. The first major peak at 4.7
`
`minutes is epinephrine bitartrate. The second major peak is R-form phenylephrine.
`
`The two minor peaks likely represent impurities present in the epinephrine
`
`bitartrate standard. This chromatogram shows that we were able to separate
`
`phenylephrine from epinephrine using the USP Monograph method. (Ex. 2009).
`
`20. Page 3 of Exhibit 2040 shows the HPLC chromatogram of
`
`enantiomerically enriched R-form phenylephrine. There is a single peak that
`
`eluted at 6.0 minutes.
`
`21. Page 4 of Exhibit 2040 shows the HPLC chromatogram of
`
`enantiomerically enriched S-form phenylephrine. There is a single peak that eluted
`
`at 6.0 minutes.
`
`22. Page 5 of Exhibit 2040 shows the HPLC chromatogram a racemic
`
`mixture of phenylephrine. There is a single peak that eluted at 6.0 minutes.
`
`23. The HPLC chromatograms presented on pages 3-5 of Exhibit 2040
`
`present the results of injection of R-form, S-form, or a racemic mixture of
`
`phenylephrine. Comparison of these chromatograms demonstrates that regardless
`
`of which sample was injected onto the column, a single peak at 6.0 minutes was
`
`obtained.
`
`24. Based on the HPLC chromatograms presented in Ex. 2040, I conclude
`
`that the USP Monograph method is incapable of separating phenylephrine
`
`enantiomers.
`
`-4-
`
`
`
`
`
`III. CONCLUDING STATEMENTS
`
`25.
`
`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.
`
`26.
`
`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: / Sailaja Machiraju /
`
`Sailaja Machiraju
`
`
`
`-5-
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