UNITED STATES DISTRICT COURT
`DISTRICT OF NEW JERSEY
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`Civil Action No. 12-2867-MLC-DEA
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`District Judge Mary L. Cooper
`Magistrate Judge Douglas E. Arpert
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`x
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`HELSINN HEALTHCARE S.A. and
`ROCHE PALO ALTO LLC,
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`
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`Plaintiffs,
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`v.
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORIES, INC.,
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`Defendants.
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`CONTAINS HIGHLY CONFIDENTIAL INFORMATION
`UNDER DISCOVERY CONFIDENTIALITY ORDER
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`EXPERT REPORT OF DR. JOANNE BROADHEAD
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`
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`4332807_1.docx
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`Helsinn Healthcare Exhibit 2030
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`Page 1 of 5
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`HIGHLY CONFIDENTIAL OUTSIDE COUNSEL'S EYES ONLY
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`pharmaceutical formulations of palonosetron contain EDTA. (‘980 Patent Exs.4, 5, 8; 3:14-20.)
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`According to one of the Syntex formulators and named inventor, Mr. Malefyt, “EDTA was an
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`important component” for stability of the palonosetron formulation. (ANDA Litigation Malefyt
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`Tr. 65:9-14.) As Mr. Malefyt further explained, the EDTA formulation of palonosetron had the
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`best stability, and a formulation sent to Japan that did not include EDTA required refrigeration
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`and was unstable. (Id. 86:14-25.) The only formulations of which Mr. Malefyt was aware that
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`improved on the stability of Phase II clinical trial formulations were formulations that contained
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`EDTA. (Id. 87:4-10.)
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`47.
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`Documents submitted on behalf of the Patent Owner also confirm that EDTA was
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`represented to be important to stability of palonosetron formulations. For example, in a
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`February 9, 2009 declaration, Danielle Bonadeo, a Helsinn employee and named inventor, made
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`numerous statements that the presence of EDTA improves stability under certain circumstances.
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`(Bonadeo Decl. ¶¶ 15-18, Feb. 9, 2009.) Likewise, a Teva witness at the ANDA trial testified
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`that batches of Teva palonosetron formulations in which EDTA was removed did not meet
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`stability parameters. (ANDA Litigation Zahavi Tr. 114:11 - 119:9.)
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`48.
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`In fact, the patent owner recommended that formulations without EDTA used in
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`Phase II studies, which included palonosetron at a low concentration (0.1 and 0.5 mg/ml), with a
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`tonicifying agent (sodium chloride) and a phosphate buffer, be refrigerated. (See Summary of
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`CMC at HELSN0334983
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`(“Phase I and
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`II clinical studies were conducted with
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`phosphate-buffered, pH 7.4 solutions of palonosetron. These formulations were not optimized
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`for chemical stability, and refrigeration was required to achieve an adequate shelf-life for the
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`clinical studies.”); id. Table; Stability Statement at HELSN0128735 (“RS-25259 has been
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`formulated as injectable solutions for clinical study containing either 0.10, 0.5, or 1.0 mg/ml of
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`4332807_1.docx
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`free base in a sodium phosphate buffer at pH 7.4 with NaCl added to render the solutions
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`isotonic. . . . [W]e recommend a 12 month shelf life for this product when stored at refrigerated
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`conditions (5°±3°C).”).) When the Patent Owner changed those formulations for Phase III
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`studies to include EDTA and citrate, refrigeration was not necessary. (Summary of CMC at
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`HELSN0334983 (“The proposed Phase III/commercial formulations have been optimized for a
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`longer shelf-life by decreasing palonosetron concentration, selecting the pH of maximum
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`stability (5.0), employing citrate buffer and EDTA as chelating agents, and changing the
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`tonicifying agent from sodium chloride to mannitol. Accelerated stability studies predict the
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`room-temperature shelf-life of the improved formulations will be in excess of three years.”).)
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`49.
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`Even where EDTA and citrate are included, as in Examples 4, 5, and 8 in the
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`patent specification, there is no indication of what stability resulted from the addition of EDTA
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`and citrate, or how stable the formulations of each of the examples were.
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`50.
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`Furthermore, regulatory guidance states that antioxidants, including antioxidant
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`synergists such as chelating agents, “should only be included in a formulation if it can be proved
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`that their use cannot be avoided.” (European CPMP Guidance at Section 2; see also Swarbrick
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`at 143.) The inclusion of EDTA in Examples 4, 5 and 8 of the patent implies that EDTA was
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`necessary for stability. The patent does not explain how the claimed stability can be achieved
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`without such a necessary component.
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`51.
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`The inclusion of EDTA presented challenges in developing a globally acceptable
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`formulation with regard to the uncertainty around the acceptability of an EDTA-containing
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`formulation in Japan. (ANDA Litigation Malefyt Tr. 86:19-25.) The continued development
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`and commercialization of an EDTA-containing formulation indicates that the Patent Owner
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`believed the EDTA to be a necessary component in achieving the desired shelf life.
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`4332807_1.docx
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`52. Many of the asserted claims do not require a chelating agent at all, but rather state
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`that a chelating agent is “optional.” (See ‘980 Patent cls.1-5, 16; ‘094 Patent cls.22-25.) These
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`claims purport to cover a broad range of compositions including those that include some
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`chelating agent and those that do not. For the asserted claims of the ‘980 and ‘094 Patent, which
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`do not require EDTA, there is no enabling disclosure as to how to achieve the claimed levels of
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`stability without undue experimentation. Claims 1 and 16 of the ‘980 Patent are particularly
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`broad in that they do not require any of the formulation features (such as chelating agents, citrate
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`buffers, mannitol, or pH adjustments) alleged to enhance stability, and there is no enabling
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`disclosure that supports these broad claims. Even for claim 6 of the ‘980 Patent and claim 27 of
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`the ‘094 Patent, which require an unspecified chelating agent, there is no disclosure of how to
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`obtain the claimed stability without the specific chelating agent EDTA.
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`53. Moreover, the common specification teaches enhancing stability with EDTA only
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`in formulations that also include a citrate buffer. (See ‘980 Patent 3:13-19.) All disclosed
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`examples of pharmaceutical formulations of palonosetron contain citrate buffer. (Id. Exs.4, 5, 8.)
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`Nevertheless the broad patent claims seek to include formulations which do not include a buffer
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`(‘980 Patent cls.1, 16) or which are buffered with an unspecified buffer which may or may not be
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`citrate (cls.2-9).
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`54.
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`Similarly, the common specification teaches enhancing stability when using
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`mannitol as a tonicity agent only in formulations that also include a chelating agent. (See id.
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`3:21-29, 5:52-66.) None of the asserted claims other than claim 27 of the ‘094 Patent, however,
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`requires mannitol with a chelating agent. Even as to claim 27 of the ‘094 Patent, the chelating
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`agent does not have to be EDTA.
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`140.
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`I understand that Helsinn may have the opportunity to address so-called
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`secondary considerations relating to obviousness.
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`I reserve the right to respond to any such
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`argument.
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`Dated:
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`January 6, 2016
`
`Dr. Joanne Broadhead
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`4332807_1.docx
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