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In re Sebela Patent Litigation

United States District Court, D. New Jersey

June 9, 2017

IN RE SEBELA PATENT LITIGATION

          OPINION

          HON. CLAIRE C. CECCHI UNITED STATES DISTRICT JUDGE.

         I. INTRODUCTION

         This is a consolidated[1] Hatch-Waxman patent infringement action brought by Plaintiff Sebela International Limited ("Sebela"). The Defendants in the consolidated action are Actavis Laboratories FL, Inc., Actavis Pharma, Inc., Andrx Corp., and Actavis, Inc.[2] (collectively, "Actavis"), and Prinston Pharmaceutical Inc., Solco Healthcare U.S., LLC, and Huahai U.S. Inc. (collectively, "Prinston").

         Plaintiff has asserted three patents against Defendants: U.S. Patent Nos. 7, 598, 271 (the "'271 patent"), 8, 658, 663 (the '"663 patent") and 8, 946, 251 (the "'251 patent"). A fourth patent, U.S. Patent No. 5, 874, 447 (the "'447 patent") was also asserted in this litigation. Sebela agreed to withdraw the claims related to the '447 patent in exchange for Defendants' agreement not to launch their ANDA products until June 10, 2017, the expiration date of the '447 patent. ECF No. 175;SOF[3]¶25.

         The '271 patent is directed to a composition relating to Sebela's BRISDELLE® paroxetine mesylate product, [4] and the '663 and '251 patents (the "method of treatment patents") are directed to methods relating to the same. Noven Therapeutics, LLC ("Noven"), was the original holder of New Drug Application ("NDA") No. 204516 for paroxetine mesylate capsules, which are marketed and sold under the trademark BRISDELLE. SOF ¶ 8. On October 16, 2014, Noven sued Actavis for infringement of the '447, '271, and '663 patents. SOF ¶ 12. On August 14, 2015, Noven filed a second suit against Actavis for infringement of the '251 patent. SOF ¶ 13. On November 26, 2014, Noven sued Prinston for infringement of the '447, '271, and '663 patents. SOF ¶ 16. On July 7, 2015, Prinston sued Noven for declaratory judgment on the '251 patent. SOF ¶ 17. On July 25, 2016, Sebela purchased all benefits and interests in the '447, '271, '663, and '251 patents and NDA No. 204516 from Noven, and on September 20, 2016, Sebela was substituted as Plaintiff. SOF ¶¶ 21-24; ECF No. 155.

         Defendants have sought approval from the United States Food and Drug Administration ("FDA") to market generic versions of paroxetine mesylate. SOF ¶¶ 71, 77. Plaintiff alleges that Defendants will infringe the patents in suit by marketing their generic products. Defendants have stipulated to infringement of the asserted claims of the '663 and '251 patents. SOF ¶¶ 49-50, 67-68.

         The Court conducted a bench trial in this matter from December 8, 2016, to December 14, 2016. The Parties submitted post-trial briefing and proposed findings of fact and conclusions of law. Closing arguments were held on February 24, 2017, and March 13, 2017. This Opinion constitutes the Court's findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52(a). The findings of fact are based on the Court's observations and credibility determinations of the witnesses who testified and a thorough review of all the evidence admitted at trial. For the reasons stated herein, the Court finds as follows:

         As to the '271 patent Plaintiff has not met its burden of proving infringement by a preponderance of evidence, so judgment of non-infringement will be entered in favor of Defendants on the '271 patent.[5]

         As to the '663 patent. Defendants have met their burden of proving by clear and convincing evidence that the '663 patent is invalid, so judgment of invalidity will be entered in favor of Defendants on the '663 patent.

         As to the'251 patent. Defendants have met their burden of proving by clear and convincing evidence that the '251 patent is invalid, so judgment of invalidity will be entered in favor of Defendants on the '251 patent.

         II. BACKGROUND[6]

         A. Parties

         Plaintiff Sebela is a Bermuda company with offices located in Hamilton, Bermuda. SOF ¶ 1. Sebela is the legal owner of all rights, title and interests in the '271, '663, and '251 patents. SOF ¶¶ 31, 40, 54. Sebela Ireland Ltd., a wholly owned subsidiary of Sebela, holds NDA No. 204516. SOF ¶ 22.

         Defendant Actavis Laboratories FL, Inc. is a Florida corporation with a place of business at Morris Corporate Center III, 400 Interpace Parkway, Parsippany, New Jersey 07054. SOF ¶ 2. Defendant Actavis Pharma, Inc. is a Delaware corporation with a place of business at Morris Corporate Center III, 400 Interpace Parkway, Parsippany, New Jersey 07054. SOF ¶ 3. Defendant Andrx Corp. is a Delaware corporation with a place of business at 4955 Orange Drive, Davie, Florida 33314. SOF ¶ 4. Defendant Actavis submitted Abbreviated New Drug Application ("AND A") No. 207129 to the FDA, including a paragraph IV certification as to each of the patents in suit. SOF ¶ 11.

         Defendant Prinston Pharmaceutical Inc. is a corporation organized and existing under the laws of Delaware with a principal place of business at 2002 Eastpark Boulevard, Cranbury, New Jersey 08512. SOF ¶ 5. Defendant Solco Healthcare U.S., LLC is a Delaware corporation with a principal place of business at 2002 Eastpark Boulevard, Suite A, Cranbury, New Jersey 08512. SOF ¶ 6. Defendant Huahai U.S. Inc., is a corporation organized and existing under the laws of New Jersey, with a place of business at 2001 Eastpark Boulevard, Cranbury, New Jersey 08512. SOF ¶ 7. Defendant Prinston filed ANDA No. 207188 with the FDA, identifying the BRISDELLE drug product, and seeking to market and sell within the United States a generic 7.5 mg paroxetine mesylate capsule product. SOF ¶ 14. ANDA No. 207188 contains a paragraph IV certification as to each of the patents in suit. SOF ¶ 15.

         B. Patents in Suit

         i. The '271 Patent

         The '271 Patent, titled "Crystalline Paroxetine Methane Sulfonate, " issued on October 6, 2009 (with certificates of correction issued on May 17, 2011, and December 22, 2015), from U.S. Application Serial No. 09/200, 743 (the "'743 application"), which was filed on November 30, 1998. SOF ¶ 27. The '743 application was filed as a divisional of U.S. Application Serial No. 08/872, 023 (the "'023 application"), which was filed on June 10, 1997, and issued as the '447 patent. SOF ¶ 27. The '743 application included a priority claim to the '023 application. SOF ¶ 27. The '271 patent relates generally to a crystalline form of paroxetine mesylate. SOF ¶ 35; JTX-2. The inventors listed on the '271 patent are Franciscus Bemardus Gemma Benneker, Frans Van Dalen, Jacobus Maria Lemmens, Theodorus Hendricus Antonium Peters, and Frantisek Picha. SOF ¶ 30; JTX-2.

         On January 31, 2001, Synthon, which was the holder of the '743 application, filed a request for an interference between the '743 application and U.S. patent No. 6, 063, 927 (the "'927 patent"), which was owned by SmithKline Beecham and claimed a crystalline form of paroxetine mesylate described by reference to 8 infrared ("IR") peaks. PFOF[7] ¶¶ 55, 62; DFOF[8] ¶ 102. The patent examiner suspended prosecution of the '743 application on February 21, 2001, PFOF ¶ 64, and the Board of Patent Appeals and Interferences (the "BPAI") instituted an interference proceeding (the "Interference Proceeding") on October 1, 2002, PFOF ¶ 67. Despite the different peak listings, applying the broadest reasonable interpretation standard, the BPAI ultimately decided the interference in Synthon's favor. See PFOF ¶ 77.

         ii. The Method of Treatment Patents

         The '663 patent, titled "Method of Treating Thermoregulatory Dysfunction with Paroxetine, " issued on February 25, 2014 (with a certificate of correction issued on October 7, 2014), from U.S Application Serial No. 12/292, 960 (the "'960 application"). The '960 application was filed on December 1, 2008, as a continuation of the now abandoned U.S. Application Serial No. 11/499, 586 (the "'586 application"), which was filed on August 4, 2006. SOF ¶ 36; JTX-3. The '633 patent relates generally to methods of using paroxetine to treat thermoregulatory dysfunction. See SOF ¶¶ 46-48; JTX-3. The sole inventor listed on the '663 patent is Patricia Allison Tewes Richards. SOF ¶ 39; JTX-3.

         The '251 patent, also titled "Methods of Treating Thermoregulatory Dysfunction with Paroxetine, " issued on February 3, 2015, from U.S. Application Serial No. 14/157, 992 (the "'992 application"), which was filed on January 17, 2014. SOF ¶ 51. The '992 application was a continuation of the '960 application. SOF ¶ 51; JTX-4. The '251 patent relates generally to methods of using paroxetine to treat thermoregulatory dysfunction. See SOF ¶¶ 62-66; JTX-4. The sole inventor listed on the '251 patent is Patricia Allison Tewes Richards. SOF ¶ 53; JTX-4.

         The specifications of the '663 patent and the '251 patent are substantively identical.[9] PFOF ¶ 207; DFOF ¶ 26. The specifications disclose that paroxetine can be used to treat hot flashes at doses of 9.5 mg down to 0.1, mg. 12/12 Tr. a.m. (Locker) 91:5-11. The specifications contain two prophetic examples. 12/12 Tr. a.m. (Locker) 91:12-92:3. Example 1 describes administering paroxetine hydrochloride and paroxetine mesylate at doses of 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, and 9.5.[10] DFOF ¶ 14; JTX-3 at 4:63-5:23. Example 2 describes administering paroxetine hydrochloride, in anhydrous form, hemihydrate form, and monohydrate form, at doses of 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, and 9.5. DFOF ¶ 15; JTX-3 at 5:25-6:23. In each example the patent concludes that "[a]fter a few days to weeks, the symptoms ameliorate." DFOF ¶ 15; JTX-3 at 5:23, 6:23.

         C. Trial Witnesses

         The following witnesses appeared and provided live testimony during the bench trial:

         i. Plaintiffs Fact Witness

         1. Scott Briggs

         The Court heard testimony from Mr. Scott Briggs, who is Chief Commercial Officer at Sebela Pharmaceutical, Inc., 12/13 Tr. (Briggs) 17:12, and who previously served as Vice President of Marketing and Sales at Noven, 12/13 Tr. (Briggs) 18:12-13. Mr. Briggs testified on issues related to the marketing and sales of Brisdelle.

         ii. Plaintiffs Expert Witnesses

         1. Allan Mverson

         The Court heard expert testimony from Allan Myerson, Ph.D. The Court accepted Dr. Myerson as an expert in the fields of crystallization, crystal and solid forms, pharmaceutical manufacturing, and industrial applications of crystallization. 12/8 Tr. a.m. (Myerson) 86:23-87:6. Dr. Myerson opined on the issues of infringement of the '271 patent and validity of the method of treatment patents.

         2. John C. Jarosz

         The Court heard expert testimony from John C. Jarosz. The Court accepted Mr. Jarosz as an expert in the fields of pharmaceutical economics and economic issues regarding secondary considerations of commercial success. 12/13 Tr. (Jarosz) 67:18-68:1. Mr. Jarosz opined on the issues related to the market performance of Brisdelle.

         3. James A. Simon

         The Court heard expert testimony from James A. Simon, M.D. The Court accepted Dr. Simon as an expert on the clinical treatment, clinical research and management of the symptoms and medical consequences of menopause, including vasomotor symptoms. 12/13 Tr. (Simon) 117:23-118:7. Dr. Simon opined on issues related to the validity of the method of treatment patents.

         4. James R. Woodworth

         The Court heard expert testimony from James R. Woodworth, Ph.D. The Court accepted Dr. Woodworth as an expert in the field of pharmacokinetics, pharmacodynamics, and clinical pharmacology. 12/14 Tr. (Woodworth) 115:6-14. Dr. Woodworth opined on issues related to the validity of the method of treatment patents.

         iii. Defendants' Expert Witnesses

         1. Robin D. Rogers

         The Court heard expert testimony from Robin D. Rogers, Ph.D. The Court accepted Dr. Rogers as an expert in the field of "solid state chemistry, including crystal engineering, crystallization, crystal characterization, including by IR spectroscopy, salts and polymorphism, including the isolation and characterization of organic compounds and their applications in pharmaceutical products." 12/9 Tr. a.m. (Rogers) 23:22-24:8. Dr. Rogers opined on the issues of infringement and invalidity of the '271 patent.

         2. Brian K. Locker

         The Court heard expert testimony from Brian K. Locker, M.D. The Court accepted Dr. Locker as an expert in treating women with thermoregulatory dysfunction associated with hot flashes. 12/12 Tr. a.m. (Locker) 87:5-13. Dr. Locker opined on the issue of validity of the method of treatment patents.

         3. Ivan T. Hoffman

         The Court heard expert testimony from Ivan T. Hoffman CPA/CFF, CLP. The Court accepted Mr. Hoffman as an expert in the field of pharmaceutical economics. 12/14 Tr. (Hoffman) 167:9-18. Mr. Hoffman opined on the issues related to the market performance of Brisdelle.

         iv. Deposition videos

         The following witnesses had video recordings of portions of their depositions played during the bench trial:

         1. Theodorus Hendricus Antonium Peters

         The Court saw video testimony from Dr. Theodorus Hendricus Antonium Peters, one of the named inventors of the '271 patent.

         2. Patricia Tewes Richards

         The Court saw video testimony from Dr. Patricia Tewes Richards the named inventor of the method of treatment patents.

         3. Joel Lippman

         The Court saw video testimony from Dr. Joel Lippman, the Chief Medical Officer of and a 30(b)(6) witness for Noven.

         D. Confidential Prosecution Documents

         Defendants have sought to introduce documents from the confidential record of the Interference Proceeding. Specifically, they seek to introduce expert declarations filed by Drs. Harry G. Brittain (DTX-14B) ("Brittain Declaration") and Wayne Genck (DTX-14C) ("Genck Declaration"), and excerpts from deposition testimony given by Dr. Bennecker in a proceeding in the United Kingdom (PTX-880) ("Bennecker Deposition").[11] ECF No. 249. On the eve of trial, the Parties informed the Court that Plaintiff objected to Defendants' use of these documents on a number of grounds. Among other things, Plaintiff challenged the authenticity of these documents on the grounds that, although they were produced by Sebela on behalf of its predecessor Synthon, see ECF No. 270 at 2, which had maintained them in its records, they were not official, certified copies. During the course of me bench trial, the Court allowed these materials to be presented and discussed by the Parties, reserving judgment on their admissibility. Prior to closing arguments, the Parties submitted briefing on the admissibility of these documents. ECF Nos. 219, 221, 229, 235. At closing arguments, it became clear that none of the Parties had actually attempted to obtain certified copies of the documents from the Patent and Trademark Office ("PTO"), so the Court advised the Parties do so. On May 1, 2017, over a montii after closing arguments, Defendants produced a copy of the certified interference file history, containing the disputed documents including the Brittain Declaration, Genck Declaration, and Bennecker Deposition. ECF No. 265. In a May 8, 2017 letter Plaintiff objected to this production as untimely and argued that its consideration would not be appropriate as the certified copies of the documents were not in evidence at the time of trial. ECF No. 270.

         The interference documents are part of the file history of the '271 patent. While Plaintiff argued at trial that the confidential documents at issue are not part of the file history because "[w]hen you obtain a certified copy it will not include the confidential [documents], " 3/13 Tr. 183:8-12, this is clearly not the case, as the certified record produced by Defendants includes the disputed confidential documents. Given the dilatory conduct giving rise to this issue, [12] and the normal amount of time it takes to obtain a certified file history, the Court will consider the certified file history. Furthermore, the production of the certified copies of the disputed documents merely confirms the authenticity of the copies that were, in fact, offered at trial. See Fed.R.Evid. 104(a). Accordingly, Plaintiffs general objections to the consideration of these documents is overruled. Objections specific to particular materials are considered below.

         E. Scientific Principles

         The patents in suit involve crystal forms of compounds, infrared spectroscopy, and the treatment of thermoregulatory disorders. The following is an introduction to some of the scientific principles at issue in this litigation.

         i. Crystals and Polymorphism

         Paroxetine is a compound that has pharmaceutical uses, including as an antidepressant and, as claimed in the patents in suit, as a drug for treating thermoregulatory dysfunction. See, e.g., JTX-4 1:51-58. Paroxetine can form a variety of salts, including paroxetine mesylate, also known as paroxetine methanesulfonate. See, e.g., JTX-1 at 1:27-33.

         Several of the patent claims at issue relate to different chemical forms of paroxetine and the arrangement of the molecules therein. When the molecules are arranged in an ordered, repeating, regular pattern, they are said to be in a crystalline form. See 12/8 Tr. a.m. (Myerson) 89:8-17; cf. 12/9 Tr. a.m. (Rogers) 25:14-15. In contrast, when the molecules are not in an ordered array, they are said to be in an amorphous form. See, e.g., 12/8 Tr. a.m. (Myerson) 90:1-6; 12/9 Tr. a.m. (Rogers) 25:14-15. In general, amorphous forms of a compound are less chemically stable and less physically stable than crystalline forms, so crystalline forms are often preferred for pharmaceutical use. See, e.g., 12/8 Tr. a.m. (Myerson) 90:9-15.

         Certain molecules have more than one repeating pattern, or crystalline form, into which they can be arranged. Each of the crystalline forms is referred to as a polymorph. 12/8 Tr. a.m. (Myerson) 92:14-18; 12/9 Tr. a.m. (Rogers) 26:10-22. Although made up of the same constituent molecules, polymorphs can have different physical and chemical properties that are pharmaceutically significant, including physical stability, solubility, and dissolution. 12/8 Tr. a.m. (Myerson) 92:24-93:3; see also 12/9 Tr. a.m. (Rogers) 26:25-27:9. When a compound has only one crystalline form, it may be referred to as "monomorphic." 12/9 Tr. p.m. (Rogers) 70:1-4.

         Polymorphism is unpredictable. 12/8 Tr. a.m. (Myerson) 94:12-95:2; see also 12/9 Tr. p.m. (Rogers) 56:20-57:1. Although compounds with molecular weights below a certain threshold can usually be crystallized with sufficient effort, 12/8 Tr. a.m. (Myerson) 95:10-20 ("[T]ypically for compounds with molecular weights below 1500 [Daltons], if you work on them long enough you can usually get them to crystallize----"[13]), it is not possible to predict how many polymorphs may exist for a given compound, 12/8 Tr. a.m. (Myerson) 95:21-96:1; 12/8 Tr. p.m. (Myerson) 5:23-6:1; see also 12/9 Tr. p.m. (Rogers) 51:2-12. A new polymorph may take decades to be discovered. 12/8 Tr. p.m. (Myerson) 7:5-17; 12/9 Tr. p.m. (Rogers) 53:3-10.

         ii. Infrared Spectroscopy

         Crystalline forms may be characterized and described using IR spectroscopy. IR spectroscopy involves shining IR radiation at a sample of the compound. Certain frequencies of radiation are absorbed by the sample as they interact with it. 12/9 Tr. a.m. (Rogers) 32:24-33:9. Which frequencies are absorbed depends on the properties of the sample, including the crystalline structure. A spectrum can be generated by plotting absorption versus IR frequency. Peaks are observed in the spectrum at those frequencies where the light was absorbed by, and therefore did not pass through, the sample. 12/8Tr. a.m. (Myerson) 101:24-102:5, 104:10-15. These peaks can be used to characterize the crystalline form. 12/8 Tr. a.m. (Myerson) 102:10-13. These peaks may be sharp or weak. 12/8 Tr. p.m. (Myerson) 22:3-8, 22:23-23:7. Typically, IR spectra are measured in units of reciprocal centimeters, also called wavenumbers. 12/8 Tr. a.m. (Myerson) 104:10-15. Often there is a greater number of peaks between 500 cm-1 and 1500 cm-1, and this region on the spectrum is referred to as the "fingerprint region." 12/8 Tr. a.m. (Myerson) 104:16-19; 105:8-12.

         There are several ways in which variation can be introduced into the measurement of peaks. These include differences in the instruments used to generate the spectra, 12/8 Tr. a.m. (Myerson) 105:17-18; 12/9 Tr. p.m. (Rogers) 40:21-22, calibration of the instrument used, 12/8 Tr. a.m. (Myerson) 105:18-23, and sample preparation (e.g., mixture of the sample with a salt, size of the grains of the powder, concentration of the powder on the disk, use of an oil mull), 12/8 Tr. a.m. (Myerson) 105:24-106:14; 12/9 Tr. p.m. (Rogers) 40:24-25. Instrument resolution can also alter the ability to distinguish peaks and can affect how the peaks look and their apparent location. 12/8 Tr. a.m. (Myerson) 107:1-13; see also 12/9 Tr. p.m. (Rogers) 41:7-9. If a low resolution is used, fewer peaks will be observed, and separate peaks may merge into a single peak which may affect apparent location. 12/8 Tr. a.m. (Myerson) 108:15-23. Typically, a resolution of 1 cm-1, 2 cm-1, or 4 cm-1 is used. 12/8 Tr. a.m. (Myerson) 109:12-19.

         The method used for identifying and locating peaks can also introduce variability in the measured value. 12/9 Tr. p.m. (Rogers) 41:3-6. Peak-picking software can use various algorithms to determine whether something is a peak and the location of the peak. 12/8 Tr. am. (Myerson) 106:15-20. Most instruments come with a default setting for identifying peaks and allow the user to adjust the settings to be more or less sensitive. 12/8 Tr. a.m. (Myerson) 106:21-25. Peak-picking software was available and in use as of 1995. 12/8 p.m. Tr. (Myerson) 4:19-21.

         In order to reduce "noise, " or variability due to factors other than the sample, a person of ordinary skill in the art ("POSA")[14] will typically run a number of scans, and then "co-add" those scans, to increase the signal to noise ratio. 12/8 p.m. Tr. (Myerson) 16:22-17:2. Typically, a POSA will perform 32 to 64 co-added scans. 12/8 Tr. p.m. (Myerson) 60:19-24, 61:18-62:2.

         Typically, the differences between peaks that a POSA would look for in distinguishing between two different polymorphs of the same compound are around 4 cm-1. 12/8 Tr. p.m. (Myerson) 72:5-10. It is possible, though unlikely, however, that a polymorph has an IR peak that is more than 18 cm-1 away from a corresponding peak in a different polymorph of the same compound. 12/8 Tr. p.m. (Myerson) 72:23-73:4, 103:16-19. While IR spectroscopy can always be used to distinguish between samples with different underlying chemical structures, it cannot always be used to distinguish between polymorphs. 12/8 Tr. p.m. (Myerson) 71:18-23. Instead, there are many instances where IR spectroscopy cannot distinguish between polymorphs. 12/8 Tr. p.m. (Myerson) 72:1-4. Accordingly, while IR spectroscopy is commonly used for identifying chemical species, it is only occasionally used by itself to distinguish between different crystalline forms. 12/8 Tr. p.m. (Myerson) 90:22-91:9; 12/9 Tr. am. (Rogers) 32:14-22.

         There are several additional methods by which crystalline forms may be characterized. These include single crystal x-ray diffraction, 12/8 Tr. a.m. (Myerson) 96:19-23, powder x-ray diffraction ("XRPD"), 12/8 Tr. a.m. (Myerson) 96:24-97:4; 12/9 Tr. a.m. (Rogers) 32:14-21, and phase transition analysis, such as by differential scanning calorimetry ("DSC"), 12/8 Tr. a.m. (Myerson) 97:12-98:8; 12/9 Tr. am. (Rogers) 32:11-13. Each of these methods was available to a POSA in 1997. 12/8 Tr. a.m. (Myerson) 99:1-3; see 12/9 Tr. p.m. (Rogers) 53:11-13. Unlike IR spectroscopy, XRPD will provide virtually conclusive evidence informing a POSA what polymorph is being analyzed. 12/8 Tr. p.m. (Myerson) 70:20-23. Accordingly, IR spectroscopy is not used nearly as often as XRPD to distinguish between crystalline forms. See 12/8 Tr. p.m. (Myerson) 70:18-72:4; 12/9 Tr. a.m. (Rogers) 32:14-22.

         iii. Thermoregulatory Disorders

         Thermoregulatory dysfunction refers to the dysfunction of a body's ability to control its temperature. 12/12 Tr. a.m. (Locker) 84:6-11. This typically occurs during menopause. 12/12 Tr. a.m. (Locker) 84:8-11. The main symptoms associated with thermoregulatory dysfunction are hot flashes or hot flushes and night sweats. 12/12 Tr. a.m. (Locker) 84:12-13; 12/13 Tr. (Simon) 119:2-8. Hot flashes, or thermoregulatory dysfunction generally, may also be referred to as vasomotor symptoms. 12/12 Tr. a.m. (Locker) 89:21-23; 12/13 Tr. (Simon) 119:9-11. The precise cause of vasomotor symptoms is unknown. 12/13 Tr. (Simon) 121:17-19; 12/14 Tr. (Simon) 12:10-14. Sixty to eighty percent of menopausal women experience vasomotor symptoms, and approximately one in five seek medical treatment for those symptoms. 12/13 Tr. (Simon) 119:16-22.

         F. Background of the Claimed Inventions

         i. Development of Crystalline Paroxetine Mesylate

         In the late 1990s, researchers at Synthon developed a crystalline form of paroxetine mesylate. See PTX-801.0003; JTX-1 at 7:45-60. Paroxetine mesylate is a salt in which the active component is the paroxetine base. Dr. Benneker, a researcher at Synthon, analyzed the crystalline form of paroxetine mesylate that had been developed and generated a list of IR peaks, the peaks now listed in claim 1 of the '271 patent. See PTX-801.0003.

         The spectrum used to identify the listed peaks was included in the prosecution history of the '271 patent. The spectrum had a resolution of 8 cm-1, rather than the standard 1 cm-1 to 4 cm-1. 12/8 Tr. a.m. (Myerson) 107:22-25, 109:12-19. At high transmission areas, the spectrum appears to show a high degree of variability in the signal due to factors other than the sample, a problem that would often be addressed by co-adding scans. 12/8 Tr. p.m. (Myerson) 16:5-17:2. The intrinsic record does not appear to indicate how many co-added scans Dr. Benneker performed. 12/8 Tr. p.m. (Myerson) 62:7-11.

         During the Interference Proceeding, Dr. Benneker submitted a declaration describing how he measured the peaks from an IR spectrum he had generated. PTX-801 ("Benneker Declaration"); see also 12/8 Tr. p.m. (Myerson) 18:1-21:22. He did not use a peak-picking algorithm to generate the list of claimed peaks in the '271 patent. Instead, he measured the peaks by hand with a ruler. 12/8 Tr. a.m. (Myerson) 107:17-21. Dr. Benneker stated that he "calculated the wavenumber for each peak by measuring with a ruler the distance between the wavenumbers marked on the X-axis." PTX-801.0004. He further stated that "[t]he measurements were made approximately to the nearest 0.5 mm." PTX-0801.0004. The Benneker Declaration further explained that he used these measurements to calculate a scale factor. He then "placed the ruler parallel to the Y-axis... directly against the side of the peak to be measured and marked this point on the X-axis." PTX-801.0004. Finally, he measured the distance "approximately to the nearest 0.5 mm" from the closest wavenumber marked on the X-axis to the marked point on the X-axis and used this measurement to calculate the peak's location. PTX-801.0004.

         To date, the crystalline form of paroxetine mesylate studied by Dr. Benneker is the only polymorphic form that has been found. 12/8 Tr. p.m. (Myerson) 9:21-10:3. In seeking to institute the Interference Proceeding, Synthon affirmatively represented to the PTO that "[a] 11 of the evidence... indicates that there is only a single crystalline form of paroxetine [mesylate]." JTX-6. Although it is theoretically possible that another crystalline form of paroxetine mesylate will be discovered in the future, 12/8 Tr. p.m. (Myerson) 10:17, Dr. Rogers testified that "it is highly unlikely" that another form would be found. 12/9 Tr. a.m. (Rogers) 96:7-20. In reaching his conclusion, Dr. Rogers considered the Genck Declaration and the Brittain Declaration, which describe a polymorph screen in which Dr. Genck attempted crystallization of paroxetine mesylate under thousands of different sets of conditions. See 12/9 Tr. a.m. 89:24-91:20. Only one form was found and Dr. Genck concluded that paroxetine mesylate was not polymorphic. 12/9 Tr. a.m. 91:15-20.[15]

         ii. Development of the Method of Treatment Patents

         The method of treatment patents claim uses of paroxetine to treat vasomotor symptoms. The asserted claims of the '663 patent are directed to the use of the mesylate salt of paroxetine, i.e., paroxetine mesylate, while the asserted claims of the '251 patent are directed more generally to any pharmaceutically acceptable salt of paroxetine. Paroxetine belongs to a class of antidepressants known as selective serotonin reuptake inhibitors ("SSRIs"). Paroxetine hydrochloride is a salt of paroxetine that has been used commercially to treat depression since 1997, under the name Paxil. 12/12 Tr. a.m. (Locker) 93:7-13.

         Vasomotor symptoms have long been treated with hormone therapy. See, e.g., 12/13 Tr. (Simon) 123:4-10. However, a large part of the population of women needing treatment are unable to take hormone therapy for vasomotor symptoms, including patients who are suffering from or at risk of developing breast cancer. 12/12 Tr. p.m. (Locker) 25:5-14; 12/13 Tr. (Simon) 123:11-22. Starting in the 1960s, researchers evaluated the efficacy of various non-hormonal treatments. 12/13 Tr. (Simon) 126:1-127:17. In the 1990s, researchers were assessing the use of a variety of antidepressants for the treatment of vasomotor symptoms, including venlafaxine (a serotonin-norepinephrine reuptake inhibitor, or "SNRI"), paroxetine, sertraline, fluoxetine, citalopram, and mirtzapine. 12/13 Tr. (Simon) 127:20-134:20. All of these agents were being tested at the antidepressant dose or higher. 12/13 Tr. (Simon) 135:6-9. An additional compound, gabapentin, also indicated efficacy during this period. 12/13 Tr. (Simon) 136:21-137:5.

         In 2000, a pilot study published by Stearns, et al., established that paroxetine hydrochloride was effective to treat hot flashes at doses as low as 10 mg/day. See 12/12 Tr. a.m. (Locker) 90:9-18, 94:7-25; JTX-33). In 2004, a patent application filed by Lemmens, et al, concluded that paroxetine mesylate was preferable to paroxetine hydrochloride as it is more highly water soluble and has better thermal stability. 12/12 Tr. a.m. (Locker) 93:17-23; PTX-983. In 2005, a more sophisticated study was published on 10 mg and 20 mg doses of paroxetine. 12/12 Tr. a.m. (Locker) 95:14; JTX-34. The second study also indicated that there was a decrease in negative side effects from the 20 mg dose to the 10 mg dose. 12/12 Tr. a.m. (Locker) 97:21-98:5. By 2005, doctors were prescribing 10 mg doses of Paxil off-label for treatment of hot flashes, 12/12 Tr. a.m. (Locker) 98:19-99:7, and doctors were using other SSRIs and SNRIs to treat hot flashes. 12/12 Tr. a.m. (Locker) 97:15-20.

         In 2002, the Women's Health Initiative ("WHI") study was published. This was a major study that clearly demonstrated increased risk of several serious conditions, including breast cancer, stroke and heart attacks, as a result of hormonal treatments. 12/13 Tr. (Simon) 124:24-125:6. This led to an increased focus on developing non-hormonal treatments for vasomotor symptoms. 12/13 Tr. (Simon) 125:16-20. However, SSRIs and SNRIs, and paroxetine in particular, have a number of side effects associated with them, including weight gain and sexual dysfunction, which are particularly problematic for menopausal women. 12/12 Tr. p.m. (Locker) 30:16-31:21; 12/13 Tr. (Simon) 141:22-143:4. Furthermore, at the time of the invention, tamoxifen was a commonly prescribed breast cancer therapy, 12/12 Tr. p.m. (Locker) 25:19-26:4; 12/13 Tr. (Simon) 144:1-16, and paroxetine was known to interfere with the efficacy of tamoxifen. 12/12 Tr. p.m. (Locker) 26:5-20; 12/13 Tr. (Simon) 144:17-20.

         Dr. Richards, the named inventor on the method of treatment patents, testified that she had experience prescribing low doses of antidepressants to treat pain, Richards Dep. 53:11-16, 53:20-54:6, knowledge that there is thermoregulatory function in the hypothalamus, and knowledge that there are serotonergic neurons in the hypothalamus. Richards Dep. 57:1-58:13. Based on this, she ...


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