The opinion of the court was delivered by: The Honorable Freda L. Wolfson, U.S.D.J.
Glossary of Abbreviations
ANDA Abbreviated New Drug Application
API Active Pharmaceutical Ingredient
DTX-# Defendant's Trial Exhibit
DX-#, col. #, ll. # Patents Exhibit Number, Column Number and Line Numbers
FDA Food and Drug Administration ("FDA")
FDCA Food, Drug and Cosmetic Act
ICDD International Center for Diffraction Data
PCT Patent Cooperation Treaty
PTO Patent and Trademark Office
PTX-# Plaintiff's Trial Exhibit
RaCL # Ranbaxy Proposed Conclusions of Law
RaFF # Ranbaxy Proposed Findings of Fact
RaR # Ranbaxy Response to Roche's Findings of Fact & Conclusions of Law
RoCL # Roche Proposed Conclusions of Law
RoFF # Roche Proposed Findings of Fact
RoRFF # Roche Response to Ranbaxy's Findings of Fact
RoRCL # Roche Response to Ranbaxy's Conclusions of Law
SF-# Stipulated facts from the Pretrial Order
SGF Simulated Gastric Fluid
STP Standard Test Procedure
USP United States Pharmacopeia
Vx-y:l Trial Transcript Volume "x" at page "y" and line "l"
This matter comes before the Court upon a Complaint brought by Plaintiff Roche Palo Alto LLC ("Roche") against Defendants Ranbaxy Laboratories Limited and Ranbaxy Inc. (collectively, "Ranbaxy") for patent infringement in violation of the Patent and the Food and Drug Laws of the United States, Titles 35 and 21 of the United States Code. In response, Ranbaxy filed a Counterclaim against Roche for declaratory judgment that the patent in suit is invalid and that Ranbaxy did not infringe the patent at issue.
This suit is based on the purported infringement on Roche's United States Patent No. 6,083,953 (the "'953 patent"). The '953 patent includes claims to the compound valganciclovir hydrochloride ("HCl") "in crystalline form," pharmaceutical compositions containing that compound "in crystalline form," and methods of using that compound "in crystalline form" to treat herpes simplex virus and cytomegalovirus ("CMV") infections. The instant action, brought under 35 U.S.C. § 271(e)(2), focuses on the meaning of "in crystalline form" and how one determines whether valganciclovir HCl is "in crystalline form." The current action arises from Ranbaxy's filing of an Abbreviated New Drug Application ("ANDA") for approval to market a generic version of Roche's antiviral drug Valcyte(r), the tradename for Roche's valganciclovir HCl tablets, prior to the expiration of Roche's '953 patent.
The Court conducted a nine-day bench trial with numerous experts and witnesses testifying as to claim construction, direct infringement, induced infringement, the prior art, the testing of valganciclovir HCl in crystalline form, and the active pharmaceutical ingredient ("API") in Ranbaxy's generic product, valganciclovir HCl in amorphous form. Roche's three theories of infringement are: (1) that Ranbaxy induces infringement because it knowingly uses a process to manufacture its tablets that permits the presence of crystalline seeds, which promotes the conversion of its valganciclovir HCl to crystalline form when exposed to moisture; (2) that Ranbaxy directly infringes because the valganciclovir HCl in its tablets will convert to the crystalline form upon ingestion; and (3) that Ranbaxy directly infringes because consumers will store Ranbaxy's tablets in pill trays, wherein the valganciclovir HCl will convert to the crystalline form. Roche relies on data from three tests presented by Dr. Jan-Olaf Henck ("Dr. Henck"): the spiking study or crystalline seed study ("seed study"), the simulated gastric fluid ("SGF") study, and the pill tray study, respectively.
Ranbaxy argues that the '953 patent is invalid based on three grounds: anticipation, failure of written description, and obviousness. First, Ranbaxy asserts that the claims of the patent in suit are anticipated. Ranbaxy, however, did not assert its anticipation claim in the Final Pretrial Order and its own experts state that the claims are not anticipated. Second, Ranbaxy asserts that the claimed invention is invalid for lack of written description support because the '953 patent does not discuss how to determine if the compound is "in crystalline form." Such argument, however, is not persuasive. A person of ordinary skill in the art understands that XRD is a reliable means to test for valganciclovir HCl in crystalline form. Further, the Court rejects Ranbaxy's argument that the '953 patent does not cover valganciclovir HCl presenting as a mixture of amorphous and crystalline material. Finally, Ranbaxy contends that the claims of the patent in suit were obvious in light of the prior art because Dr. Lilia Beauchamp's ("Dr. Beauchamp") prior patent, United States Patent No. 5,043,339 (the "'339 patent"), and papers teach valganciclovir, the oral biovailability of the compound, and crystallinity. The Court disagrees because Ranbaxy does not meet its heavy burden of proving by clear and convincing evidence that the crystalline form of the compound was taught by prior art or is obvious. Thus, the Court finds that the '953 patent is valid.
In light of the evidence presented at trial, the Court does not find that Ranbaxy infringed on Roche's '953 patent. Roche relies solely on the existence of a single XRD peak at 3.5° 2è to demonstrate the presence of valganciclovir HCl in crystalline form. This premise, as Ranbaxy argues and the Court agrees, is flawed because Roche has not shown by the preponderance of the evidence that only valganciclovir HCl "in crystalline form" exhibits this peak. Therefore, the Court finds that the mere presence of a peak at 3.5° 2è, without more, cannot be used as a determinative factor to find that Ranbaxy's tablets infringe on the '953 patent. Thus, the Court finds that Roche fails to prove its infringement case.
Roche is the assignee of the '953 patent issued on July 4, 2000.*fn1 SF-3. The patent in suit includes "claims to the compound valganciclovir [HCl] in crystalline form, pharmaceutical compositions containing the compound, and methods of using the compound to treat herpes simplex virus and [CMV] infections." SF-21; DTX-1. On September 28, 2000, Roche filed a New Drug Application ("NDA"), which was approved on March 29, 2001, for valganciclovir HCl tablets for use in treating CMV retinitis in AIDS patients. SF-23. Roche filed a supplemental NDA, on November 11, 2002, to use its tablets in the prevention of CMV disease in certain solid organ transplant patients, which the Food and Drug Administration ("FDA") also approved. SF-25. Roche sells its valganciclovir HCl tablets under the tradename Valcyte(r) ("Valcyte"). SF-24.
Defendant/Counterclaimant Ranbaxy Inc. ("RI"), based in Princeton, New Jersey, markets and sells generic drug products throughout the United States that Defendant/Counterclaimant Ranbaxy Laboratories Limited ("RLL") manufactures in India. SF-2. On December 22, 2005, RLL filed ANDA No. 78-078, seeking FDA approval to market generic 450 mg valganciclovir HCl tablets containing the same amount of drug substance and imparting the same medical benefit as Valcyte. SF-4, 8. The FDA has tentatively approved this ANDA. V5-158:11-16. On March 17, 2006, Ranbaxy sent a notice to Roche, pursuant to 21 U.S.C. § 355(j)(2)(B)(iv), certifying that, under the Food, Drug and Cosmetic Act ("FDCA") Section 505(j)(2)(A)(vii), paragraph IV, the manufacture, use, sale, or offer for sale of tablets under Ranbaxy's ANDA would not infringe the '953 patent. PTX-287; SF-5.*fn2
Roche filed a Complaint against Ranbaxy alleging infringement of the '953 patent under 35 U.S.C. § 271(e)(2), on April 28, 2006. On August 15, 2006, Roche filed an Amended Complaint, which added a claim for inducing infringement under 35 U.S.C. § 271(b) and further requested a judgment and decree that the '953 patent is valid and enforceable. SF-12. On September 25, 2006, Ranbaxy filed its Answer and Counterclaims, denying infringement, counterclaiming for noninfringement and invalidity of the '953 patent, and requesting an award of attorney's fees and costs, pursuant to the "exceptional case" provision of 35 U.S.C. § 285. SF-13; Answer & Counterclaims ¶¶ A-G. Motions for summary judgment were denied by the Court, after which, a nine-day bench trial was conducted in December of 2008. Subsequently, the parties submitted proposed Findings of Fact and Conclusions of Law, which were supplemented by Reply briefs.
A. CMV, Valcyte, and the '953 Patent
CMV is present in a large percentage of the adult population and generally produces no symptoms. Stipulation Regarding Expert Test. of David M. Snydman, M.D. ("Snydman Stip.") ¶ 5. CMV, however, can cause serious problems in persons with depressed immune systems, such as AIDS patients and organ transplant recipients who are taking immunosuppressive medication to prevent the rejection of a transplanted organ. Id.; V1-84:21-85:23. In AIDS patients, a common manifestation is CMV retinitis, which can result in blindness. V1-85:24-86:2. In organ transplant recipients, CMV can cause rejection of the transplanted organ and increase the cost of medical care by 40 to 80% in the first year after the transplant. Snydman Stip. ¶¶ 6-7.
Valcyte is an orally administered antiviral medication, which the FDA approved for the treatment of CMV retinitis in AIDS patients and for the prevention of CMV disease in organ transplant recipients. V1-56:3-22; PTX-653 at 8. Valcyte is "considered the 'gold standard,' the 'drug of choice,' the 'treatment of choice,' and the 'standard of care' for the prevention and treatment of CMV disease." RoFF 3 (citing V8-159:5-11; V1-86:3-6; Snydman Stip. ¶¶ 8, 22). The active ingredient in Valcyte is the subject matter of claim 1 of the '953 patent, valganciclovir HCl in crystalline form. Snydman Stip. ¶ 23; V1-55:1-12; PTX-653, ll. 11, 19.
The '953 patent contains six claims. Claim 1, the only independent claim, of the '953 patent reads: "The compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy-3-hydroxy-1-propanyl-L-valinate hydrochloride in crystalline form." DTX-1, col. 30, ll. 42-44. The parties agree for purposes of this case that the chemical name refers to valganciclovir HCl, so claim 1 means valganciclovir HCl "in crystalline form." V9-85:11-13. The parties disagree as to the meaning of only one claim term: the requirement that the compound be "in crystalline form." RoFF 10; RaFF 1. Claim 1 is a compound claim and not a manufacturing claim, and covers valganciclovir HCl in crystalline form regardless of how it is produced. V2-108:11-21; see Part III.A., infra. Claims 2-6 relate to a pharmaceutical composition comprising the compound and involve methods of treating viral infections by administering the compound; these claims are not in dispute. See n. 42, infra.
B. Background of Crystalline and Noncrystalline Materials
A crystalline material is a material composed of crystals, which are solids that have molecules organized into a repeating pattern in three dimensions, containing a three-dimensional long range order. V2-80:2-8; V6-25:12-17. By contrast, an amorphous material is noncrystalline material that has molecules distributed randomly in a solid material, lacking long range order. V6-25:12-23, 27:19-28:8; V2-80:2-13; V10-175:10-177:1, 180:21-181:2; PTX-772 at 1 ("[T]he crystalline state [of solids] differs from the amorphous state in the regular arrangement of the constituent molecules, atoms or ions into some fixed and rigid pattern known as a lattice."). Amorphous material has greater free energy than crystalline material due to the random distribution of its molecules and is thermodynamically inclined to convert to crystalline form. RoFF 7; V2-80:2-23. Increases in temperature and exposure to water or humidity can promote this conversion. RoFF 7; V2-80:24-82:2.
Ranbaxy argues that crystalline and amorphous solids are endpoints on a continuum, and there may be numerous noncrystalline, semi-amorphous solids between these endpoints. RaFF 9 (citing V6-26:8-27:12, 29:21-30:23; DTX-803.1). According to Ranbaxy, crystalline and amorphous solids can transition among each other based on the conditions to which the material is exposed, and these transitions can take varying amounts of time. Id. (citing V6-28:9-29:20). Roche maintains, and Ranbaxy does not dispute, that crystalline and amorphous solids may co-exist in the same compound as a mixture. A physical mixture of amorphous and crystalline solids is not the same as a semi-amorphous or a partially ordered solid.*fn3 V6-37:3-38:10. Roche has not demonstrated that semi-amorphous or partially ordered solids do not exist. At trial, Dr. Henck initially denied the existence of partially ordered solids, and instead asserted that a material can be either crystalline or amorphous with no intermediate state in between these two forms. V2-98:22-24; V10-175:10-16, 180:21-181:2, PTX-572. He admitted, however, that "there are materials that are noncrystalline but [also] not amorphous." V3-60:24-61:7.*fn4 Further, prior to this litigation, Dr. Henck co-authored an article, entitled Designing a Molecular Delivery System Within a Preclinical Timeframe, in Drug Discovery Today ("Molecular Delivery System") in which he wrote:
Solids can also produce diffuse scattering. For amorphous and disordered solids, only diffuse scattering is produced. For systems with intermediate order between crystals and amorphous, a mixture of diffuse scattering and Bragg peaks is observed. DTX-821 at 3 (emphasis added); see V10-181:3-19; V10-179:20-23.11. Thus, Court finds that semi-amorphous or partially ordered solids do exist, as well as mixtures of amorphous and crystalline solids.
C. X-ray Diffraction Testing
The parties' experts agree that the "the primary method of choice" among persons of skill in the art and the "best technique" for determining whether a material is in crystalline form is powder X-ray diffraction, or "XRD." V2-83:1-6; V6-162:22-164:4; V7-42:6-44:2. Indeed, Ranbaxy relied on XRD as the sole basis for the contention that its valganciclovir HCl is not "in crystalline form" in its Paragraph IV notice sent to Roche. V2-105:4-106:8; PTX-287 at 3.
When a crystalline material is subjected to XRD, the X-rays are diffracted at specific angles ("degrees 2è" or "°2è"), resulting in a pattern similar to a fingerprint, which exhibits one or more sharp, well-defined "peaks." V2-83:13-84:14; V6-33:21-34:11. An amorphous material subjected to XRD does not produce peaks, but exhibits broad humps, referred to as a "halo" pattern. V2-93:15-94:9; V6-33:6-20; DTX-183 at 7. According to Ranbaxy, the XRD pattern of a semi-amorphous or a partially ordered solid depends on the amount of order present in the material and can exhibit both an amorphous hump and broad, ill-defined peaks. V6-34:12-20. Conversely, a physical mixture containing both crystalline and amorphous solids exhibits the broad hump characteristic of the amorphous material superimposed on the sharp, well-defined XRD peaks of the crystalline material. V6-34:21-36:11, 155:15-156:20. Thus, the peak positions of a crystalline solid will not change if mixed with an amorphous solid nor will it exhibit the broad, ill-defined peaks characteristic of a partially ordered solid. V6-36:12-37:2.
At trial, Dr. Henck testified that noncrystalline solids with intermediate order, which exhibit one low angle peak, do not exist. V10-178:13-17. The Court finds this position unpersuasive in light of Dr. Rogers' testimony and the different XRD patterns presented at trial. Indeed, Dr. Henck admits that solids in different states produce different XRD patterns. DTX-821 at 3; see Part II.B., supra. Thus, the evidence shows that noncrystalline solids with intermediate order do exist and can exhibit a single low angle peak. See Part II.D.2., infra.
D. Valganciclovir HCl Forms and XRD Testing
1. Valganciclovir HCl Forms
Valganciclovir HCl exists in at least two forms: crystalline and amorphous.*fn5 V6-156:21-159:2. In its March 1996 "RS-79070-194 Preformulation Book" ("Preformulation Book"), Roche stated that "[t]here are two crystalline forms (X and Y) and two metastable forms (A and B) of the racemic mixture of the diastereomers of [valganciclovir HCl]." DTX-589 at 9; V6-38:13-39:20; V3-65:18-66:2. Roche contrasted the two crystalline forms of valganciclovir HCl, Forms X and Y, with the two noncrystalline, metastable forms of valganciclovir HCl, Forms A and B. V6-38:25-39:7, 46:1-9; V3-66:22-25. Roche described valganciclovir HCl Form A as a "semi-amorphous, flake-like material" that is "not stable under ambient conditions," which "converted to Form X" under accelerated conditions of 98% relative humidity for three days. DTX-104 at 16; V6-168:9-21. Roche described Form B as a "gelatinous amorphous material" that is "not stable under ambient conditions" and "converted to a crystalline form." DTX-104 at 16; V4-168:22-25; V2-142:8-143:1. Thus, Roche determined that Forms A and B are neither crystalline nor stable, and converted to crystalline under certain conditions. DTX-589 at 15, 26.
In July 1998, Dr. Henck's employer, SSCI, conducted various tests on the compound valganciclovir HCl for Roche. DTX-216; V6-46:10-19. SSCI repeated the statement found in Roche's Preformulation Book that "[t]here are two crystalline forms (X and Y) and two metastable forms (A and B) of the racemic mixture of the diastereomers of [valganciclovir HCl]." DTX-216 at 4. SSCI also determined that there was little difference between the various forms (crystalline and metastable) and found that the XRD patterns of "X and A are difficult to distinguish." DTX-216 at 4-5.*fn6 SSCI speculated that while the XRD patterns of Forms X and Y are similar, the XRD pattern of Form A "could be interpreted as arising from poorly crystalline Form X." Id. at 4. Therefore, Roche characterized Forms A and B as less stable than the "very crystalline" Forms X and Y. Id. at 9.
Roche submitted its NDA for Valcyte to the FDA, on August 15, 2000, six weeks after the '953 patent issued with claims limited to valganciclovir HCl "in crystalline form;" Roche's prior attempts to obtain a patent for valganciclovir HCl had been unavailing and it was only after adding the claim limitation of "in crystalline form" that it was successful. DTX-659; DTX-1. In its NDA, Roche wrote: "There are two crystalline forms of valganciclovir HCl (termed X and Y) and an amorphous form." DTX-659 at 1; V3-67:1-15; DTX-803.3; V6-48:22-49:4, 49:16-22. Roche stated that "[n]o crystalline forms other than form X and Y have been observed." DTX-659 at 1; V3-67:16-68:11. Roche summarized its studies on valganciclovir HCl explaining:
Early in the development process, two metastable forms (originally called A and B) were thought to be present; however, these appear to be merely amorphous material containing low amounts of crystalline material.
DTX-659 at 1; see also DTX-803.8; V6-55:16-56:19, 165:1-167:8; V3-141:15-142:8. Thus, contrary to its prior characterizations, in its NDA, Roche changed its own definition of these metastable forms by claiming that they do not exist; rather, Roche re-defined these "metastable forms" as merely mixtures of amorphous and crystalline material, and therefore, classified them as containing Forms X and Y, making them "in crystalline form."*fn7
Although Ranbaxy does not dispute that amorphous and crystalline valganciclovir HCl can co-exist as a mixture, it contends that additional forms of valganciclovir HCl also exist. Specifically, Ranbaxy submits that there are other semi-amorphous forms between pure amorphous and pure crystalline; for example, Ranbaxy cites to Roche's own initial descriptions of Forms A and B, of valganciclovir HCl. For support, Ranbaxy relies on the opinion of Dr. Robin D. Rogers ("Dr. Rogers"), who is an expert in solid state chemistry, XRD, and various aspects of crystallinity. V6-21:1-25:10; DTX-656. Dr. Rogers explained that Form A is a partially ordered solid between crystalline and amorphous on the continuum. DTX-803.09; V6-59:7-60:20.*fn8 Consistent with Roche's initial characterizations and Ranbaxy's submissions, the Court finds that there are other possible, semi-amorphous forms of valganciclovir HCl, and these other forms are not "in crystalline form." V6-58:11-21, 67:15-20; see Part III.A., infra. In contrast, Roche claims that Forms A and B do not exist because they are merely mixtures of crystalline and amorphous forms, as opposed to semi-amorphous material. The Court finds, however, that Roche has failed to prove that position.
2. Whether a Sole Peak at 3.5° 2è Indicates Valganciclovir HCl in Crystalline Form
As a preliminary matter, the parties' experts agree that every XRD pattern of crystalline valganciclovir HCl, namely, Forms X and Y, contain a peak at 3.5° 2è, which is used as a "reference peak to determine crystalline valganciclovir [HCl]." V2-131:15-22. "In Dr. Henck's expert opinion, a peak at 3.5° 2è is the 'distinguishing fingerprint' or 'signature peak' for identifying valganciclovir [HCl] in crystalline form." RoFF 41 (citing V2-131:23-132:2, 10-19). Ranbaxy's expert, Dr. Rogers, agrees that crystalline valganciclovir HCl always has an XRD peak at 3.5° 2è, V6-169:25-170:5, and admits that he has never seen an XRD pattern of crystalline valganciclovir HCl that did not have an XRD peak at 3.5° 2è. V6-170:6-9. Further, Ranbaxy's expert Dr. Jeremy Karl Cockcroft ("Dr. Cockcroft"), an expert in solid state structural characterization, agreed that he has never seen an XRD pattern of crystalline valganciclovir HCl that did not have a peak at 3.5° 2è, and upon inquiry by the Court, that in this case "distinctive" peak and "strongest" peak have the same meaning. V7-44:22-45:10.
The parties, however, disagree whether a single peak is determinative of whether a sample of valganciclovir HCl is in crystalline form; specifically, whether a sole XRD peak at 3.5° 2è establishes the presence of valganciclovir HCl "in crystalline form." Dr. Henck testified that a person of skill in the art understands that the presence of a compound "in crystalline form" is detected by an XRD pattern that records "at least one peak." V2-103:16-104:2, 17-22. Citing to Dr. Henck, Roche asserts that it is accepted practice among crystallographers that when looking at a sample that consists of a mixture of different compounds, and there is one unique peak that can identify a specific crystalline material and no other component of the mixture exhibits a peak at that position, a single peak in an XRD is enough to identify that specific compound. V2-84:15-25, 132:3-9, 133:14-17. Roche argues, and Dr. Rogers agrees, that when the ingredients of a sample are known, a single peak can be determinative of whether a specific compound in the sample has crystalline material. RoFF 39; RaFF 22-23.*fn9 On the other hand, a single peak cannot be used to identify the presence of a specific material in an unknown sample when that single peak is not unique to the material being assessed. V6-60:21-63:7.
In this case, the excipients, coating, and active ingredient in Ranbaxy's tablets are all known.*fn10 V6-171:4-18; V2-132:10-19. The parties' experts agree, however, that Forms X and Y of valganciclovir HCl, as well as what Roche originally categorized as Forms A and B, demonstrate a strong distinctive peak at 3.5§ 2è. V3-68:12-22; V6-57:7-59:3. Thus, the inquiry is whether the mere presence of a peak at 3.5§ 2è sufficiently distinguishes valganciclovir HCl in crystalline form -- whether it is pure crystalline or in a mixture of crystalline material and other forms -- from other possible semi-amorphous forms of valganciclovir HCl. The Court finds that it does not.
Dr. Henck contends that an XRD peak at 3.5° 2è alone is sufficient to establish the presence of crystalline valganciclovir HCl, V3-61:13-24; he asserts that this peak appears in what Ranbaxy might refer to as noncrystalline forms because these forms are in actuality merely mixtures of amorphous and crystalline valganciclovir HCl, and not distinctive, separate forms of semi-amorphous material. V3-142:9-143:4. Underlying Dr. Henck's conclusion is his assumption that there are no semi-amorphous forms of valganciclovir HCl, and that Roche's early categorizations that Forms A and B are semi-amorphous were inaccurate. Dr. Henck, however, fails to offer support for this conclusion.*fn11 Rather, he admits that a peak at 3.5° 2è does not distinguish among the XRD patterns for Forms X, Y, and the contested Forms A and B; in fact, he made no effort to determine the peaks necessary to distinguish among these forms. V3-68:12-22; see V6-44:13-45:25, 58:22-9, 59:3. Further, in Roche's Preformulation Book, the XRD patterns for pure crystalline Forms X and Y, as well as "metastable" Forms A and B each contained a prominent XRD peak at 3.5° 2è. DTX-104 at 19, 23-24. Because of its own unproven assumption that semi-amorphous forms of valganciclovir HCl do not exist, Roche concludes that a peak at 3.5° does uniquely identify valganciclovir HCl in crystalline form. However, the Court finds this assumption erroneous, and thus, Roche's own testing does not establish that a peak at 3.5° is unique to the crystalline forms. V6-44:1-45:25; DTX-803.02.
Dr. Rogers explains, and the Court agrees, that in this case, a peak at 3.5° 2è alone does not establish the presence of valganciclovir HCl "in crystalline form" because other possible semi-amorphous forms may also exhibit a peak at this position. V6-63:8-22. While the height of the peak or limit of detection may vary based on whether the API is contaminated with valganciclovir HCl "in crystalline form," see Part II.E.1., infra, and thus a single peak at 3.5° 2è alone with more definitive characteristics could be sufficient for detection, there is insufficient evidence in the record as to what the height of the peak or the area under the curve should be for the various forms of valganciclovir HCl, and specifically for Forms X and Y. Furthermore, Roche does not explain nor demonstrate by a preponderance of the evidence that the peak cannot be formed by other possible semi-amorphous forms. See Part III.B.1., infra (discussing how this peak could be the result of semi-amorphous material or some other excipient mixed with valganciclovir HCl). Thus, based on the record, because the mere presence of a peak at 3.5° 2è does not distinguish between valganciclovir HCl "in crystalline form," Forms X and Y, and other possible semi-amorphous forms, that particular peak cannot alone establish the presence of valganciclovir HCl in crystalline form in Ranbaxy's tablets.
3. Multi-Peak "Fingerprint" Indicates Crystalline Valganciclovir HCl
In its NDA, Roche provided XRD patterns for Forms X and Y, DTX-659 at 3, the only two known and recognized forms of crystalline valganciclovir HCl. V2-131:8-14. The XRD patterns for crystalline Forms X and Y show, inter alia, the strongest peak at 3.5° 2è, with additional strong peaks and 9.5° and 11.8° 2è, which is consistent with Roche's Preformulation Book. DTX-104 at 19; DTX-803.02; V2-134:7-135:15; V3-93:8-17; V6-40:10-41:11; V7-18:15-24. Roche's NDA submission also contained an XRD pattern for amorphous valganciclovir HCl, showing the hump characteristic of amorphous material and no peaks. DTX-659 at 2, 5; DTX-803.06-07; V6-54:3-55:8. The XRD patterns for the contested Forms A and B show a strong peak at 3.5° 2è, but do not show the peaks at 9.5° and 11.8° 2è, characteristic of crystalline Forms X and Y. V6-42:25-43:7, 43:13-25, 56:20-57:20; DTX-104 at 23-24. Thus, according to Ranbaxy, semi-amorphous Forms A and B of valganciclovir HCl may be distinguished from the crystalline Forms X and Y based on the lack of the presence of peaks at 9.5° and 11.8° 2è. V6-58:22-59:6.
Roche asserts that every XRD pattern of crystalline valganciclovir HCl contains a peak at 3.5° 2è, but the presence, as well as the height, width, and position of a peak, or absence of peaks at other angles, such as 9.5° and 11.8° 2è, can vary based on numerous factors, including but not limited to, preparation of the sample, how the sample was obtained, and other components in the sample.*fn12 RoFF 53; V2-91:24-93:14. For example, samples of both Forms X and Y of crystalline valganciclovir HCl prepared with isopropanol solvent display a peak at 3.5° 2è as well as at 9.5°, 11.8°, 14.7°, 15.6°, and 17.1° 2è. V2-134:7-135:21; DTX-104 at 16. A sample of crystalline valganciclovir HCl prepared with a different solvent, ethanol, still contains a peak at 3.5° 2è, but only has weak peaks at 9.5° and 14.7° 2è and no peaks at 11.8°, 15.6°, and 17.1° 2è. V2-135:22-137:10; PTX-281A. In another sample of crystalline valganciclovir HCl obtained from an ethanol solvent and then exposed to ambient conditions for two hours, the XRD pattern has a peak at 3.5° 2è and weak peaks at 9.5° and 11.8° 2è and no peaks at 14.7°, 15.6°, and 17.1° 2è. V2-137:11-138:14; PTX-282A. In the Form X and Y samples of crystalline valganciclovir HCl prepared with isopropanol and the two samples of valganciclovir HCl prepared with ethanol, PTX-281A and PTX-282A,*fn13 the ...