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Glaxosmithkline LLC v. Banner Pharmacaps, Inc.

United States District Court, Third Circuit

August 9, 2013

GLAXOSMITHKLINE LLC (f/k/a SMITHKLINE BEECHAM CORPORATION), Plaintiff,
v.
BANNER PHARMACAPS, INC., et al., Defendants.

Jack B. Blumenfeld, Esq., Wilmington, Delaware; William F. Lee, Esq., Boston, Massachusetts; Lisa J. Pirozzolo, Esq., Boston, Massachusetts; Christopher R. Noyes, Esq., New York, New York; Attorneys for Plaintiff GlaxoSmithKline LLC.

John C. Phillips, Jr., Esq., Wilmington, Delaware; Phillip B. Philbin, Esq., Dallas, Texas; C. Kyle Musgrove, Esq., Washington, D.C.; Michael M. Shen, Esq., Washington, D.C.; Thomas B. King, Esq., Irvine, California; James H. Wallace, Jr., Esq., Washington, D.C.; Mark A. Pacella, Esq., Washington, D.C.; Attorneys for Defendants.

Richard L. Horwitz, Esq., Wilmington, Delaware; Kenneth G. Schuler, Esq., Chicago, Illinois; Stephen R. Howe, Esq., Chicago, Illinois; Attorneys for Defendant Roxane Laboratories, Inc.

OPINION AFTER TRIAL

RICHARD G. ANDREWS, District Judge.

Plaintiff Glaxosmithkline LLC ("GSK") asserts one patent, [1] U.S. Patent No. 5, 565, 467 ("the '467 Patent") against Defendants Banner Pharmacaps, Inc., Roxane Laboratories, Inc., Watson Laboratories, Inc.- Florida, Mylan, Inc., Mylan Pharmaceuticals, Inc., and Impax Laboratories, Inc. (collectively "Defendants").[2] The '467 Patent is directed at the synthetic drug compound dutasteride as well as the pharmaceutically acceptable solvates of dutasteride. Each Defendant has filed at least one Abbreviated New Drug Application ("ANDA"), seeking to market generic drug products containing dutasteride. Dutasteride is marketed under the brand name Avodart, and is used to treat androgen responsive or mediated conditions, including benign prostatic hyperplasia ("BPH"), more commonly known as enlarged prostate. Dutasteride is a selective dual inhibitor of the enzyme known as 5-a reductase ("5AR"). The 5AR enzyme converts testosterone into dihydrotestosterone ("DHT"). DHT plays an essential role in the development of the male prostate, but also may cause undesired androgen action resulting in an enlarged prostate later in life. By inhibiting 5AR, dutasteride is able to halt the conversion of testosterone into DHT and is thus able to treat BPH and possibly other conditions.

Defendants stipulated to infringement, but contend that the '467 Patent is invalid due to the failure to meet the written description and enablement requirements, as well as due to the existence of intervening anticipatory prior art. Defendant Roxane also independently asserts that the utility requirement is not met. The Court held a bench trial from January 28 through January 30, 2013.[3] This Memorandum Opinion represents the Court's findings of facts and conclusions of law. As explained below, the Defendants did not prove any of the invalidity defenses by clear and convincing evidence, and thus the Court finds in favor of GSK on all issues.

I. WRITTEN DESCRIPTION & ENABLEMENT

The Court first addresses the defenses of written description and enablement under ยง 112. Defendants argue that although the '467 Patent claims the entire universe of pharmaceutically acceptable solvates of dutasteride, it fails to disclose or enable a single solvate of dutasteride, much less solvates that satisfy the complete scope of the Court's claim construction. GSK disagrees, arguing that solvates are well-known in the art of drug development, the specification expressly describes solvates of dutasteride, and the creation and testing of dutasteride solvates would be routine for someone skilled in the art. Claim 1 of the '467 Patent claims: "[dutasteride] or a pharmaceutically acceptable solvate thereof." The Court construed two terms. (D.I. 243). The first is "solvate, " construed as "a complex formed by dutasteride with a solvent in which dutasteride is reacted or from which it is precipitated or crystallized." The second term is "pharmaceutically acceptable, " construed as "suitable for use when administered to the recipient thereof in a pharmaceutical."

The parties agree that one of ordinary skill in the art would have an advanced degree in organic or medicinal chemistry, with some experience in drug discovery and development. (Tr. at 130, Dr. Rogers; Tr. at 645-46, Dr. Byrn). The relevant time period is the early to mid-1990s. Defendants further propose that a person of ordinary skill would have access to a team of drug development scientists, including biologists, pharmacologists, and solid-state chemists and formulation scientists. ( Id. ). The Court accepts these proposals for its definition of a person skilled in the art.

(A). Written Description

(i). Findings of fact.

1. One of ordinary skill in the art would have an advanced degree in organic or medicinal chemistry, with some experience in drug discovery and development, and access to a team of drug development scientists, including biologists, pharmacologists, and solid-state chemists and formulation scientists. (Tr. at 130, Dr. Rogers; Tr. at 645-46, Dr. Byrn).
2. The relevant time period is the early to mid-1990s. See '467 Patent.
3. Claim 1 of the '467 Patent recites: "[dutasteride] or a pharmaceutically acceptable solvate thereof."
4. "Solvate" is construed as "a complex formed by dutasteride with a solvent in which dutasteride is reacted or from which it is precipitated or crystallized."
5. "Pharmaceutically acceptable" is construed as "suitable for use when administered to the recipient thereof in a pharmaceutical."
6. The solvate concept is introduced in the specification as follows:
Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." Solvates of [dutasteride] are within the scope of the invention.
It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms of [dutasteride] or the pharmaceutically acceptable solvates thereof are within the scope of the present invention.
'467 Patent at 3:59-4:12.
7. Technologies such as high throughput screening, which allows the rapid identification of solvates, did not exist in 1993. (Tr. at 128-29).
8. The drug compound dutasteride is the key structural component distinguishing the '467 Patent from the prior art. See '467 Patent.
9. A solvate is detected when a person skilled in the art sees a complex of a solvent and a chemical compound, regardless of whether it is said to be reacted, precipitated, or crystallized. (Tr. at 201-03, Dr. Rogers; PTX 222).
10. The concept of solvation has been known in the art for over 100 years. (Tr. at 201-03, Dr. Rogers).
11. Steroids in particular have been known to be prone to solvate formation since 1983. (Tr. at 670, Dr. Byrn; PTX 135).
12. Dutasteride is a steroid. '467 Patent at 10:18.
13. The universe of solvents thought to be pharmaceutically acceptable was well-known and relatively small. (Tr. at 222-29, Dr. Rogers; Tr. at 661, 666-68, Dr. Byrn).
14. All solvates of dutasteride retain the molecular structure and chemical function of dutasteride, and if those solvates were to arrive at the active sites, they would have the therapeutic effect. (Tr. at 653-54, Dr. Bryn; Tr. at 233-34, Dr. Rogers).
15. A "pharmaceutically acceptable solvate" that is "suitable for use" does not need to meet all the requirements of a finished drug product. ( See D.I. 226, p. 42-43).
16. The "suitable for use when administered to the recipient thereof as a pharmaceutical" construction of "pharmaceutically acceptable solvate" requires the solvate to be safe and to offer some therapeutic effect. ( Id. ).
17. It would be routine for a person skilled in the art to select a solvent to make a safe solvate, meeting the first "suitable for use" requirement. See Factual Finding # 13.
18. For the solvate to offer some therapeutic effect, it must be bioavailable. (Tr. at 234-36, Dr. Rogers; Tr. at 703, Dr. Byrn).
19. To achieve bioavailability, the solvate must be dissolved and have the requisite solubility in the body. (Tr. at 234-35, Dr. Rogers).
20. Solvate formation within a series of related compounds tends to lack a discernible pattern, with each compound having a unique response to solvate formation. (PTX 144 at 234; see also DTX 88 at 1148).
21. It can be difficult or even impossible to predict whether a particular solvate form will offer bioavailability prior to the solvate's actual formation. (Tr. at 654, 800-01, Dr. Byrn; see DTX 309 at 4).
22. Routine testing techniques allow the bioavailability of a solvate to be determined after the fact. (Tr. at 111-14, 209, Dr. Rogers).
23. To ascertain solubility of a particular form in 1993, one would perform a solubility test. (Tr. at 235, Dr. Rogers).
24. A solubility test could be done within a week. (Tr. at 235-36, Dr. Rogers).
25. Example 3D of the '467 Patent's specification shows dutasteride dissolved in a solution. '467 Patent at 15:21-25.
26. A chemical reaction as it is typically referred to involves the transformation of a compound's chemical identity via the creation or destruction of covalent bonds. (Tr. at 114-18, Dr. Rogers).
27. The specification at times uses the word "reaction" in conjunction with examples of such covalent bond formation. (Tr. at 751-53, Dr. Byrn; '467 Patent at 5:37-44, 7:63-68; 12:29-45).
28. Example 3D does not style itself as a reaction, but rather a dissolution, and does not depict the creation of covalent bonds. (467 Patent at 15:21-25).
29. The term "reacted" is used in the context of solvation. '467 Patent at 3:61.
30. Solvation does not involve the transformation of chemical identity, i.e., the creation of covalent bonds. (Tr. at 653-54, Dr. Bryn; Tr. at 233-34, Dr. Rogers).
31. A "reacted" solvate would not require the creation of covalent bonds. ( See id. ).
32. Solvation has been closely associated with dissolution for over 100 years. (PTX 222 at 160).
33. Solvates can form when an organic compound is dissolved in water. (Tr. at 202-03, Dr. Rogers).
34. Solvent molecules interact with dissolved molecules of a compound to create a solvate. (Tr. at 201-03, Dr. Rogers; PTX 222; PTX 340).
35. The Avodart label is identified as a dissolved compound but is not labeled as a solvate. (Tr. at 758-762, Dr. Byrn; DTX 438 at 11-12).
36. Example 3D depicts the dissolution of the steroid dutasteride in the safe solvent known as propylene glycol. (Tr. at 255, Dr. Rogers).
37. Example 3D describes a solvate of dutasteride. (Tr. at 688, Dr. Byrn).

(ii). Legal discussion and conclusions of law.

The written description "must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.'" Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). The test is whether the disclosure "reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Id. This requires an "objective inquiry into the four comers of the specification from the perspective of a person of ordinary skill in the art." Id. This is a question of fact. Id.

"[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology." Id. "[The] sufficient description of a genus requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can visualize or recognize' the members of the genus." Id. at 1350. "A written description of an invention involving a chemical genus, like a description of a chemical species, "requires a precise definition, such as by structure, formula, [or] chemical name, " of the claimed subject matter sufficient to distinguish it from other materials.'" Boston Scientific Corp. v. Johnson & Johnson, 647 F.3d 1353, 1363 (Fed. Cir. 2011) (citations omitted). Factors to be examined include "the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.'" Ariad, 598 F.3d at 1351. "A patent is presumed to be valid, and this presumption can only be overcome by clear and convincing evidence to the contrary." Id. at 1354.

As discussed above, the '467 Patent claims both dutasteride and pharmaceutically acceptable solvates thereof. The dispute as to written description is focused on the pharmaceutically acceptable solvate limitation of the claim, as Defendants argue that those solvates are not adequately described. The solvate concept is introduced in the specification as follows:

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." Solvates of [dutasteride] are within the scope of the invention.
It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms of [dutasteride] or the pharmaceutically acceptable solvates thereof are within the scope of the present invention.

'467 Patent at 3:59-4:12. Defendants argue that these conclusory statements are not sufficient to adequately describe solvates, as the specification must adequately describe all three solvate subgroups included in the Court's construction, i.e., crystalline, precipitated, and reacted solvates. Defendants rely on Eli Lilly Co. v. Teva Pharmaceuticals USA, Inc., 619 F.3d 1329 (Fed. Cir. 2010). In that case, the claim term "in particulate form" was construed broadly to include drug particles of a particular measurement in both the bulk form and within the tablet form after formulation. Id. at 1344. The specification, however, only described the measurement of the drug particles in the bulk form. Id. at 1345. It did not describe the measurement within the formulated tablet. Id. For this reason, the specification did not adequately describe the "in particulate form" claim term. Id.

Defendants also rely on Boston Scientific Corp. v. Johnson & Johnson, 647 F.3d 1353 (Fed. Cir. 2011). In that case, the patent claimed both rapamycin and its structurally similar macrocyclic analogs. Id. at 1362. The patent was invalid for failing to adequately describe and enable those macrocyclic analogs, even though rapamycin itself was fully disclosed. Id. at 1366-67. "There [was] insufficient correlation between the function and structure of rapamycin and its analogs to provide adequate written description support for the entire genus of macrocyclic lactone analogs of rapamycin." Id. at 1366. The reasons provided also included "the absence of information regarding structural characteristics of macro cyclic lactone analogs or examples of macrocyclic lactone analogs in the specification, the unpredictability of the art and the nascent state of using drug-eluting stents to inhibit restenosis[.]" Id. at 1366-67.

GSK disagrees with the relevance of this authority, arguing that as a matter of law the specification need not disclose solvates of a drug compound where the underlying drug compound is adequately disclosed. In support of this argument, GSK cites two opinions from the Board of Patent Appeals and Interferences ("BPAI"). They are Ex Parte Sabine Germeyer, 2010 WL 4961695 (B.P.A.I. Dec. 1, 2010) and Ex parte Yijuan Chern, 2011 WL 5080233, *1-2 (B.P.A.I. Oct. 24, 2011). In Germeyer, the Examiner rejected the application for failing to describe and enable "hydrates" of the claimed compounds, focusing on the difficulty of predicting hydrate structures.[4] 2010 WL 4961695 at *2. The BPAI reversed the Examiner, finding that the claims included using any available hydrate, and did not require a hydrate having a specific or identified structure. Id. at *3. The BPAI also found that hydrates form naturally, whether or not their structures can be predicted in advance. Id. Finally, it was noted that no evidence was provided that a hydrate cannot be used until its structure is identified. Id.

GSK also cites Ex parte Yijuan Chern, where the BPAI held that solvates of a drug compound were described and enabled even though the specification did not disclose specific solvate chemical structures or methods of making those solvates, and that the formation of a particular solvate was unpredictable. The BPAI held that solvates need not be described or enabled, as the claimed drug compound itself was a sufficient common structural feature to meet the requirements of the law. Id. at *3. Finally, it was noted that the applicants did not claim that their inventive contribution was to provide solvates of the drug compound, but to use the drug compound to treat Huntington's disease. Id.

GSK argues that this authority is persuasive for the conclusion that claimed solvates of a drug compound need not be individually described or enabled. The BPAI decisions, however, concern patents filed more than 15 years after the '467 Patent. They thus have reduced persuasive value as to the relevant state of the art here. Technologies such as high throughput screening, which allows the rapid identification of solvates, did not exist in 1993.[5] The concept, however, that the drug compound is the key structural feature of the solvate was applicable at the time of the '467 Patent's filing, and has some value here. As to Defendants' case law, the Court does not agree that the specification must independently describe crystalline, precipitated, and reacted solvates as subgroups of the genus of pharmaceutically acceptable solvates. The claim recites "pharmaceutically acceptable solvates." There is no reason why a person skilled in the art would not credit a patentee with possession of a solvate merely because the patentee did not disclose solvates formed by each solvation process. Regardless of the characterization of the chemical process forming a solvate, i.e., whether it is said to be reacted, precipitated, or crystallized, a solvate is a solvate, and a solvate is detected when a person skilled in the art sees a complex of a solvent and a chemical compound.[6] The language of the specification itself suggests that any one of the solvate forms will suffice equally.[7] There is no suggestion that the scope of the invention may only be satisfied where solvates formed by each ...


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