SUE L. ROBINSON, Senior District Judge.
This action arises out of the filing of Abbreviated New Drug Application ("ANDA") No. 207583 by defendant Paddock Laboratories, LLC seeking to produce and market a generic testosterone undecanoate intramuscular injection. (D.I. 67 at ¶ 10) On November 20, 2014, plaintiffs Endo Pharmaceuticals Solutions Inc., Bayer Intellectual Property GmbH, and Bayer Pharma AG (collectively "plaintiffs") brought this action alleging infringement of U.S. Patent Nos. 7,718,640 (the "'640 patent") and 8,338,395 (the "'395 patent") (collectively, "the patents-in-suit").
II. FINDINGS OF FACT AND CONCLUSIONS OF LAW
A. Technology at Issue
The '640 patent was filed on March 12, 2004 and issued on May 18, 2010. (JTX 1) The '395 patent was filed on February 24, 2009 and issued on December 25, 2012.
The invention is directed to injectable compositions using long-term acting testosterone esters for testosterone replacement therapy. After injection, "physiologically normal levels of testosterone in serum are reached within a short time period . . . [and] maintained for an extended period of time, without showing fluctuations in the hypogonadal range." (Id. at 2:57-64) Claim 2 of the '640 patent provides for a 750 mg version of the composition of claim 1, which recites "[a] composition formulated for intramuscular injection in a form for single injection which contains 250 mg/ml testosterone undecanoate in a vehicle containing a mixture of castor oil and benzyl benzoate wherein the vehicle contains castor oil in a concentration of 40 to 42 vol %." Claim 18 of the '395 patent provides for a 750 mg version of the composition and method described by claim 14, which recites:
The embodiment of the invention is Aveed, which contains testosterone undecanoate (TU) as an active ingredient. It is approved by the FDA as a testosterone replacement therapy in adult males for conditions associated with testosterone deficiency or absence of endogenous testosterone. Aveed is sold in the United States as a series of 3 ml (750 mg) intramuscular injections given at initiation, at four weeks, and then every 10 weeks thereafter. Each vial of Aveed contains 750 mg testosterone undecanoate dissolved in a mixture of 885 mg castor oil and 1500 mg benzyl benzoate. (D.I. 67, ex. 1 at ¶¶ 6-7) Hypogonadism is a chronic condition requiring lifelong therapy. (D.I. 73 at 524:12-18)
B. Obviousness Standard
"A patent may not be obtained . . . if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art." 35 U.S.C. § 103(a). Obviousness is a question of law, which depends on underlying factual inquiries.
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007) (quoting Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18 (1966)).
"[A] patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art." KSR, 550 U.S. at 418. Likewise, a defendant asserting obviousness in view of a combination of references has the burden to show that a person of ordinary skill in the relevant field had a reason to combine the elements in the manner claimed. Id. at 418-19. The Supreme Court has emphasized the need for courts to value "common sense" over "rigid preventative rules" in determining whether a motivation to combine existed. Id. at 419-20. "[A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." Id. at 420. In addition to showing that a person of ordinary skill in the art would have had reason to attempt to make the composition or device, or carry out the claimed process, a defendant must also demonstrate that "such a person would have had a reasonable expectation of success in doing so." PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed. Cir. 2007).
A combination of prior art elements may have been "obvious to try" where there existed "a design need or market pressure to solve a problem and there [were] a finite number of identified, predictable solutions" to it, and the pursuit of the "known options within [a person of ordinary skill in the art's] technical grasp" leads to the anticipated success. Id. at 421. In this circumstance, "the fact that a combination was obvious to try might show that it was obvious under § 103." Id.
A fact finder is required to consider secondary considerations, or objective indicia of nonobviousness, before reaching an obviousness determination, as a "check against hindsight bias." See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1079 (Fed. Cir. 2012). "Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented." Graham, 383 U.S. at 17-18.
"Patents are presumed to be valid, and overcoming that presumption requires clear and convincing evidence." 35 U.S.C. § 282; Spectrum Pharm., Inc. v. Sandoz Inc., 802 F.3d 1326, 1333 (Fed. Cir. 2015) (citing Microsoft Corp. v. i4i Ltd. P'ship., 564 U.S. 91, 95 (2011) (holding that an invalidity defense must be proved by clear and convincing evidence)). In conjunction with this burden, the Federal Circuit has explained that,
PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1304 (Fed. Cir. 2008) (citations omitted).
C. Prior Art
A trio of prior art scientific articles — Behre,
Behre compared the half-life of a single dose of 1,000 mg TU in castor oil with a single dose of 1000 mg TU in tea seed oil. (JTX 3) Nieschlag investigated the suitability of using four intramuscular injections of 1000 mg TU in castor oil at six week intervals. (JTX 4) von Eckardstein described a clinical trial investigating the efficacy and safety of prolonged TU treatment at extended injection intervals over a 3.2 year period. Seven patients (who had participated in the study described in Nieschlag) received four injections at six week intervals, followed by a gradual increase in the interval between the fifth and tenth injections. After the tenth injection, the interval was increased to twelve weeks. (JTX 5)
The 2002 guidelines of the American Association of Clinical Endocrinologists (AACE) ("the AACE guidelines") describe a normal testosterone range as "generally between 280 and 800 ng/dl" (9.7 to 27.7 nmol/I). (JTX 41 at 448) The FDA refers to a normal testosterone range of 300-1000 ng/dl.
Defendant's expert, Dr. Peter Schlegel ("Dr. Schlegal"),
Dr. Tarantino explained that although the Articles only disclosed dissolving TU in castor oil, "the issues of viscosity and . . . solubility would make it obvious that another vehicle was being used." (D.I. 72 at 91:13-93:10; 107:13-20) He admitted that he did not cite to any prior art data or do any testing of the solubility of TU in castor oil for his opinions. Instead, he testified based on what he "saw here" and his knowledge of lipidation.
Dr. Tarantino opined that a person of ordinary skill would look to marketed products (which provide knowledge of safety, tolerance, and injectability) first. A formulator would be "remiss" in not trying the vehicle of Proluton since "both drugs are closely related chemically. Sometimes even when drugs aren't closely related chemically, co-solvent systems that were used in prior products are used." It is "common sense from every standpoint that you can imagine." (Id. at 76:13-77:9, 86:10-87:17, 89:19-91:1, 96:24-98:3, 169:7-170:13) Moreover, a formulator would expect that the "pharmaceutical dosage form . . . [of] 250 milligrams per ml testosterone . . . [could] be safely and effectively administered." (Id. at 98:4-12) He concluded that it would have been obvious to one of ordinary skill in the art "to replace [the testosterone ester of Proluton] with TU and test it, because you would anticipate little or no manufacturing or regulatory difficulties." (Id. at 93:12-94:4) Dr. Tarantino also pointed to Riffkin, which "mentions benzyl benzoate and benzyl alcohol resulting in a more favorable viscosity, making it easier to inject." (Id. at 87:18-89:2) He testified that benzyl benzoate was the "go-to" excipient for reasons including safety and acceptability. (Id. at 89:24-90:2) He concluded that any ratio of castor oil to benzyl benzoate as a vehicle for testosterone injectables would be obvious, as the excipients "have been around a long time," therefore, combining and optimizing the solubility and viscosity is "what [he] did every day." (Id. at 150:23-151:19)
Plaintiff's expert, Dr. Robert Williams, Ill ("Dr. Williams"),
2. Using a lower dose of TU
Dr. Schlegel explained that "[t]he two most common changes that are made in terms of treating patients with injectable agents are to change the dose amount or the dose interval, frequency between injections." (D.I. 73 at 264:21-265:2, 287:1-23) Dr. Schlegel testified that he uses the AACE guidelines (which reflected the state of the art at that time) in his practice. (Id. at 271:24-274:23, 308:9-13, 349:10-350:2) He relied on the AACE guidelines for the normal range of testosterone (280 to 800 ng/dl) to formulate his opinions. According to Dr. Schlegel, although the FDA sometimes refers to a 300-1000 ng/dl range, a testosterone level of 1000 ng/dl or more is "relatively unusual" and "not a common
Dr. Schlegel agreed that the Articles do not suggest lowering the dose of TU from 1000 mg to 750 mg, but maintained that they "pointed out specifically overdosing" certain patients.
Plaintiffs' expert, Dr. Hartmut Derendorf ("Dr. Derendorf'),
3. Two-phase dosing
Dr. Schlegel pointed out that drug accumulation was noted in Nieschlag. "In Nieschlag, without changing the interval of injections, the [authors] noticed increasing . . . testosterone . . . with subsequent injections, suggesting the need to have a second interval of injection after . . . reach[ing] a steady state." The "data on serum testosterone levels with increasing intervals of injection" supports the concept of a maintenance phase. He opined that von Eckardstein "really is a two-phase treatment regimen, [with t]he second phase of treatment . . . really designed to figure out" the appropriate interval. Further, an initial or loading dose is common. "[D]ecreasing the amount of the initial dose would prevent the overshooting in terms of testosterone levels." He explained that once a steady state of testosterone is reached, a clinician "can allow a longer period of time for that testosterone to be absorbed into the body and still maintain normal testosterone levels, [which is] observed in the increasing intervals that are provided in von Eckardstein." (D.I. 73 at 281:18-286:3)
Dr. Derendorf explained that drug accumulation is a "normal phenomenon." (Id. at 365:13-22) He testified that the Articles did not disclose a different interval between the first and second injections compared to subsequent injections. Moreover, he opined that having a different dosing interval between the first two injections and subsequent injections is unusual. (Id. at 406:1-17)
Dr. Derendorf explained that as a pharmacokineticist, his "role is to help . . . identify the dose and dose regimen that has the highest probability of success. [His] role is usually to identify a population dose, something that would be used for the approval of a product where it ends up in a label . . . ."
Dr. Derendorf explained that when trying "to identify the optimum dosing regimen," the starting point "is the assessment of dose linearity." The use of predictive models is easier with linear pharmacokinetics. (Id. at 368-369) He analyzed the Articles and opined that the published data and graphs are inconsistent with linear pharmacokinetics. He explained that "[a]n oily depot injection of a prodrug is a very complex route of drug administration." Some sources of variability are partition coefficient, viscosity, and patient effects. The formulation depends on what oil is used and what co-solvent if any (and how much) is used. He opined that "the likelihood of simple linear pharmacokinetics is not very high." (Id. at 372-389) He concluded that a person of ordinary skill could not "extrapolate with any reasonable likelihood of success from the prior art that a different dose and a different dosing regimen . . . would result in serum testosterone levels inside the therapeutic range." Moreover, the person of ordinary skill would need "[a]dditional studies with different doses and different dosing regimens in order to characterize the system[.]" (Id. at 391-392; JTX 19) Dr. Derendorf testified that to reach the change in dose and regimen disclosed in the disputed claims from the pharmacokinetic data in the prior art would require "complicated," "lengthy," and "expensive studies." (Id. at 409:17-410:2) In his opinion, Dr. Schlegel's suggestions assumed dose linearity. Dr. Derendorf testified that dose linearity would need to be established with additional data before a person of ordinary skill "could start to come up with [a] prediction." (Id. at 408:11-24)
On cross-examination, Dr. Derendorf was asked a series of questions about certain statements made in the literature, such as, "drug absorption from an oil solution follows first-order kinetics after intramuscular administration." He responded that such statements were too general and explained that there were other variables to consider. (Id. at 411-426; JTX 11, 32, 38) He was also asked about an article published in 2006. He explained that the Cmax are "not proportional . . . after later doses" and the "data [does not] confirm[ ] linearity," but conceded that the Cavg value
Dr. Willliams explained that the iterative process of formulation development requires that a formulator develop prototypes and then test them. If the prototype is deemed unacceptable, the process starts anew. (D.I. 73 at 454:17-458:15) He agreed that pharmacokinetic testing and research occurs prior to clinical testing. (Id. at 504:14-505:20)
C. Motivation to Combine
The parties generally agree that the person of ordinary skill in the art would consist of a team made up of a pharmacokineticist, a clinician, and a formulation scientist. (D.I. 73 at 263:21-23, 267:8-12, 360:8-12, 452:23-453:10, 453:20-458:3) There is no dispute that the prior art does not disclose the use of a 750 mg TU injection dose or the specific interval regimen.
Defendant argues that plaintiffs focus on the motivation to create a long-acting testosterone replacement therapy (a problem identified in the patent) to the exclusion of other motivations such as problems of solubility and viscosity of a high TU concentration formulation or providing a safe and effective therapy to patients. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007) ("[A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed."). Regardless, the patents and the prior art describe solving the same problem — treating men with hypogonadism. It is defendant's burden to prove by clear and convincing evidence that a person of ordinary skill in the art would have been motivated to combine the Articles (and other cited prior art) with the vehicle used in Proluton.
Defendant first argues that a person of ordinary skill would have recognized that the formulation disclosed in the Articles must have used a co-solvent, and that such cosolvent was benzyl benzoate. The expert testimony on this point consists of opinion on whether or not the stated concentration of TU "could" have dissolved in the volume of castor oil. Beyond that question, the cited prior art (Riffkin and Proluton) does suggest the use of a co-solvent. However, it is certainly not a given (as defendant argues) that a person of ordinary skill would have understood that the particular co-solvent was benzyl benzoate, as opposed to one of the other co-solvents known in the art. (JTX 6) Dr. Williams pointed out that there are other co-solvents to choose from. Moreover, even knowing the co-solvent would not provide a person of ordinary skill the particular ratio disclosed by the patents-in-suit. The court concludes that the Articles do not disclose benzyl benzoate as a co-solvent (or the particular ratio used by the patents-in-suit).
Dr. Schlegal used the AACE guidelines to the exclusion of other published ranges for the normal levels of testosterone, and reached his opinion based on the notion that the Articles suggested "overdosing" of patients. He opined that the overdosing would provide a reason for a person of ordinary skill to reduce the TU dose from 1000 mg to 750 mg. This reasoning is contradicted by the fact that after Nieschlag, the same authors undertook another study (von Eckardstein) using 1000 mg of TU. Dr. Schlegal also opined that after reducing the dose, a person of ordinary skill would use routine experimentation to come up with the particular dosing regimen disclosed by the patents-in-suit. He bolstered this opinion by explaining that clinicians routinely make dose and regimen adjustments for testosterone therapies. In contrast, Dr. Derendorf opined that such dose and regimen changes would require more than routine experimentation.
The record demonstrates that there were a number of co-solvents that could have been used for the formulation. Although defendant has successfully identified the elements of the asserted claims (but not the specific quantities of TU and solvents) in the prior art, defendant has not met its burden, by clear and convincing evidence, to show that a person of ordinary skill would combine the elements in the manner claimed.
Defendant's contention that the Nebido composition is inherently disclosed in the prior art misapplies the doctrine of inherency. In the context of an obviousness inquiry, inherency may supply a missing claim limitation only if the limitation at issue is the "natural result" of the combination of prior art elements. PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1194-95 (Fed. Cir. 2014) (cautioning that "the use of inherency, a doctrine originally rooted in anticipation, must be carefully circumscribed in the context of obviousness."); see also Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268-69 (Fed. Cir. 1991) (an inherent limitation is one that is "necessarily present" and not one that may be established by "probabilities or possibilities."). At bar, the presence of benzyl benzoate or its ratio with castor oil is not inherent in the prior art simply because the Nebido composition was used in the studies that formed the basis of the Articles. (JTX 3-5) Defendant has failed to establish that the Articles barred the possibility of an alternative vehicle being used in the prior art compositions.
D. Secondary Considerations
Plaintiffs allege a long-felt but unmet need for a long-acting testosterone replacement. Dr. Sliwinski testified that the available therapies required frequent visits and resulted in unstable testosterone levels. The therapies also required clinicians to adjust dosages for individual patients. (D.I. 74 at 528:16-529:17, 526:11-21,) Dr. Sliwinski testified that he uses Aveed for certain of his patients, who find it convenient to come for an injection just five times a year. The testosterone levels are "smooth." He conceded that Aveed does not work for all patients. He opined that the occurrence of pulmonary oil micro-embolisms ("POME"), which prompted additional measures by the FDA for Aveed's administration, were likely due to improper injection technique. (Id. at 534-538) In his opinion, in 2003, there existed a need for long term therapy, notwithstanding the available therapies (including an implantable pellet, Testopel). (Id. at 540-541)
Dr. Schlegel explained that Testopel was longer-acting than Aveed. Assuming there was a need, Dr. Schlegel explained that Aveed does not fulfil it due to the occurrence of POME and the additional measures required by the FDA. The additional measures make it difficult for busy offices to administer the injections. He concluded that Aveed "did and did not" meet the long felt need. The lower frequency of injections is convenient, but the administration is cumbersome and, therefore, seldom used. (D.I. 73 at 289-293) Defendant's expert, Ivan T. Hofmann, analyzed certain financial data on hormone and testosterone products and concluded that Aveed is not commercially successful.
The court concludes that, on the record at bar, there existed a need for a longacting testosterone therapy. Defendant offers testimony (based on Aveed's commercial success) that Aveed did not fill such need. This testimony is more indicative of a lack of commercial success, a secondary consideration not advanced by plaintiffs.
For the foregoing reasons, the court finds that defendant has not met its burden to prove, by clear and convincing evidence, that claim 2 of the '640 patent and claim 18 of the '395 patent are invalid for obviousness. An appropriate order shall issue.