Court: District Court, D. New Jersey; October 31, 2018; Federal District Court
Consolidated Hatch-Waxman actions for infringement of United States Patent No. 8,822,438 ('438 patent) involve plaintiffs Janssen Biotech, Inc., Janssen Oncology, Inc., Janssen Research & Development, LLC, and BTG International Ltd., who co-own the patent. The '438 patent includes twenty claims related to treating prostate cancer using abiraterone acetate and prednisone. The defendants—various generic drug companies—seek to manufacture and sell a generic version of ZYTIGA and are accused of infringing claims 4, 8, 11, 19, and 20, which are dependent on claim 1 of the patent, based on their Abbreviated New Drug Applications (ANDAs). Plaintiffs assert that approval of these ANDAs would lead to induced and contributory infringement under 35 U.S.C. §§ 271(b) and 271(c). The defendants deny infringement and claim the patent is invalid due to obviousness and inadequate written description.
Defendants filed a motion for summary judgment on November 3, 2017, which was heard on February 9, 2018. The court did not rule on the motion, acknowledging factual issues requiring trial. Concurrently, on January 17, 2018, the Patent Trial and Appeal Board (PTAB) found the patent invalid, with a motion for reconsideration pending. The court held a bench trial from July 23 to August 2, 2018, after which parties submitted post-trial briefs and proposed findings.
The court's findings concluded that the '438 patent is invalid for obviousness, although it deemed the written description adequate. Additionally, to assist in potential appellate review, the court addressed infringement issues, ruling that if the patent were valid, the defendants' marketing of abiraterone would infringe the patent under either induced or contributory infringement theories.
On July 31, 2015, plaintiffs initiated a lawsuit for infringement of the '438 patent concerning defendants’ ANDA filings to market generic abiraterone acetate 250 mg tablets, involving multiple defendants linked to specific ANDA numbers. Subsequent to the filing, several defendants were dismissed without prejudice after agreeing to be bound by the case's judgment. Notably, on April 20, 2018, plaintiffs entered into a license agreement with Apotex, leading to its dismissal from the action.
On September 28, 2015, an amended complaint was filed against Hetero USA Inc. for its ANDA filing related to the same drug, but Hetero withdrew its ANDA and was dismissed on March 13, 2017. A separate action against Amerigen was filed on May 2, 2016, regarding its ANDA filing and was consolidated with the initial case on July 29, 2016. Another action against Teva was filed on August 25, 2017, for its ANDA seeking approval for a higher dosage of the same drug, with a subsequent dismissal of Teva Pharmaceuticals Industries, Ltd. after it agreed to be bound by the judgment. This case was also consolidated with the original action on January 8, 2018.
The '438 patent pertains to treating metastatic castration-resistant prostate cancer (mCRPC) using a combination of abiraterone and prednisone. Prostate cancer, characterized by uncontrolled growth of prostate tissue, can metastasize to other organs. Androgens, particularly testosterone, facilitate the growth of prostate cancer cells, making androgen deprivation therapy (ADT), which has been the primary treatment since the 1940s, essential for managing metastatic prostate cancer by reducing androgen levels.
ADT (androgen deprivation therapy) is ineffective as a permanent solution for prostate cancer, eventually leading to castration-resistant cancer in patients. Abiraterone, a second-line therapy discovered in the 1990s, inhibits the CYP17 enzyme involved in androgen production. Dr. Johann de Bono posited that while abiraterone reduces androgen levels, it may cause an accumulation of non-androgenic steroids that activate androgen receptors, leading to resistance. To address this, he suggested administering a glucocorticoid, such as prednisone, to suppress those upstream steroids.
The '438 patent, issued on September 2, 2014, and originally filed by Alan H. Auerbach and Arie S. Belldegrun, with Dr. de Bono later added as an inventor, encompasses methods for treating prostate cancer. It asserts that hormones like testosterone and dihydrotestosterone promote prostate cancer growth, and hormone therapy can mitigate this. The patent highlights the utility of CYP17 inhibitors for treating androgen-dependent cancers, specifically through the combination of abiraterone acetate and other therapeutic agents, including prednisone.
Claim 1 of the patent outlines a treatment method involving the administration of therapeutically effective amounts of both abiraterone acetate and prednisone to prostate cancer patients. Claims 2-20 specify further limitations related to dosages and types of prostate cancer. Plaintiffs allege infringement of claims 4, 8, 11, 19, and 20, detailing specific dosages of 1000 mg/day of abiraterone acetate and 10 mg/day of prednisone.
The Court's order on June 27, 2016, established the agreed-upon constructions for undisputed terms in the '438 patent, specifically defining the preamble of claim 1 as a method limited to the treatment of refractory prostate cancer. The term "refractory prostate cancer" is defined as prostate cancer that does not adequately respond to anti-cancer treatment, including cases of recurrence. The term "therapeutically effective amount" refers to a sufficient dosage for cancer treatment. Following a hearing on November 10, 2016, the Court's Markman opinion clarified the terms "treatment" and "treating" to encompass the eradication, management, or control of cancer cells and minimizing cancer spread.
Clinical trials for abiraterone and prednisone were conducted to assess their safety and efficacy for FDA approval of ZYTIGA. These trials occur in phases: Phase I focuses on safety, Phase II tests a larger population, and Phase III evaluates efficacy and safety for regulatory approval. Cougar Biotechnology licensed abiraterone in April 2004, and Dr. de Bono designed the COU-AA-001 trial, aimed at assessing abiraterone's safety and effectiveness in men with metastatic castration-resistant prostate cancer (mCRPC).
The 001 trial consisted of two phases: Phase I involved dose escalation of abiraterone (250-2000 mg), while Phase II standardized the dosage at 1000 mg. An extension phase was proposed for patients whose cancer progressed, administering 0.5 mg of dexamethasone to evaluate whether it could reduce resistance to abiraterone. Dr. de Bono suggested that prednisone would have similar effects to dexamethasone. The Institutional Review Board approved the study, which published results indicating that abiraterone demonstrated anti-tumor activity through reduced Prostate-Specific Antigen (PSA) levels, involving 54 patients, with at least 30 receiving combination therapy with dexamethasone.
Resistance to abiraterone monotherapy in some patients was mitigated by the addition of glucocorticoids, resulting in significant PSA declines in 10 out of 30 patients during a Phase II study, indicating a potential anti-cancer effect attributed to the suppression of upstream steroids. The COU-AA-002 trial, similar to COU-AA-001, was conducted in the U.S. and subsequently approved by the FDA. Initially designed to continue with abiraterone monotherapy, the trial's Phase II protocol was amended to include combined administration of abiraterone and prednisone after insights from the 001 study. Patients received 1,000 mg of abiraterone and 10 mg of prednisone daily, and results were documented in a clinical study report submitted to the FDA, which outlined the study design and emphasized the necessity of low-dose glucocorticoids to manage mineralocorticoid side effects.
The report concluded that abiraterone acetate exhibited promising anti-tumor activity in advanced castration-resistant prostate cancer, with tumor responses noted even in patients previously treated with ketoconazole. While the maximum tolerated dose was not definitively established, the 1,000 mg/day dose was well tolerated with no dose-limiting toxicities. Dr. Robert Charnas indicated that the combination treatment made it difficult to isolate the individual effects of abiraterone and prednisone.
Subsequent trials, COU-AA-003 and COU-AA-004, evaluated the efficacy of abiraterone in patients post-chemotherapy, with significant PSA declines observed. The COU-AA-301 trial served as the pivotal study, comparing the combination treatment to a control arm and demonstrating substantial efficacy and safety, supporting the NDA application for ZYTIGA®.
The 301 trial involved daily administration of 1000 mg of abiraterone and 10 mg of prednisone, resulting in positive patient outcomes. The Independent Data Monitoring Committee recommended discontinuing the placebo control arm for ethical reasons, leading to all participants receiving the active treatment. The trial indicated that the combination therapy improved median overall survival by four months. Results from multiple trials, including 001 to 004 and 301, were submitted to the FDA, although no direct comparison between abiraterone monotherapy and combination therapy was conducted. The COU-AA-302 trial, which led to an update of the ZYTIGA® label in 2018, compared abiraterone plus prednisone against prednisone plus placebo, involving patients not requiring chemotherapy. The same dosages were used, and the trial indicated that corticosteroid administration improved the tolerability of abiraterone acetate, alleviating symptoms associated with mineralocorticosteroid excess. The control arm was also discontinued for ethical reasons, with results showing a 60% reduction in the risk of progression or death and a median survival improvement of about four months. Prior to the invention detailed in the '438 patent, treatment options for prostate cancer were limited, with significant debate in the scientific community regarding androgen dependence. Relevant prior art included several studies and trials related to treatments for hormone-refractory metastatic prostate cancer.
F.D. Fossa et al. conducted a Phase III study comparing flutamide and prednisone for prostate cancer patients with progression after androgen-ablation therapy. Marwan Fakih et al. reviewed glucocorticoid treatments for prostate cancer, while Katherine Harris et al. examined the use of low-dose ketoconazole with hydrocortisone in androgen-independent cases. A. O'Donnell et al. investigated the hormonal effects of abiraterone acetate in prostate cancer patients, and L. Vidal et al. focused on overcoming resistance to targeted therapies. Gerhardt Attard et al. discussed the use of novel lyase inhibitors to block androgenic steroid synthesis for metastatic prostate cancer treatment.
The FDA requires substantial evidence of safety and effectiveness for drug approval, necessitating a New Drug Application (NDA). ZYTIGA® was approved under NDA No. 202379, submitted in December 2010 for treatment in combination with prednisone for men with metastatic castration-resistant prostate cancer (mCRPC). A pre-NDA meeting between the FDA and Cougar Biotechnology on November 9, 2010, allowed for discussions about the NDA and provided initial feedback.
The scientific rationale for abiraterone acetate's development highlighted concerns about potential mineralocorticoid excess and associated toxicities, which were observed in early Phase 1 and 2 studies. Consequently, these studies incorporated low-dose corticosteroids to mitigate side effects. The NDA included a summary of clinical efficacy demonstrating the benefits of abiraterone with prednisone across various studies, recommending specific dosages of 1000mg/day for abiraterone and 10mg/day for prednisone to alleviate mineralocorticoid-related toxicities.
On April 26, 2011, the FDA completed its medical review, assessing data on overdose, drug abuse, and withdrawal concerns, noting the concurrent use of prednisone to manage mineralocorticoid excess. The FDA approved the NDA on April 28, 2011, allowing ZYTIGA® to be marketed alongside prednisone for mCRPC treatment, as listed in the FDA's Orange Book.
NDA holders must list in the Orange Book all patents associated with a drug that could lead to patent infringement claims if a non-licensed party manufactures, uses, or sells the drug. The '438 patent is listed for NDA No. 202379, and all defendants were aware of this patent when they filed Paragraph IV certifications for their ANDAs. The FDA-approved product label for ZYTIGA includes essential prescribing information and reflects the FDA's perspective on the drug's usage.
The Indications and Usage section specifies that ZYTIGA, a CYP17 inhibitor, is indicated in combination with prednisone for treating metastatic castration-resistant prostate cancer (mCRPC) and, as of the 2018 approval, metastatic high-risk castration-sensitive prostate cancer (CSPC). The Dosage and Administration section outlines the recommended doses for both conditions. Warnings and Precautions indicate potential side effects, including hypertension and hypokalemia. The 2018 label also omitted a prior warning regarding the co-administration of corticosteroids. Section 14 highlights clinical studies supporting ZYTIGA's efficacy, and each defendant has filed an ANDA to market a generic version of ZYTIGA (abiraterone acetate tablets).
The FDA mandates that drug manufacturers submit a side-by-side comparison of proposed labels to existing brand labels when filing an application. Proposed generic drug labels are generally similar to the branded counterparts. The defendants' proposed labels for their generic products reflect the same indication for metastatic castration-resistant prostate cancer (mCRPC) as the ZYTIGA® label, with "abiraterone acetate" replacing "ZYTIGA." However, these labels do not include the mCSPC indication added to ZYTIGA® in 2018. The recommended dosage across defendants' labels is 1000 mg/day of abiraterone acetate and 10 mg/day of prednisone, with certain labels mirroring pre-2018 ZYTIGA® dosage instructions. Some defendants' labels retain a warning about corticosteroid co-administration that was removed from the 2018 ZYTIGA® label, which the FDA has instructed Teva to eliminate.
Additionally, pharmaceutical companies must submit marketing materials that cannot mischaracterize a drug's indication. Various ZYTIGA® marketing documents highlight prednisone's role in reducing adverse reactions related to mineralocorticoids, while others promote ZYTIGA® and prednisone as effective for prostate cancer treatment. The Hatch-Waxman Act aims to balance policy interests between encouraging drug innovation and facilitating market entry for generics.
Inducing research and development of new drugs and allowing competitors to market low-cost generics is central to the legal framework established by the Hatch-Waxman Act. A brand-name drug manufacturer must submit a New Drug Application (NDA) to the FDA, which includes details about the drug's components, labeling, and scientific safety and efficacy data (21 U.S.C. 355(b)(1)). In contrast, generic manufacturers can streamline their approval process through an Abbreviated New Drug Application (ANDA) or a 505(b)(2) application, which allows them to reference existing safety and efficacy information from the Orange Book (Takeda Pharm. U.S.A. Inc. v. W.-Ward Pharm. Corp. 785 F.3d 625, 629).
When filing an ANDA, the applicant must confirm that the generic drug will not infringe the brand's patents. This can be done through a paragraph IV certification claiming that a listed patent is invalid or not infringed (21 U.S.C. 355(j)(2)(A)(vii)(IV). Such a certification constitutes an act of infringement, allowing the brand to sue immediately (35 U.S.C. 271(e)(2)(A)). Consequently, the FDA cannot approve the ANDA until 30 months have passed or the court finds the patent invalid/non-infringed (21 U.S.C. 355(j)(5)(B)(iii).
The burden of proving patent invalidity falls on the ANDA applicant after asserting invalidity in a paragraph IV certification (In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig. 676 F.3d 1063, 1078). Patents and their claims are presumed valid unless rebutted by clear and convincing evidence (35 U.S.C. 282(a)). Conversely, once non-infringement is claimed, the patent holder must demonstrate infringement by a preponderance of the evidence (SmithKline Diagnostics, Inc. v. Helena Labs. Corp. 859 F.2d 878, 889).
Plaintiffs may allege induced and contributory infringement (35 U.S.C. 271(b), (c)), while defendants may challenge the patent's validity based on inadequate written descriptions and obviousness. The validity issues will be addressed first in section II.A.
The '438 patent is deemed to have an adequate description, as determined in subsection II.A.1. However, it is found invalid due to obviousness in subsection II.A.2. In section II.B, if the patent were valid, defendants' actions would infringe it, with subsection II.B.1 concluding that the defendants' labels would induce infringement and subsection II.B.2 confirming contributory infringement. The defendants argue the patent is invalid due to lack of written description and obviousness, but the court prioritizes discussing validity before infringement claims. The defendants previously succeeded in invalidity challenges during three inter partes review (IPR) proceedings before the PTAB, with decisions from January 17, 2018, currently under reconsideration. Regarding the written description, the court disagrees with the defendants' assertion that the patent does not meet the requirements of 35 U.S.C. § 112. The patent must clearly describe the invention and its use, enabling a skilled artisan to practice it without further instruction. The '438 patent specifies the administration of two drugs for treating mCRPC, and the court finds that it adequately identifies prednisone as an anti-cancer agent, countering the defendants' claims that it lacks sufficient disclosure regarding treatment efficacy.
"Anti-cancer agent" is defined as any therapeutic agent that kills or inhibits the proliferation of cancer cells. The '438 patent lists specific anti-cancer agents, including mitoxantrone, paclitaxel, and prednisone, which is also classified as an antibiotic agent. The specification also includes steroid agents like hydrocortisone and dexamethasone, stating that steroids should be administered in sufficient amounts to treat cancer, alone or with a 17a-hydroxylase/C17,20-lyase inhibitor. The patent drafter's definitions guide the interpretation of claims, establishing that the written description is adequate.
In addressing the issue of obviousness under 35 U.S.C. 103, defendants argue that combining abiraterone acetate with prednisone would have been obvious to a person of ordinary skill in the art (POSA) by the priority date of August 25, 2006, for three reasons: for anti-cancer effects, to mitigate side effects, and for palliative properties. Obviousness is assessed based on four factors: the scope of prior art, differences from the claims, the skill level in the field, and objective considerations such as commercial success. The evidence presented at trial focused on the prior art and objective considerations, emphasizing that the novelty of a combination therapy may lie in the combination of known elements.
The motivation for a person of ordinary skill in the art (POSA) to combine prior art does not need to be explicitly stated in the references but can derive from various sources, including common knowledge, the overall prior art, or the nature of the problem being addressed. Relevant case law emphasizes that while the motivation can be implicit, there must be a connection between the claimed invention and objective indicia, with evidence being commensurate with the claims' scope. Determining the required nexus involves assessing whether the marketed product embodies the claimed features, a factual question that courts approach flexibly rather than formulaically.
The defendants argue that prior art would have motivated a POSA to combine abiraterone with prednisone, suggesting that the known anti-cancer effects of prednisone and its role in alleviating side effects would have driven such a combination. This rationale implies that the motivations for combining therapies do not have to align precisely with the inventor's original intentions, as established in prior rulings. Thus, the law does not mandate that combinations arise from the same motivations as those of the inventor.
Defendants argue that the effects of prednisone provide a strong rationale for its combination with abiraterone in treatment, suggesting that the motivation to develop this combination goes beyond mere coincidence. While the case law indicates that an inventor must have an awareness of relevant science to avoid claims of obviousness, the combination therapy in question appears to align with established treatment methods for prostate cancer. Specifically, it targets metastatic castration-resistant prostate cancer (mCRPC) using a regimen of 1000 mg of abiraterone and 10 mg of prednisone daily, aiming to slow disease progression and improve patient outcomes, as evidenced by clinical results such as prolonged survival and reduced PSA levels.
The prior art highlights significant studies that support the potential of abiraterone, including Barrie's 1994 study on ketoconazole, which spurred interest in finding a more effective treatment for hormone-dependent prostate cancer. Subsequent research, including Potter's 1995 findings and Jarman's 1998 clinical evaluations, further established abiraterone as a promising candidate for treating prostatic carcinoma. O'Donnell's 2004 trial, which involved human subjects, indicated that abiraterone effectively lowered testosterone levels, reinforcing its therapeutic viability. Notably, this trial did not involve glucocorticoids, but it did discuss the potential benefits of co-administering a glucocorticoid with abiraterone, underpinning the rationale for the combination therapy being evaluated.
In the trial, a single dose of abiraterone was administered to non-castrate males, resulting in reduced testosterone levels, although not below castrate levels. When non-castrate males received 500 milligrams of abiraterone daily for twelve days, testosterone suppression was not sustained. The O'Donnell 2004 trial deemed abiraterone safe but concluded that sustained testosterone suppression was not achieved in non-castrate patients, indicating that abiraterone is better suited as a second-line treatment following castration. Further studies suggested that an 800-milligram daily dose of abiraterone could suppress testosterone below castrate levels, showing promise as a second-line hormonal treatment for prostate cancer. The trial compared abiraterone to ketoconazole, highlighting abiraterone’s selective inhibition of testosterone production. O'Donnell's findings were published in the British Journal of Cancer after significant delays.
Additionally, prior art included the Tannock 1996 study, which involved palliation for refractory prostate cancer patients treated with mitoxantrone and prednisone, noting that prednisone alleviated side effects of the chemotherapy. Sartor 1998 evaluated prednisone's effects on PSA levels in hormone-refractory patients, finding that nearly half achieved a significant decline in PSA, suggesting prednisone is tolerated and may be effective for some patients with metastatic castration-resistant prostate cancer (mCRPC).
Sartor (1998) proposed that a decline in PSA levels exceeding 50% could indicate prolonged survival in patients. Fossa (2001) studied 201 patients with metastatic disease post-castration, dividing them into two groups: one receiving prednisone and the other flutamide. Among the 101 patients receiving 20 mg of prednisone daily, 21 showed a PSA decline of over 50%, but there was no significant difference in overall survival between the groups. Fossa suggested low-cost prednisone as a standard first-line treatment for hormone-refractory prostate cancer (HRPC), while advocating for further exploration of combination therapies.
Fakih (2002) reviewed glucocorticoids' antitumor mechanisms in prostate cancer, noting their potential to suppress adrenal androgens and provide negative feedback to the pituitary gland, thus reducing androgen levels. Harris (2002) conducted a phase II study with 28 men suffering from androgen-independent cancer, assessing the efficacy of 200 mg of ketoconazole three times daily with hydrocortisone. The study found that glucocorticoids might have direct antitumor effects through interactions with androgen receptors or by inhibiting the hypothalamic-pituitary-adrenal axis.
Prior studies on combination therapy include Gerber (1990), which examined PSA changes in 15 men with hormone-refractory metastatic prostate cancer treated with ketoconazole and prednisone. Ketoconazole acts as a non-specific inhibitor of adrenal steroid synthesis, causing adrenal insufficiency, while abiraterone is a selective CYP17 inhibitor. In the Gerber study, 12 out of 15 patients showed decreased PSA levels, with a median response duration of three months; three patients had prolonged responses over eight months. Gerber concluded a small subset of patients may benefit from ketoconazole and glucocorticoid treatment. O'Donnell (2004) reported favorable outcomes with abiraterone but noted reduced adrenal reserve in treated patients, a finding echoed by Attard (2005), which indicated diminished cortisol response in patients post-treatment.
Researchers proposed that deficiencies in hormone levels could be mitigated by administering steroids, particularly during stress, with suggestions that glucocorticoid replacement may be necessary due to adrenocortical suppression. O'Donnell (2004) noted the common practice of administering hydrocortisone alongside aminoglutethimide and ketoconazole, while emphasizing the need for further studies on the continuous requirement for glucocorticoid therapy in patients treated with abiraterone acetate. Attard (2005) recommended monitoring for glucocorticoid insufficiency in patients receiving daily abiraterone for advanced prostate cancer, while Garnick (2006) highlighted that abiraterone's development as a second-line therapy could lead to luteinizing hormone hypersecretion, potentially necessitating glucocorticoid treatment.
Dr. de Bono and Lara Vidal's 2004 review discussed strategies to combat resistance to cancer therapies, underscoring hormone therapy's central role in treating metastatic prostate cancer. They pointed out that low adrenal androgen levels could hinder treatment response but could be addressed by low steroid doses or enzyme inhibitors like abiraterone or ketoconazole. The authors advocated for drug combinations to enhance treatment outcomes, although such approaches present logistical challenges due to the need for multiple industry partnerships.
Sartor (2006) noted the historical use of secondary hormonal manipulations in hormone-refractory prostate cancer, although the lack of demonstrated survival advantages has led to disagreement about their efficacy. In evaluating ZYTIGA®'s commercial success, the plaintiffs presented various arguments regarding its market performance, including significant sales totaling over $5.7 billion from April 2011 to the end of 2017, but these arguments were assessed with skepticism and given less weight overall.
Plaintiffs provided evidence indicating that 85% to 95% of ZYTIGA® prescriptions coincided with prednisone prescriptions. During ZYTIGA®'s successful market period, a blocking patent was held, specifically U.S. Patent No. 5,604,213, issued on February 18, 1997, which expired in December 2016. This patent, titled "17-Substituted Steroids Useful in Cancer Treatment," discusses various steroids, including abiraterone, and its application for prostate cancer treatment, demonstrating abiraterone's superior testosterone inhibition compared to ketoconazole. In 2004, BTG granted Cougar Biotechnology an exclusive license to develop abiraterone under this patent.
Plaintiffs argue that the anti-cancer effect of combining abiraterone with prednisone was unexpected, citing the failure of two other CYP17 inhibitors and the reluctance of pharmaceutical companies to pursue abiraterone post-1999. In counterargument, defendants noted that alternative treatments like Taxotere and Jevtana also provided survival benefits.
By the priority date of August 25, 2006, abiraterone was recognized in the art for its selective CYP17 inhibition, representing an improvement over ketoconazole, which had broader metabolic interference. Both drugs are steroid inhibitors, but abiraterone was noted for its more effective testosterone suppression. Prior art identified abiraterone as a second-line treatment for prostate cancer, and literature suggested prednisone could palliate symptoms and lower PSA levels, indicating an anti-cancer effect.
The administration of 20 mg/day of prednisone as monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC) is supported by prior art, including Sartor 1998, despite its retrospective nature and potential sample bias. Such prior art does not need to be scientifically validated to provide a rationale for combining treatments. Sartor 1998 indicates that prednisone can reduce PSA levels in some mCRPC patients, which a person of ordinary skill in the art (POSA) would recognize as indicating an anti-cancer effect, corroborated by references from Fossa 2001, Fakih 2002, and Harris 2002. While reduced PSA levels do not guarantee survival benefits, they are a recognized measure of prostate cancer progression.
There is sufficient motivation for a POSA to combine abiraterone with prednisone. Gerber 1990 suggests that increasing PSA levels can be treated with a combination of ketoconazole and glucocorticoids, confirming that such combinations are safe and effective for advanced hormone-refractory prostate cancer. O'Donnell 2004 notes that in clinical practice, hydrocortisone is often administered alongside ketoconazole and indicates that further studies on abiraterone and glucocorticoid coadministration are necessary. Specific dosages between 10-20 mg of prednisone and 800 mg of abiraterone are identified in prior art.
A POSA would logically consider substituting abiraterone for ketoconazole, continuing the glucocorticoid coadministration due to potential side effects from abiraterone's CYP17 inhibition, such as reduced cortisol levels and increased risk of adrenal insufficiency. Plaintiffs' concerns regarding the Synacthen test for adrenal insufficiency are acknowledged but do not diminish the significance of O'Donnell 2004, which predicts some effect on adrenal reserve from steroid synthesis pathways. It is suggested that practitioners can manage these side effects through glucocorticoid coadministration.
The paper does not definitively conclude that coadministration is unnecessary but suggests it may not always be required. It emphasizes that prior art does not "teach away" from a combination therapy if it merely shows a preference for alternatives without discrediting the claimed invention. The plaintiffs' arguments regarding the existence of other treatment options and more promising anti-cancer agents are acknowledged but countered by the prior art's indication of coadministration of abiraterone with glucocorticoids. It notes that prior art does not need to designate a combination as the most desirable to suggest its desirability. The prior art established that glucocorticoids, despite side effects, were generally well-tolerated, and the presence of alternative treatments does not imply a person skilled in the art (POSA) would exclude prednisone. The conclusion is that the prior art supports combining abiraterone with prednisone with reasonable success probability. The plaintiffs’ secondary considerations do not outweigh the primary findings of obviousness. Commercial success is discussed, noting that ZYTIGA®'s significant sales imply a presumption of its patent's obviousness unless a clear nexus between the success and the claimed invention can be established. If the features driving commercial success were known in prior art, they do not support a claim of non-obviousness. Furthermore, if market entry by competitors is blocked by patents, it weakens the argument for non-obviousness of the claims.
Evidence of commercial success related to a patent can be diminished by the existence of a blocking patent, which is an earlier patent that must be licensed to practice a later patent. This situation often arises between a pioneer patent and an improvement patent. The presence of a blocking patent can deter investment in the later invention due to the risk of infringement liability, thereby reducing incentives for innovation in that area. In the case of ZYTIGA® combination therapy, the defendants argue that the earlier blocking patent, which granted exclusive rights to market abiraterone from 1997 to 2016, limited market entry and thus influenced the commercial success of the product. Janssen counters this by asserting that they were willing to license the '213 patent rights from 2000 to 2004, although these licensing efforts were minimal. After Cougar Biotechnology obtained an exclusive license in 2004, entry by non-licensees was effectively blocked until 2006. The ongoing existence of the blocking patent and exclusive licensing discouraged potential market entrants during a time when the obviousness of the combination therapy was becoming apparent. While commercial success of abiraterone is acknowledged, it is noted that this success does not necessarily negate the strong evidence of obviousness. Additionally, ZYTIGA's sales may not be solely attributed to the patented therapy. Overall, the factor of market skepticism regarding the commercial success of ZYTIGA is considered neutral.
Evidence of industry skepticism supports a finding of non-obviousness when skilled artisans express doubts about the feasibility of a solution. The plaintiff cites various factors, including delayed publication of study results, negative feedback, lack of licensing partnerships, uncertainty among researchers, and prior skepticism regarding hormonal therapies, primarily focused on abiraterone rather than the claimed combination. Contextually, prior art indicated potential for combining abiraterone with glucocorticoids for prostate cancer treatment, and by 1997, experts had recognized abiraterone as a viable treatment option.
The analysis of long-felt needs requires consideration of the identified problem and prior efforts to resolve it, with courts typically referencing the filing date of the invention to determine unmet needs. Evidence of unexpected results can counter a prima facie case of obviousness by demonstrating that the invention offers surprising advantages compared to prior art, which must be significantly different rather than merely improved.
The plaintiffs assert that their invention is an advancement over prior art due to reduced toxicity, better tolerance, and improved survival rates. However, defendants highlight the existence of contemporaneous FDA-approved alternatives like Jevtana and Xtandi. Although ZYTIGA® shows a survival improvement of about four months over existing treatments, this is characterized as an incremental advance rather than a revolutionary one, particularly in treating patients with severe conditions like metastatic castration-resistant prostate cancer (mCRPC).
The analysis determines that while evidence of unmet need and prior failures exist, they are not compelling enough to overcome the conclusion of obviousness regarding the abiraterone/prednisone combination therapy. The professional approval factor is somewhat favorable to the plaintiff, supported by studies and references from skilled contemporaries indicating that the invention was not considered obvious at the time. However, the existence of prior peer-reviewed literature foreshadowing the patented combination outweighs these factors, leading to a finding of obviousness and the invalidation of the '438 patent.
In addressing potential infringement, the court considers claims of both induced and contributory infringement, presuming the '438 patent's validity. The plaintiffs argue that the ANDA label, which outlines the approved use of the combination therapy, would lead physicians to infringe the claimed method. The defendants counter that the FDA-approved use of prednisone is only for palliative purposes, not for its anti-cancer effects, thus claiming the label does not induce infringement. The court acknowledges the complexity of this argument, as the administration described in the patent aligns with the label's indications, despite the defendants' request to differentiate the components' contributions as per the FDA's classification.
The Court emphasizes that it cannot reassess clinical data as if it were a regulatory body nor redefine FDA approval beyond the actual ruling. The matter at hand is not an appeal of the FDA's decision, but rather an exploration of its scope. Liability for patent infringement extends to those who induce others to infringe under 35 U.S.C. § 271(b). Induced infringement requires proof that the defendant knowingly aided another's direct infringement and had the intent to cause such infringement. Mere knowledge of the infringing acts is insufficient; actual intent must be demonstrated, which can be established through circumstantial evidence.
In the context of FDA approval, defendants argue that the '438 patented method requires both abiraterone and prednisone to have anti-cancer effects. They claim the FDA only approved prednisone for its palliative effects, making their ANDA submissions inadequate in meeting the claim's limitation of "therapeutically effective amount." Defendants support their position by highlighting several points: the clinical trials do not support prednisone's anti-cancer effect, the ZYTIGA® label lacks clarity regarding prednisone’s role, NDA submissions focused on abiraterone, the FDA approval package does not endorse prednisone for its combined effect with abiraterone, and marketing materials promote prednisone solely for mitigating side effects. The FDA’s approval indicates that drugs can only be marketed for specific indications if proven safe for their intended use per the FDCA.
FDA regulations require that the "Indications and Usage" section of a drug label must clearly state approved uses supported by substantial evidence from adequate and well-controlled studies. It must specify indications for treatment, prevention, mitigation, cure, diagnosis of recognized diseases or conditions, or relief of associated symptoms. Indications cannot be implied from other sections of the label. The FDA grants approval for a drug's specific uses based on demonstrated safety and efficacy, rather than a blanket approval for general marketing.
In the context of the Bayer Schering case, the court examined the marketing of a generic version of Yasmin, an oral contraceptive. The defendants sought approval for the same use as the branded drug. Although they acknowledged that their labels stated the drug was for oral contraception, they argued that other effects mentioned in the "Clinical Pharmacology" section did not imply FDA approval for those uses. The Federal Circuit held that only indications explicitly stated in the "Indications and Usage" section are FDA-approved, rejecting the idea that a use could be implied from other parts of the label. This ruling emphasized that an indication must be clearly established in the approved label to affirm its safety and efficacy.
The court clarified that references in the Clinical Pharmacology section of a drug label do not equate to FDA approval for specific uses. Specifically, the mention of drospirenone's properties does not imply an approved use for Yasmin beyond contraception. The Federal Circuit reviewed extrinsic evidence, including physicians' statements and marketing materials, asserting that while the FDA was aware of Yasmin's potential effects, it had not approved the drug for those additional uses. Consequently, the court ruled that Yasmin was only approved as an oral contraceptive, and the defendants' marketing aligned with that approval, thereby avoiding infringement claims.
Regarding ZYTIGA®, the court emphasized that its Indications and Usage section clearly states the drug is approved for use in combination with prednisone for treating metastatic castration-resistant prostate cancer (mCRPC). Testimony from FDA experts supported the notion that prednisone's inclusion in the Indications section indicated FDA approval for more than just managing side effects. The court reiterated that indications must be explicitly stated in the Indications and Usage section, as implied uses are not permissible under FDA regulations. This principle was reinforced by precedent cases, highlighting that claims of implied use cannot override explicit labeling. The court also indicated a reluctance to assign significant weight to other evidence presented by the defendants.
The FDA recognized prednisone's palliative benefits but emphasized abiraterone's anti-cancer effects in the New Drug Application (NDA). Marketing materials highlighted prednisone's palliative qualities without referencing its anti-cancer properties. However, this does not contradict the FDA's approval of the label's Indications and Uses, as established in Bayer Schering. The approval does not imply that prednisone was solely recognized for its palliative effects, nor does it attribute specific efficacy percentages to each component of the combination therapy. The FDA approved the combination treatment for metastatic castration-resistant prostate cancer (mCRPC) based on available studies, despite potential design flaws in those studies. The defendants challenged the validity of the combination-study clinical trials, arguing they did not adequately isolate prednisone's independent contribution to the treatment's efficacy. Nonetheless, the FDA's approval stands, and methodological lessons from Bayer's case support this conclusion.
The excerpt also references two additional cases: Warner-Lambert, where the court affirmed that the approved indication for gabapentin (partial seizure) was distinct from a method for treating neurodegenerative diseases, and Allergan, where an ANDA applicant was not liable for patent infringement because the approved indication did not include the patented methods. In all three cases, the courts focused on comparing label wording to patent claims, a method that supports the conclusion that the ZYTIGA® label's indication aligns with the patent claims regarding combination therapy. The clarity of the ZYTIGA® label is affirmed.
ZYTIGA, administered with prednisone, is approved for treating metastatic castration-resistant prostate cancer (mCRPC), aligning with the patent's Claim 1. The efficacy of this combination is supported by clinical studies that demonstrate its anti-cancer effects, with the labeling emphasizing the necessity of both drugs rather than one alone. The FDA's approval validates this combination as the patented treatment method.
The inquiry into the ANDA defendants' proposed labels reveals an intent to induce infringement of the '438 patent, which specifies administering effective doses of abiraterone acetate and prednisone. The labels suggest active encouragement for physicians to infringe the patent, as seen in past case law where product labeling for a patented method constitutes inducement. Courts have held that offering a product with the intention of promoting its use in a way that infringes a patent can lead to liability for induced infringement. Therefore, the labeling must clearly instruct and encourage the infringement to establish intent, going beyond merely including infringing instructions.
The excerpt analyzes the intent to induce patent infringement through product labeling. It establishes that a label must actively encourage, recommend, or promote infringement to demonstrate intent, as supported by case law. Specifically, the sale of a product labeled for use via a patented method constitutes inducement. The court examines whether the proposed labels for various defendants' products indicate such intent toward physicians. The labels are largely identical to the approved ZYTIGA® label, substituting the trademark with the chemical name "abiraterone acetate," while retaining similar indications for treating metastatic castration-resistant prostate cancer (mCRPC). Each defendant's label explicitly states that the tablets are indicated in combination with prednisone for this treatment. Furthermore, the Dosage and Administration sections of the defendants' labels mirror the ZYTIGA® label, recommending the same dosages of abiraterone and prednisone, reinforcing the intent to induce infringement. The consistency across labels in both indications and dosage supports the conclusion that the defendants intended for physicians to prescribe abiraterone acetate alongside prednisone for mCRPC treatment.
The relevant target group for the Abbreviated New Drug Application (ANDA) is mCRPC patients, with significant similarities between the plaintiffs' and defendants' Indications and Dosing sections. Defendants argue that the labels do not explicitly direct doctors to use prednisone for cancer treatment, instead addressing its side effects, and claim they lack knowledge of prednisone's anti-cancer effects, asserting that such ignorance prevents them from being seen as intentionally promoting its use. However, the intent required in patent infringement cases, particularly in pharmaceuticals, does not equate to the specific intent found in criminal law. Legal precedents indicate that selling a product with a label authorizing use in a patented method constitutes inducement to infringe that patent. The key issue is whether the label instructs users to perform an infringing action. Past cases have established that instructions within the label alone can demonstrate the necessary intent to encourage infringement, independent of external physician knowledge.
In this case, the ANDA labels strongly imply an intent to encourage infringing use, particularly as Claim 1 of the '438 patent outlines a method for treating prostate cancer with abiraterone and prednisone, which is directly promoted by the defendants' labels. The dependent claims specify dosages and the type of prostate cancer being treated, with defendants' labels aligning closely with these claims. Previous rulings have found induced infringement when labels lacked significant differences from plaintiffs' labels. Defendants' argument hinges on cases where intent was not inferred due to the infringing use being merely an option; however, this is not applicable here as the Indication and Dosing sections explicitly instruct the infringing use.
The patent in question claims a method for orally administering a specific drug with food, while the defendants' ANDA labels indicate the drug can be taken with or without food. The court determined that the label's wording does not instruct or encourage infringement of the patent, allowing for both options without preference. In a separate case, the court ruled that a label directing physicians to consider pharmacokinetics did not constitute infringement since it did not instruct any specific action. The defendants' abiraterone labels, however, explicitly instruct the use of abiraterone with prednisone for treating metastatic castration-resistant prostate cancer (mCRPC), which the court found indicative of potential infringement. The court rejected the defendants' argument that doctors might prescribe prednisone for non-patented uses, emphasizing that the labels' explicit indications imply infringement. The court noted that induced infringement can be established even if a product has substantial non-infringing uses, and it cited prior cases where labels that led to patented treatments constituted intentional inducement. Ultimately, the court concluded that the defendants' labels would infringe upon the patent and that there was sufficient evidence of the defendants’ intent to induce infringement.
Defendants submitted Abbreviated New Drug Applications (ANDAs) to market abiraterone, indicating use alongside prednisone in a manner consistent with the patented method described in the '438 patent. The proposed labels for the defendants' products mirror those of ZYTIGA®, leading to a conclusion that, if the '438 patent is valid, the defendants would intentionally induce infringement by marketing their products with these labels.
Additionally, plaintiffs allege contributory infringement, asserting abiraterone is a significant component of the patented invention. This claim is less developed in the parties' arguments, and the finding of induced infringement makes it largely redundant. Contributory infringement under 35 U.S.C. § 271(c) requires proof of: 1) direct infringement, 2) knowledge of the patent by the accused infringer, 3) the component lacking substantial noninfringing uses, and 4) the component being a material part of the invention. Defendants concede the first, second, and fourth elements, with the dispute centering on the third element concerning prednisone's potential noninfringing uses.
Defendants argue that prednisone has substantial non-infringing uses, particularly as a glucocorticoid replacement. However, the court finds this argument unconvincing, noting that using prednisone in the context of treating metastatic castration-resistant prostate cancer (mCRPC) would inherently replicate the patented method. The distinction between infringing and non-infringing uses is deemed subjective, depending on the prescribing physician's intent, contrasting with precedent cases where the uses were clearly delineated. Thus, the court rejects the defendants' reliance on prior case law that involved off-label uses unrelated to the patented method.
The court noted that it is unreasonable to expect Apotex to promote its FDA-approved gabapentin for a use that might infringe Warner-Lambert's patent, especially given that this use represents a minor portion of overall sales. In the current case, the FDA-approved use aligns with the patented combination method, unlike the prior situation involving gabapentin. The court highlighted that a physician's intent does not alter the pharmacological effects of prednisone when administered to a patient receiving abiraterone, and referenced a prior case where a drug's dosage directly treated an underlying condition, implicating performance of a patented method.
Defendants contended that their ANDA labels promote abiraterone monotherapy, which is an off-label use. The court found insufficient evidence to suggest that this use is substantial, contrasting it with a previous ruling where a significant percentage of product sales were for non-infringing uses. The warning section of the label actually discourages off-label use by indicating potential negative effects from withdrawing prednisone from therapy. As a result, the court concluded that contributory infringement exists.
The '438 patent was deemed invalid due to obviousness but was sufficiently described. Plaintiffs proved that, if valid, the defendants' actions would amount to induced and contributory infringement. The document also mentions that the infringement claim related to U.S. Patent No. 5,604,213 against Actavis was dismissed after the patent expired. Rising Pharmaceuticals replaced Citron as a defendant following the transfer of its ANDA. The court explored the broad interpretation of treatment terms to include pain reduction and glucocorticoid replacement, referencing relevant scientific backgrounds and individuals involved in the case.
Prednisone was unavailable in the U.K. at the time referenced. Prostate-specific antigen (PSA) levels are utilized to monitor anti-tumor activity in hormone therapy, with rising PSA levels indicating cancer progression and falling levels suggesting control of the disease. Multiple peer-reviewed studies support these findings. The 001 trial indicated that disease progression during abiraterone monotherapy may be linked to increased upstream corticosteroids, which could be managed by adding a glucocorticoid. There was debate regarding whether the decision to add prednisone was prompted by a patient's death related to hypokalemia in March 2008; however, it was confirmed that the decision was made in 2007, prior to the incident. The standard review timeline for a New Drug Application (NDA) is about ten months, with priority reviews shortening this to approximately six months.
The defendants do not seek to bar the plaintiffs from litigating validity issues previously lost at the Patent Trial and Appeal Board (PTAB), but rather the plaintiffs aim to prevent defendants from asserting patent invalidity, which the defendants succeeded in at the PTAB. This argument, previously rejected by the Court, raises questions about the purpose and interpretation of the estoppel provision under 35 U.S.C. § 315(e)(2). The Court highlighted that while the statute can be interpreted as the plaintiffs suggest, its intent is to prevent abuse of inter partes proceedings, thereby requiring parties to assert all invalidity claims or risk losing them. The Court expressed concerns that requiring a party to remain silent in court due to prior success at the PTAB could lead to unjust outcomes, such as injunctions against infringement based on patents already deemed invalid. The discussion also touched on whether a party could prevail in court despite losing in an inter partes proceeding if prior art was available, indicating that only unsuccessful or unsubmitted arguments may be barred in subsequent litigation.
Section 315(e)(2) establishes that a petitioner who is unsuccessful in an inter partes review (IPR) cannot claim in district court that a patent claim is invalid based on any grounds previously raised or that could have been raised during the IPR. This was highlighted in the case of *Depomed Inc. v. Purdue Pharma LP*, where the court's discussion noted the implications of finality regarding the PTAB's decision, which is currently under reconsideration. The court concluded that the PTAB's decision is not "final" for the purposes of Section 315(e), thereby allowing for the consideration of validity issues without estoppel.
The concept of finality should align with the context of exhaustion and appealability, as parties cannot appeal to the Federal Circuit until all rehearing requests have been exhausted, making the PTAB's decision final and appealable only then. A contrary interpretation could lead to issues, such as a mandatory injunction based on a PTAB decision viewed as "final" solely for estoppel purposes when the plaintiff seeks reconsideration.
The excerpt also addresses the level of skill of a person having ordinary skill in the art (POSA), which is deemed quite high, defined as a physician specializing in oncology or urology with significant experience and access to experts in related fields. Factors influencing the determination of a POSA's skill level include the inventor's education, the types of problems in the art, prior art solutions, the pace of innovation, technology sophistication, and the educational background of active workers in the field. The defendants defined a POSA as a physician with relevant advanced degrees and practical experience, indicating collaboration with specialists in related scientific areas.
Plaintiffs defined a Person of Ordinary Skill in the Art (POSA) as a physician specializing in urology or medical oncology with significant experience treating prostate cancer, collaborating with experts in endocrinology, biochemistry, pharmacology, or molecular biology. Experts from both parties agreed that differences in their definitions would not impact their opinions. Defendants requested the Court to disregard portions of Dr. de Bono's testimony, claiming it was not disclosed before trial, particularly regarding prior art and clinical trials. Although this objection was not raised during the trial, the Court considered it. The contested testimony, while technical, was deemed within Dr. de Bono’s expertise and relevant to understanding the clinical trials, thus admissible under Rule 701 of the Federal Rules of Evidence. The patent in question referenced ketoconazole in relation to abiraterone, and it was noted that publication delays for the O'Donnell 2004 study did not lead to immediate marketing of abiraterone. The Court dismissed plaintiffs' speculation linking these delays to skepticism about abiraterone therapy due to lack of supporting testimony. Additionally, the plaintiffs presented net sales figures of $5.7 billion for ZYTIGA® abiraterone acetate tablets, which do not precisely reflect the patented invention that includes prednisone. The Court emphasized that commercial success must correlate to the patented compound and noted that failure to connect commercial success to undisclosed features in prior art weakens its evidentiary value.
Plaintiffs present suggestive evidence indicating that 85% to 95% of ZYTIGA® prescriptions coincide in timing with prednisone fills. The court considers relevant case law regarding specific intent to induce infringement, noting that past rulings have typically rejected the idea that a drug's use can be inferred from label sections other than indications and usage. For instance, in United Therapeutics Corp. v. Sandoz, Inc., the court distinguished between warnings and instructions, stating that warnings inform about risks without prescribing actions, while instructions direct specific actions. Similar conclusions were reached in Otsuka Pharm. Co. Ltd. v. Torrent Pharm. Ltd. Inc., where safety information was deemed insufficient to establish inducement of a claimed method. In Sanofi v. Glenmark Pharm. Inc., the court emphasized that physicians primarily refer to the indications and usage section, which also directs them to clinical studies. The 2018 ZYTIGA® label modification, adding an indication for mCSPC, is deemed not to change the label's substance, and the defendants did not seek to market the drug for this new indication. Furthermore, there is insufficient evidence that the defendants took steps to avoid infringement, and their removal of references to allegedly infringing indications suggests a lack of specific intent to encourage infringement.
