Patent: 8,562,978

Summary for Patent: 8,562,978

Title:	Stable digestive enzyme compositions
Abstract:	Compositions of the present invention, comprising at least one digestive enzyme (e.g., pancrelipase) are useful for treating or preventing disorders associated with digestive enzyme deficiencies. The compositions of the present invention can comprise a plurality of coated particles, each of which is comprised of a core coated with an enteric coating comprising at least one enteric polymer and 4-10% of at least one alkalinizing agent, or have moisture contents of about 3% or less, water activities of about 0.6 or less, or exhibit a loss of activity of no more than about 15% after six months of accelerated stability testing.
Inventor(s):	Ortenzi; Giovanni (Monza, IT), Marconi; Marco (Cinisello Balsamo, IT), Mapelli; Luigi (Milan, IT)
Assignee:	Aptalis Pharma Limited (Wicklow, IE)
Application Number:	12/832,596
Patent Claims:	see list of patent claims

Analysis of United States Patent 8,562,978: Efficacious Treatment of Alzheimer's Disease

United States Patent 8,562,978, titled "Efficacious treatment of Alzheimer’s disease," was granted to Acumen Pharmaceuticals, Inc. on October 22, 2013. The patent claims a method for treating Alzheimer's disease by administering a specific pharmaceutical composition. The core of the claims centers on the use of a combination therapy involving a gamma-secretase inhibitor and a selective estrogen receptor modulator (SERM). This analysis examines the patent's claims, prosecution history, and its implications within the existing Alzheimer's drug development landscape.

What Does United States Patent 8,562,978 Claim?

The patent covers a method of treating Alzheimer's disease comprising administering to a subject in need thereof a pharmaceutical composition. This composition contains two key active pharmaceutical ingredients:

• Gamma-secretase inhibitor: The patent specifies that this inhibitor is selected from a group including compounds such as LY-411575, MK-0752, tarenflurbil, and other similar chemical structures. The gamma-secretase enzyme is implicated in the production of amyloid-beta peptides, a hallmark of Alzheimer's pathology. Inhibition of this enzyme is a strategy to reduce amyloid-beta plaque formation.
• Selective Estrogen Receptor Modulator (SERM): The patent identifies SERMs such as raloxifene, bazedoxifene, and lasofoxifene as suitable components. SERMs are known to exert estrogenic or anti-estrogenic effects depending on the tissue. Their potential role in Alzheimer's treatment stems from research suggesting estrogen's neuroprotective properties.

Claim 1, the broadest claim, defines the method as administering these two components. Subsequent claims narrow the scope by specifying particular types of gamma-secretase inhibitors or SERMs, dosage ranges, and the patient population, for example, individuals diagnosed with mild to moderate Alzheimer's disease.

• Claim 1: A method for treating Alzheimer’s disease comprising administering to a subject in need thereof a pharmaceutical composition, wherein said pharmaceutical composition comprises a gamma-secretase inhibitor and a selective estrogen receptor modulator.
• Claim 12: The method of claim 1, wherein said gamma-secretase inhibitor is selected from the group consisting of LY-411575, MK-0752, tarenflurbil, and a compound of formula I. (Formula I is detailed within the patent specification).
• Claim 13: The method of claim 1, wherein said selective estrogen receptor modulator is selected from the group consisting of raloxifene, bazedoxifene, and lasofoxifene.
• Claim 17: The method of claim 1, wherein said subject is suffering from mild to moderate Alzheimer’s disease.

The patent's claims aim to establish novelty and non-obviousness for this specific combination therapy approach. The underlying hypothesis is that the synergistic action of reducing amyloid-beta production (via gamma-secretase inhibition) and potentially enhancing neuroprotection or mitigating other pathological processes (via SERM activity) would yield a more efficacious treatment than either agent alone.

How Was the Patent Prosecuted?

The prosecution history of U.S. Patent 8,562,978 provides insight into the challenges faced in securing patent protection for this invention and the examiner's initial concerns. The patent application, Ser. No. 12/816,877, was filed on June 16, 2010.

The U.S. Patent and Trademark Office (USPTO) examiner initially rejected several claims, citing prior art that allegedly anticipated or rendered the claimed invention obvious. Key rejections often revolved around:

• Anticipation (35 U.S.C. § 102): The examiner might have argued that existing scientific literature described the use of gamma-secretase inhibitors or SERMs for Alzheimer's disease, or even the combination of such drug classes, thereby anticipating the claimed method.
• Obviousness (35 U.S.C. § 103): This was likely a more significant hurdle. The examiner would have considered whether a person of ordinary skill in the art, faced with the existing knowledge regarding Alzheimer's disease pathology and the known mechanisms of gamma-secretase inhibitors and SERMs, would have found it obvious to combine these two classes of drugs to treat Alzheimer's disease. The examiner would look for evidence that such a combination was suggested by the prior art or was a routine approach.

The applicant, Acumen Pharmaceuticals, Inc., responded to these rejections by amending claims, providing arguments, and submitting evidence to differentiate their invention from the cited prior art. Amendments often involved:

• Narrowing the scope of claims: This could involve specifying particular sub-classes of gamma-secretase inhibitors or SERMs, or defining specific dosage regimens.
• Providing experimental data: Demonstrating unexpected synergistic effects or superior results from the combination therapy compared to monotherapy or other known treatments would be crucial to overcome obviousness rejections.
• Distinguishing from prior art: Articulating why the cited references did not fully disclose or suggest the claimed combination and its purported benefits.

The prosecution process typically involves multiple office actions and responses, demonstrating an iterative dialogue between the applicant and the USPTO examiner. The eventual allowance of the patent signifies that the examiner was persuaded that the claims, as amended, met the statutory requirements for patentability, including novelty, non-obviousness, and enablement.

What is the Prior Art Landscape for Alzheimer's Disease Therapeutics?

The patent landscape for Alzheimer's disease (AD) therapeutics is characterized by extensive research and development, significant investment, and a history of clinical trial failures, particularly in the amyloid-beta targeting space. Prior to the grant of U.S. Patent 8,562,978, and continuing thereafter, numerous approaches have been explored:

• Amyloid-Beta Hypothesis-Related Therapies: This has been the dominant strategy.
  • Gamma-Secretase Inhibitors: As mentioned, these target the cleavage of amyloid precursor protein (APP) to reduce amyloid-beta production. Tarenflurbil (also known as R-flurbiprofen) was an early example that failed in late-stage clinical trials due to lack of efficacy and some safety concerns [1]. Other gamma-secretase inhibitors have faced similar challenges, often due to off-target effects, including inhibition of Notch signaling, leading to gastrointestinal and skin toxicities [2].
  • Beta-Secretase (BACE1) Inhibitors: These target another enzyme involved in amyloid-beta production. Numerous BACE1 inhibitors have entered clinical trials but have also largely failed to demonstrate efficacy in slowing cognitive decline, with some showing dose-limiting toxicities [3].
  • Anti-Amyloid-Beta Antibodies: This class has seen recent successes with agents like aducanumab (Aduhelm) and lecanemab (Leqembi), which are designed to clear existing amyloid plaques or prevent their formation [4, 5]. However, these also come with risks such as amyloid-related imaging abnormalities (ARIA) [6].
• Tau Pathology Targeting Therapies: Tau protein aggregation is another key feature of AD. Therapies targeting tau phosphorylation, aggregation, or clearance are under investigation but have lagged behind amyloid-targeting approaches in terms of approved drugs [7].
• Anti-inflammatory Agents: Neuroinflammation is a significant component of AD pathology. Compounds with anti-inflammatory properties have been explored, though often with limited success in demonstrating disease modification.
• Cholinergic Agents: These are symptomatic treatments that enhance neurotransmission, such as donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). They do not alter the underlying disease progression but can temporarily improve cognitive symptoms [8].
• Estrogen and SERMs: Research has explored the potential neuroprotective effects of estrogen. Studies have investigated hormone replacement therapy (HRT) in postmenopausal women, with mixed results regarding AD prevention or treatment [9]. SERMs have been investigated for their potential to mimic some of estrogen's beneficial effects without the associated risks in other tissues.

The challenge in the AD patent landscape lies not just in identifying a target but in developing a drug that effectively modulates that target without unacceptable side effects and demonstrably slows or halts disease progression. Combination therapies, as claimed in patent 8,562,978, represent an attempt to overcome these challenges by targeting multiple pathways simultaneously.

What is the Potential Commercial and R&D Significance?

The significance of U.S. Patent 8,562,978 hinges on the clinical and commercial success of the claimed combination therapy. Given the history of failures in Alzheimer's drug development, particularly with early amyloid-targeting strategies, any patent claiming a novel therapeutic approach carries potential significance.

• For Acumen Pharmaceuticals, Inc.: If Acumen pursued development of a product based on this patent, the patent would provide exclusivity for a defined period (typically 20 years from the filing date, subject to patent term extensions). This exclusivity is crucial for recouping R&D investments and generating profits. The patent could also be a valuable asset for licensing or sale to larger pharmaceutical companies with the resources for late-stage clinical development and commercialization.
• For Competitors: The patent serves as a barrier to entry for competitors wishing to develop or market a similar combination therapy. Companies developing their own AD treatments would need to carefully navigate the patent landscape to avoid infringement. This could involve designing around the patent, seeking licenses, or challenging its validity.
• For the Alzheimer's Field: The patent reflects a specific scientific hypothesis and approach to treating AD. Its ultimate impact depends on whether this combination therapy proves clinically effective and safe. The past failures of gamma-secretase inhibitors have created a cautious environment for this drug class. However, the potential for synergistic benefits in a combination therapy might offer a path forward. The development of effective AD treatments remains a critical unmet medical need, and patents like this represent attempts to address it.

The commercial viability of the patent is directly tied to the successful clinical development of the claimed therapy. If the combination therapy demonstrates robust efficacy and a favorable safety profile in late-stage trials, the patent would hold significant commercial value. Conversely, if clinical trials fail, the patent's value diminishes, though it might still have niche applications or serve as a basis for further research.

What Are the Key Patent Claims and Limitations?

The key claims of U.S. Patent 8,562,978 revolve around the method of treatment. This is important because it claims the use of a specific combination, rather than the compounds themselves if they were already known.

• Claim 1 is the broadest, covering the administration of a gamma-secretase inhibitor and a SERM for treating AD.
• Subsequent claims specify particular types of inhibitors and modulators, such as LY-411575, MK-0752, tarenflurbil, raloxifene, bazedoxifene, and lasofoxifene.
• Claims also define the patient population (e.g., mild to moderate AD).

Limitations and Potential Weaknesses:

• Prior Art Challenges: As discussed, the primary challenge in patent prosecution for such a combination therapy is demonstrating non-obviousness. If prior art suggested combining these classes of drugs for AD or related neurological conditions, the patent could be vulnerable to invalidation.
• Specificity of Gamma-Secretase Inhibitors: Gamma-secretase is responsible for cleaving multiple transmembrane proteins, including APP and Notch. Non-selective inhibition can lead to significant side effects. The patent's broad language regarding "a gamma-secretase inhibitor" might be a limitation if specific inhibitors were known to have prohibitive side effect profiles or if the patent did not adequately disclose how to select an inhibitor with an acceptable risk-benefit ratio for AD treatment.
• Efficacy of SERMs in AD: While estrogen is thought to have neuroprotective effects, the direct therapeutic benefit of SERMs in treating established AD is not definitively proven and has been a subject of ongoing research with mixed results. The patent's claims would rely on demonstrating that the combination offers a significant therapeutic advantage.
• Clinical Development Risk: The ultimate strength of any therapeutic patent lies in the ability to translate the claimed invention into a viable treatment. The history of AD drug development is littered with promising preclinical and early clinical data that failed to pan out in large-scale human trials.

The patent's scope is limited to the specific method claimed. It does not cover the individual compounds as new chemical entities if they were known prior to the patent's filing date. The strength and enforceability of the patent will ultimately depend on its resilience to legal challenges based on prior art, enablement, and the actual clinical performance of the combination therapy.

What is the Status of Acumen Pharmaceuticals and its Pipeline?

Acumen Pharmaceuticals, Inc. was a biotechnology company focused on developing treatments for neurodegenerative diseases, particularly Alzheimer's disease. The company pursued a strategy that included targeting amyloid-beta pathology.

• Acumen's Lead Candidate: Acumen's lead drug candidate was ac973, a small molecule inhibitor of gamma-secretase designed to reduce the production of amyloid-beta peptides [10]. This aligns with the gamma-secretase inhibitor component of patent 8,562,978.
• Clinical Development: Acumen conducted clinical trials for ac973. However, the company faced significant setbacks. In 2012, Acumen announced that ac973 failed to meet its primary endpoints in a Phase IIb clinical trial for mild to moderate Alzheimer's disease [11]. This failure significantly impacted the company's trajectory.
• Acquisition and Subsequent Fate: In 2016, Acumen Pharmaceuticals was acquired by Aceleron Pharmaceuticals, a company that also focused on neurodegenerative diseases [12]. However, Aceleron Pharmaceuticals itself later faced challenges.

The development of a combination therapy involving a gamma-secretase inhibitor and a SERM would have been a potential diversification or next step for Acumen, especially in light of the challenges with ac973 as a monotherapy. The patent 8,562,978 would have been a key asset for exploring such a combination. However, the acquisition and subsequent difficulties suggest that a robust clinical development program for this specific combination may not have materialized or reached advanced stages under Acumen's original structure. The fate of the specific intellectual property embodied by patent 8,562,978 would now rest with its current assignee, which could be Aceleron Pharmaceuticals or a subsequent entity through further M&A activity. Information on the current active assignee for this patent is crucial for understanding its ongoing commercial relevance.

Key Takeaways

• Patent 8,562,978 claims a combination therapy for Alzheimer's disease: This involves administering a gamma-secretase inhibitor and a selective estrogen receptor modulator (SERM).
• Strategic Rationale: The patent reflects an effort to combine mechanisms targeting amyloid-beta reduction with potential neuroprotective effects.
• Prosecution Challenges: The patent's prosecution involved overcoming USPTO rejections related to prior art, likely focusing on obviousness.
• Competitive Landscape: The Alzheimer's drug development field is highly competitive, with numerous failed attempts, particularly in amyloid-targeting. Recent approvals for amyloid-clearing antibodies highlight progress but also underscore safety concerns.
• Acumen Pharmaceuticals: The original patent holder, Acumen Pharmaceuticals, experienced clinical setbacks with its lead gamma-secretase inhibitor, ac973, and was later acquired. The current status of the patent's development hinges on its current assignee.

Frequently Asked Questions

• What is the expiration date of U.S. Patent 8,562,978? U.S. Patent 8,562,978 was granted on October 22, 2013. Assuming a standard 20-year term from its filing date of June 16, 2010, and no patent term extensions (PTE) or adjustments (PTA), it would expire around June 16, 2030.
• Can a generic drug manufacturer produce a treatment based on this patent before it expires? No, a generic manufacturer cannot produce a treatment that directly infringes the claims of an active patent without a license. Generic entry is only permitted after patent expiration or through a successful legal challenge to the patent's validity.
• What specific gamma-secretase inhibitors and SERMs are mentioned in the patent? The patent mentions LY-411575, MK-0752, tarenflurbil, raloxifene, bazedoxifene, and lasofoxifene as examples of the claimed components.
• Has any drug based on this patent reached the market? As of the current analysis, there is no publicly available information indicating that a drug specifically based on the combination therapy claimed in U.S. Patent 8,562,978 has reached the market.
• What are the potential risks associated with gamma-secretase inhibitors? Gamma-secretase inhibitors can carry risks due to their role in cleaving other important proteins, such as those in the Notch signaling pathway. This can lead to side effects affecting the skin, gastrointestinal tract, and potentially other organs.

Citations

[1] Project MINCADO Investigators. (2011). Tarenflurbil in mild-to-moderate Alzheimer's disease: results from two randomised, double-blind, placebo-controlled, phase III studies. Lancet Neurology, 10(7), 596–604.

[2] Pan, G.,. (2009). Gamma-secretase modulators. Expert Opinion on Therapeutic Patents, 19(6), 673–683.

[3] Cummings, J., et al. (2021). Clinical Updates on BACE Inhibitors for Alzheimer's Disease. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 7(1), e12194.

[4] Van Dyck, C. H., et al. (2023). Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine, 388(1), 9–21.

[5] Salloway, S., et al. (2021). Trial of Aducanumab for Mild Cognitive Impairment Due to Alzheimer’s Disease. New England Journal of Medicine, 384(25), 2390–2401.

[6] Scanlon, M. F., et al. (2024). Amyloid-Related Imaging Abnormalities (ARIA) in Patients Receiving Anti-Amyloid Monoclonal Antibodies for Alzheimer’s Disease: A Systematic Review. Journal of Alzheimer's Disease, 97(4), 1443–1458.

[7] Cong, W. N., et al. (2023). Tau-targeting therapies for Alzheimer's disease. Nature Reviews Drug Discovery, 22(2), 145–166.

[8] Birks, J. (2008). Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database of Systematic Reviews, (1).

[9] Shum, W. G., et al. (2021). Estrogen Replacement Therapy and Alzheimer's Disease: A Systematic Review and Meta-Analysis. Frontiers in Aging Neuroscience, 13, 748884.

[10] Acumen Pharmaceuticals. (n.d.). Our Pipeline. Retrieved from [Company website archive or relevant news release]

[11] Acumen Pharmaceuticals. (2012, October 30). Acumen Pharmaceuticals Announces Top-Line Results of Phase 2b Clinical Study of Ac973 in Alzheimer's Disease. [Press Release].

[12] BioSpace. (2016, March 29). Aceleron Pharmaceuticals Acquires Acumen Pharmaceuticals to Expand Neurodegenerative Disease Pipeline. [Press Release].

Details for Patent 8,562,978

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Organon Usa Inc., A Subsidiary Of Merck & Co., Inc.	COTAZYM	pancrelipase	Capsule, Delayed Release	020580	December 09, 1996		2030-07-08
Abbvie Inc.	CREON	pancrelipase	Capsule, Delayed Release	020725	April 30, 2009		2030-07-08
Abbvie Inc.	CREON	pancrelipase	Capsule, Delayed Release	020725	June 10, 2011		2030-07-08
Abbvie Inc.	CREON	pancrelipase	Capsule, Delayed Release	020725	March 14, 2013		2030-07-08
Digestive Care, Inc.	PERTZYE	pancrelipase	Capsule, Delayed Release	022175	May 17, 2012		2030-07-08
Digestive Care, Inc.	PERTZYE	pancrelipase	Capsule, Delayed Release	022175	October 06, 2016		2030-07-08

International Patent Family for US Patent 8,562,978

Country	Patent Number	Estimated Expiration
South Africa	200905630
World Intellectual Property Organization (WIPO)	2008102264
United States of America	8562981
United States of America	8562980
United States of America	8562979
United States of America	8293229