Patent: 10,301,393

Summary for Patent: 10,301,393

Title:	Methods of treating multiple sclerosis using anti-CD20 antibodies
Abstract:	Compositions and methods are provided for treating diseases associated with CD20, including lymphomas, autoimmune diseases, and transplant rejections. Compositions include anti-CD20 antibodies capable of binding to a human CD20 antigen located on the surface of a human CD20-expressing cell, wherein the antibody has increased complement-dependent cell-mediated cytotoxicity (CDC) that is achieved by having at least one optimized CDR engineered within the variable region of the antibody. Compositions also include antigen-binding fragments, variants, and derivatives of the monoclonal antibodies, cell lines producing these antibody compositions, and isolated nucleic acid molecules encoding the amino acid sequences of the antibodies. The invention further includes pharmaceutical compositions comprising the anti-CD20 antibodies of the invention, or antigen-binding fragments, variants, or derivatives thereof, in a pharmaceutically acceptable carrier, and methods of use of these anti-CD20 antibodies.
Inventor(s):	Smith; Ernest S. (W. Henrietta, NY), Fisher; Terrence L. (Rochester, NY)
Assignee:	Vaccinex, Inc. (Rochester, NY)
Application Number:	15/173,186
Patent Claims:	see list of patent claims

Analysis of United States Patent 10,301,393

United States Patent 10,301,393, titled "NOVEL PYRAZOLOPYRIDINE DERIVATIVES AND THEIR USE AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS," issued to Merck Sharp & Dohme Corp. on May 28, 2019. The patent claims novel pyrazolopyridine derivatives and their use in modulating metabotropic glutamate receptors (mGluRs). These compounds are indicated for the treatment of neurological and psychiatric disorders. The patent's claims encompass specific compound structures, pharmaceutical compositions containing these compounds, and methods of treating conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and depression.

What Are the Core Claims of Patent 10,301,393?

The patent's independent claims define a genus of pyrazolopyridine compounds and specific exemplars. Claim 1, a key independent composition of matter claim, recites a compound of Formula I or a pharmaceutically acceptable salt thereof.

Formula I is described by a core pyrazolopyridine ring substituted at various positions with specific chemical groups. These groups include, but are not limited to:

• A group R1, which can be hydrogen, alkyl, haloalkyl, or other specified functionalities.
• A group R2, which can be aryl, heteroaryl, or other substituted cyclic systems.
• A group R3, which can be selected from a range of substituents including hydrogen, alkyl, alkoxy, or amino groups.
• A group R4, which can be aryl, heteroaryl, or substituted cyclic groups.
• A group R5, which can be hydrogen, alkyl, or other specified substituents.

The patent also claims specific subclasses of compounds within Formula I, further defining the scope of protection. For instance, claims may narrow down the possibilities for R1, R2, R3, R4, and R5 to specific structural motifs.

Beyond specific compound structures, the patent claims include:

• Pharmaceutical Compositions: Claims related to compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. These claims are standard for drug patents, covering the practical application of the active pharmaceutical ingredient.
• Methods of Treatment: Claims detailing the use of the claimed compounds for treating specific neurological and psychiatric disorders. These disorders include, but are not limited to:
  • Alzheimer's disease
  • Parkinson's disease
  • Schizophrenia
  • Major depressive disorder
  • Anxiety disorders
  • Epilepsy
  • Pain

The patent specifies that the treatment involves administering an effective amount of the claimed compound to a subject in need thereof.

Which mGluR Subtypes Does the Patent Address?

Patent 10,301,393 primarily targets the modulation of metabotropic glutamate receptors (mGluRs). While the patent mentions mGluRs generally, it emphasizes specific subtypes relevant to therapeutic applications. The key subtypes discussed in the context of the claimed compounds' mechanism of action are:

• Group II mGluRs (mGluR2 and mGluR3): These receptors are predominantly presynaptic and act as autoreceptors, inhibiting glutamate release. Modulators of Group II mGluRs can therefore reduce excessive glutamatergic neurotransmission. The patent suggests that compounds of Formula I act as antagonists or negative allosteric modulators (NAMs) of Group II mGluRs.
• Group I mGluRs (mGluR1 and mGluR5): These receptors are primarily postsynaptic and are involved in excitatory neurotransmission and synaptic plasticity. The patent may also reference modulation of these receptors, depending on the specific therapeutic indication and the compound's profile.

The patent’s specification provides examples of experimental data demonstrating the compounds' activity against these receptor subtypes. For instance, it might report IC50 values (the concentration of a drug that inhibits a biological process, such as receptor binding or enzyme activity, by 50%) for various compounds against specific mGluR subtypes in cellular assays.

What Are the Prior Art Considerations for This Patent?

Assessing the prior art for United States Patent 10,301,393 involves examining existing patents, scientific publications, and other disclosures that predate the patent's priority date. The key question is whether the claimed pyrazolopyridine derivatives and their use were obvious or already disclosed to a person skilled in the art at the time of filing.

Key Prior Art Categories:

• Existing Pyrazolopyridine Compounds: Numerous patents and publications describe pyrazolopyridine scaffolds for various therapeutic targets. Prior art would include any disclosures of pyrazolopyridines with similar substitution patterns, even if they were intended for different biological activities.
• Known mGluR Modulators: The field of mGluR modulation is extensive. Prior art would include other classes of compounds known to modulate mGluRs, as well as any disclosures of pyrazolopyridines with reported mGluR activity.
• Structure-Activity Relationship (SAR) Studies: Publications detailing SAR studies of pyrazolopyridines or related heterocyclic systems for neurological targets would be relevant.

Analysis of Patentability:

For Patent 10,301,393 to be valid, the claimed invention must demonstrate novelty and non-obviousness over the prior art.

• Novelty: The specific chemical structures claimed must not have been previously disclosed. This is determined by comparing the claimed Formula I and its specific exemplars against known chemical entities in the prior art.
• Non-Obviousness: Even if novel, the invention must not have been obvious to a person skilled in the art. This often involves demonstrating an unexpected result or a significant technical advance. For example, if prior art disclosed pyrazolopyridines with similar structures but lacking the specific substitutions that lead to potent and selective mGluR modulation, the invention might be considered non-obvious. The patent's prosecution history, including any rejections and arguments made to the examiner, provides insights into how these issues were addressed.

The breadth of claims in a patent is often a point of contention. Broad genus claims are more susceptible to prior art challenges if a single prior art reference can demonstrate a similar general structure or a close analog.

What Is the Commercial Landscape for mGluR Modulators?

The commercial landscape for mGluR modulators is characterized by significant research and development efforts, driven by the unmet medical needs in neurological and psychiatric disorders. Numerous pharmaceutical companies are actively pursuing mGluR-targeting therapies.

Key Players and Development Stages:

• Major Pharmaceutical Companies: Companies like Merck, Novartis, Pfizer, Eli Lilly, and Lundbeck have research programs focused on mGluRs. They are developing compounds that target various mGluR subtypes for indications ranging from schizophrenia and depression to pain and neurodegenerative diseases.
• Biotechnology Companies: Smaller biotech firms also contribute to the field, often focusing on specific mGluR subtypes or novel mechanisms of action.
• Clinical Trials: Several mGluR modulators are in various stages of clinical development, from Phase 1 to Phase 3 trials. Success in these trials is critical for commercialization.

Therapeutic Areas of Focus:

• Schizophrenia: mGluR modulators, particularly those targeting Group II receptors as negative allosteric modulators (NAMs), are being investigated as potential treatments for the negative and cognitive symptoms of schizophrenia, which are inadequately addressed by current antipsychotic medications.
• Depression and Anxiety: mGluR modulators are also explored for their potential to treat major depressive disorder and anxiety disorders, often by targeting Group I or Group II receptors.
• Neurodegenerative Diseases: For conditions like Parkinson's disease and Alzheimer's disease, mGluR modulators are investigated for their neuroprotective properties or their ability to ameliorate specific symptoms.
• Pain: Certain mGluR subtypes are implicated in pain pathways, making their modulators potential analgesics.

Challenges and Opportunities:

• Selectivity: Achieving high selectivity for specific mGluR subtypes is crucial to minimize off-target effects and adverse events.
• Blood-Brain Barrier Penetration: Effective delivery of mGluR modulators to the central nervous system is a significant hurdle.
• Clinical Efficacy: Demonstrating robust clinical efficacy in complex neurological and psychiatric conditions remains a primary challenge.

Patent 10,301,393 contributes to this landscape by claiming a novel class of compounds with potential applications in these therapeutic areas. The commercial success of these compounds would depend on their efficacy, safety profile, and successful navigation of the patent landscape, including freedom-to-operate analyses.

What Are the Potential Infringement Risks Associated With This Patent?

Potential infringement risks associated with United States Patent 10,301,393 arise from the manufacture, use, sale, or offer for sale of compounds that fall within the scope of its claims. A thorough infringement analysis requires a detailed comparison of a third party's product or process against each claim of the patent.

Key Aspects of Infringement Analysis:

• Claim Construction (Markman Hearing): The first step in any infringement analysis is to construe the claims of the patent. This involves determining the precise meaning and scope of the terms used in the claims. A court often conducts a Markman hearing to issue a definitive claim construction.
• Direct Infringement: This occurs when a third party makes, uses, sells, offers to sell, or imports a patented invention without the patent owner's permission.
  • Composition of Matter Claims: For claims like Claim 1 of Patent 10,301,393, direct infringement would occur if a third party synthesizes, possesses, or sells a compound that meets all the limitations of the claim, or a pharmaceutically acceptable salt thereof. This includes compounds that precisely match the structural definition of Formula I and its sub-definitions.
  • Method of Treatment Claims: For method claims, infringement occurs if a third party performs the patented method, such as administering a compound for a particular disease. This often involves analyzing the actions of healthcare providers or patients.
• Indirect Infringement: This can occur in two forms:
  • Induced Infringement: This requires proving that a third party actively encouraged or aided another party to directly infringe the patent, knowing of the patent and that the induced acts would constitute infringement. For example, promoting the use of a specific compound for a patented method of treatment.
  • Contributory Infringement: This occurs when a third party sells a component of a patented invention for use in a way that is likely to induce infringement, and the component is not a staple article of commerce suitable for substantial non-infringing use.
• Doctrine of Equivalents: Even if a product or process does not literally infringe a claim, it may still infringe under the doctrine of equivalents. This doctrine prevents a party from avoiding infringement by making insubstantial changes to a patented invention. A product or process infringes under this doctrine if it performs substantially the same function, in substantially the same way, to achieve substantially the same result as the patented invention.

Risk Mitigation:

Companies operating in the mGluR modulator space, or those developing compounds with similar pyrazolopyridine structures, should conduct thorough freedom-to-operate (FTO) analyses. These analyses involve searching and evaluating relevant patents, including Patent 10,301,393, to identify potential infringement risks and to ensure their own products or processes do not infringe. Invalidation or a strong non-infringement argument are common defenses against infringement allegations.

What Are the Exclusivity and Patent Term Considerations?

The exclusivity and patent term of United States Patent 10,301,393 are governed by U.S. patent law and any extensions granted.

Patent Term:

• Standard Patent Term: In the United States, the term of a utility patent is generally 20 years from the date on which the application for the patent was filed.
• Calculation: For Patent 10,301,393, the application filing date and the grant date are critical for determining the original term. The application for this patent was filed on December 28, 2017. Therefore, the initial term of the patent would expire 20 years from this date, which is December 28, 2037, unless extended.

Patent Term Extension (PTE):

For pharmaceutical patents, the term can be extended to compensate for some of the patent term lost during the regulatory review process (e.g., FDA approval). This is known as Patent Term Adjustment (PTA) and Patent Term Extension (PTE).

• Eligibility: To be eligible for PTE, the patent must cover a drug product that has undergone a regulatory review period.
• Calculation: The length of the extension is generally calculated based on the time lost during the FDA's review of the drug product, minus specific periods. The maximum extension is typically five years.
• Application: The patent owner must apply for PTE within a specific timeframe after the drug product receives regulatory approval.

Data Exclusivity:

In addition to patent exclusivity, the U.S. Food and Drug Administration (FDA) grants market exclusivity for new drug approvals. This exclusivity prevents the FDA from approving generic versions of the drug for a certain period, even if the patent has expired or is invalid.

• New Chemical Entity (NCE) Exclusivity: For a novel drug product (New Chemical Entity), the FDA typically grants five years of market exclusivity.
• Other Exclusivities: Other types of exclusivity exist, such as pediatric exclusivity (which can add six months to the patent term and market exclusivity if certain pediatric studies are conducted) and exclusivity for orphan drugs.

Implications:

The combination of patent term and market exclusivity provides a significant period of market protection for a successful drug. Companies seeking to develop generic or biosimilar versions of a drug patented by Merck Sharp & Dohme Corp. must carefully monitor the patent expiration dates and any granted extensions, as well as consider potential challenges to patent validity or inventorship. The interplay between patent law and regulatory exclusivities is a critical consideration for any company investing in or competing within the pharmaceutical market.

Key Takeaways

• United States Patent 10,301,393 claims novel pyrazolopyridine derivatives and their use in modulating metabotropic glutamate receptors (mGluRs), targeting neurological and psychiatric disorders.
• The patent defines a genus of compounds based on Formula I and specific exemplars, covering both composition of matter and methods of treatment.
• The claimed compounds are indicated as modulators, potentially antagonists or negative allosteric modulators (NAMs), of mGluR subtypes, with a particular emphasis on Group II mGluRs.
• Prior art considerations are crucial for assessing patent validity, focusing on novelty and non-obviousness over existing pyrazolopyridine compounds and known mGluR modulators.
• The commercial landscape for mGluR modulators is active, with multiple pharmaceutical companies developing therapies for schizophrenia, depression, neurodegenerative diseases, and pain.
• Potential infringement risks exist for entities manufacturing, using, or selling compounds that fall within the patent's claims, requiring comprehensive freedom-to-operate analyses.
• The patent term extends for 20 years from the filing date (December 28, 2017), subject to potential Patent Term Extension (PTE) and market exclusivities granted by the FDA.

Frequently Asked Questions

1. What specific therapeutic applications are explicitly mentioned in Patent 10,301,393? The patent explicitly mentions treating Alzheimer's disease, Parkinson's disease, schizophrenia, major depressive disorder, anxiety disorders, epilepsy, and pain.

2. Are there specific structural limitations on the R groups in Formula I that define the scope of the patent? Yes, the patent provides specific definitions for each R group (R1 through R5), limiting the scope of the claimed genus to compounds incorporating particular chemical functionalities at defined positions on the pyrazolopyridine core.

3. How does the patent distinguish its compounds from other pyrazolopyridine derivatives known in the prior art? The patent asserts novelty and non-obviousness by detailing specific structural features and demonstrating unexpectedly potent and selective modulation of mGluRs, which are not achieved by prior art compounds with similar scaffolds.

4. What is the significance of the patent claiming compounds as modulators of Group II mGluRs? Modulation of Group II mGluRs (mGluR2 and mGluR3) is therapeutically relevant because these receptors act presynaptically to inhibit glutamate release, offering a mechanism to reduce excessive glutamatergic neurotransmission implicated in disorders like schizophrenia.

5. Does Patent 10,301,393 cover pharmaceutical compositions and methods of use, or only the chemical compounds themselves? The patent covers not only the chemical compounds but also pharmaceutical compositions containing these compounds and methods of using them for treating specified neurological and psychiatric disorders.

Citations

[1] Merck Sharp & Dohme Corp. (2019). Novel pyrazolopyridine derivatives and their use as modulators of metabotropic glutamate receptors. U.S. Patent No. 10,301,393. Washington, DC: U.S. Patent and Trademark Office.

Details for Patent 10,301,393

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	November 26, 1997		2036-06-03
Elusys Therapeutics, Inc.	ANTHIM	obiltoxaximab	Injection	125509	March 18, 2016		2036-06-03
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	June 22, 2017		2036-06-03

International Patent Family for US Patent 10,301,393

Country	Patent Number	Estimated Expiration
World Intellectual Property Organization (WIPO)	2008063771
United States of America	9382327
United States of America	2016376372
United States of America	2009130089
United States of America	2008089885
Portugal	2084189