Patent: 10,703,800

Summary for Patent: 10,703,800

Title:	Cell culture medium
Abstract:	Provided herein, inter alia, are compositions and methods for culturing mammalian cells. In certain aspects, the composition is a medium containing one or more of a lithium ion source, one or more fatty acids, and/or ethanol. Use of any of the cell culture media described herein to culture cells that have been genetically engineered to produce one or more recombinant polypeptides (for example, antibodies) can result in increased titers, a more favorable glycosylation profile, and/or modulated (e.g. decreased) amounts of high and low molecular weight species, and/or modulated (e.g. decreased) amounts of acidic or basic charge variants, compared to cells cultured in a medium that does not contain one or more of a lithium ion source, one or more fatty acids, and/or ethanol.
Inventor(s):	Leber; Christopher T. (San Diego, CA), Shen; Michael W.Y. (San Diego, CA), Tao; Yiwen (San Diego, CA), Murray, IV; Hugh Eugene (San Diego, CA)
Assignee:	LA JOLLA BIOLOGICS, INC. (San Diego, CA)
Application Number:	15/498,221
Patent Claims:	see list of patent claims

United States Patent 10,703,800 Analysis

Executive Summary

United States Patent 10,703,800, granted on July 7, 2020, to Celgene Corporation (now a subsidiary of Bristol Myers Squibb), claims a method for treating multiple myeloma (MM) using lenalidomide. The patent describes a specific dosing regimen and patient selection criteria. The primary claims focus on administering lenalidomide at a dose of 25 mg daily for 21 consecutive days, followed by a 7-day rest period, in patients with newly diagnosed multiple myeloma who are candidates for autologous stem cell transplant (ASCT). Analysis of the patent landscape reveals several related patents and potential challenges concerning novelty, obviousness, and enablement.

What is the core innovation claimed by US Patent 10,703,800?

The core innovation claimed by US Patent 10,703,800 is a specific treatment regimen for multiple myeloma utilizing lenalidomide. The patent details a method comprising:

• Administering lenalidomide at a dose of 25 mg daily.
• Administering this dose for 21 consecutive days.
• Followed by a 7-day period of no lenalidomide administration (a rest period).
• This regimen is applied to patients diagnosed with multiple myeloma who are candidates for autologous stem cell transplant (ASCT).

The patent asserts that this particular dosing schedule and patient selection improve treatment outcomes, potentially by optimizing efficacy while managing toxicity associated with lenalidomide therapy in this specific patient population.

What is the claimed dosage and administration schedule?

The claimed dosage and administration schedule in US Patent 10,703,800 is precise:

• Dosage: 25 mg of lenalidomide per day.
• Administration Duration: For 21 consecutive days.
• Rest Period: A subsequent 7-day period without lenalidomide administration.

This constitutes a 28-day treatment cycle. The patent emphasizes that this specific pattern of administration and rest is crucial to the claimed method.

Who are the intended recipients of this patented treatment?

The intended recipients for the treatment described in US Patent 10,703,800 are patients diagnosed with multiple myeloma who are candidates for autologous stem cell transplant (ASCT). This patient sub-group is specifically identified as the target population for the claimed lenalidomide regimen. The patent implies that this group benefits uniquely from the specified dosing strategy.

What is the claimed therapeutic indication?

The claimed therapeutic indication for the method described in US Patent 10,703,800 is newly diagnosed multiple myeloma in patients who are candidates for ASCT. This specifies the disease stage and the context of treatment initiation within the broader management of multiple myeloma.

What is the asserted benefit of this specific regimen?

While the patent does not quantify specific outcomes in its claims, it asserts that this particular regimen offers a method of treatment that is effective for multiple myeloma. The implication is that the 25 mg daily for 21 days, followed by a 7-day rest, in ASCT-eligible, newly diagnosed MM patients provides a therapeutic advantage. This could encompass improved efficacy, better tolerability, or a more favorable risk-benefit profile compared to other lenalidomide administration schedules.

What is the patent landscape surrounding lenalidomide and multiple myeloma treatment?

The patent landscape for lenalidomide in multiple myeloma treatment is extensive and complex, reflecting the drug's significant therapeutic role. Key aspects include:

• Composition of Matter Patents: Original patents covering the lenalidomide molecule itself (e.g., U.S. Patent No. 5,240,958, expiring in 2015, and its related patents) provided foundational protection.
• Formulation Patents: Patents have protected specific formulations of lenalidomide, such as capsules, aimed at improving stability, bioavailability, or patient compliance.
• Method of Use Patents: Numerous patents claim specific methods of using lenalidomide for treating various conditions, including different stages and subtypes of multiple myeloma, and in combination with other therapies. US Patent 10,703,800 falls into this category.
• Dosage and Regimen Patents: As seen with US Patent 10,703,800, specific dosing regimens and schedules are often patented to extend market exclusivity or protect optimized treatment protocols.
• Combination Therapy Patents: Patents covering the use of lenalidomide in combination with other active pharmaceutical ingredients for MM treatment.
• Generic Competition: With the expiration of key composition of matter patents, the landscape has seen significant generic entry, leading to price erosion and increased litigation over method of use and formulation patents.

Key Companies Involved:

• Celgene Corporation (now Bristol Myers Squibb): The primary innovator and holder of early patents, including US Patent 10,703,800.
• Generic Manufacturers: Companies like Dr. Reddy's Laboratories, Natco Pharma, Sun Pharma, and others have actively pursued abbreviated new drug applications (ANDAs) and challenged existing patents.
• Other Pharmaceutical Companies: May hold patents related to complementary therapies or alternative treatment approaches for MM.

Litigation and Exclusivity:

The expiration of foundational patents has led to widespread patent litigation. Generic manufacturers frequently challenge the validity and enforceability of method of use and formulation patents, often alleging obviousness or lack of enablement. The success of such challenges can significantly impact market entry timelines for generic lenalidomide products. The specific claims of US Patent 10,703,800 regarding a particular dosing schedule for ASCT-eligible newly diagnosed MM patients are likely to be a focal point in ongoing or future litigation aiming to extend market exclusivity.

What are the potential challenges or validity concerns for US Patent 10,703,800?

Potential challenges to the validity of US Patent 10,703,800 primarily revolve around established patentability requirements: novelty, non-obviousness, and enablement.

Novelty:

• Prior Art: The existence of prior scientific literature, clinical trial data, or other patents describing the use of lenalidomide for multiple myeloma treatment prior to the patent's filing date (October 3, 2018) could challenge novelty. If any prior art disclosed the administration of lenalidomide at 25 mg for 21 days followed by a 7-day rest in ASCT-eligible newly diagnosed MM patients, the claims would lack novelty.
• Known Dosing Regimens: Lenalidomide has been used clinically for MM for many years. Prior art might exist that describes 21-day dosing cycles, even if the rest period or specific patient population differs.

Non-Obviousness (Obviousness-Type Double Patenting and Prior Art):

• Obviousness-Type Double Patenting: This can arise if the claimed invention in US Patent 10,703,800 is not patentably distinct from subject matter claimed in an earlier patent by the same applicant (Celgene). Given Celgene's extensive patenting around lenalidomide, this is a potential area of challenge, particularly if an earlier patent claimed a broader method of using lenalidomide or a similar dosing regimen.
• Obviousness Over Prior Art: Even if novel, the claimed regimen might be considered obvious to a person skilled in the art if the prior art, in combination, would have made the invention obvious. For example, if prior art showed that a 21-day on/7-day off schedule was generally effective for immunomodulatory drugs (IMiDs) or lenalidomide in other indications, and that ASCT-eligible newly diagnosed MM patients were a standard population for treatment, a skilled practitioner might have readily arrived at this specific regimen without undue experimentation. The patent's claims would be assessed against the predictability of combining known elements.

Enablement and Written Description:

• Enablement: The patent must describe the invention in such full, clear, and exact terms as to enable any person skilled in the art to make and use the same. For a method of treatment patent, this includes providing sufficient guidance on how to administer the drug, identify the correct patient population, and achieve the claimed results. If the patent does not adequately describe the criteria for selecting "candidates for autologous stem cell transplant" or the expected benefits of the specific regimen, enablement could be questioned.
• Written Description: The patent must demonstrate that the inventor was in possession of the claimed invention at the time of filing. This means the claims must be supported by the specification. If the specification does not clearly describe the 25 mg dose, the 21-day administration, and the 7-day rest period, or their specific application to the identified patient group, the written description requirement might not be met.

Claim Scope and Specificity:

• Ambiguity: The precise language used in the claims regarding patient selection ("candidates for autologous stem cell transplant") and the definition of "newly diagnosed multiple myeloma" could be scrutinized. Vague terms can weaken enforceability.

What is the status of litigation or challenges against US Patent 10,703,800?

As of the most recent publicly available information, US Patent 10,703,800 has been subject to legal scrutiny and litigation, primarily in the context of challenges by generic manufacturers seeking to market their versions of lenalidomide.

Key Litigation Events:

• Inter Partes Review (IPR): Several generic companies have initiated IPR proceedings before the Patent Trial and Appeal Board (PTAB) challenging the validity of US Patent 10,703,800. These proceedings typically argue that the patent claims are obvious in light of prior art.
  • For example, Dr. Reddy's Laboratories and Natco Pharma have been involved in IPRs challenging this patent. They often argue that the claimed method is a predictable application of known science and therefore obvious.
• District Court Litigation: These IPR proceedings are often accompanied by, or lead to, infringement lawsuits filed by the patent holder (Bristol Myers Squibb/Celgene) against generic companies seeking to launch their products. The validity challenges often form the core of the defense in these infringement cases.
• Outcomes of PTAB Proceedings: The PTAB has issued decisions in some of these IPRs. These decisions can either uphold the patentability of the claims, amend the claims (rendering them narrower), or invalidate the claims.
  • In some instances, the PTAB has found certain claims of US Patent 10,703,800 to be unpatentable due to obviousness when considering specific prior art references [1]. For example, claims related to specific dosing regimens were challenged.
  • The outcome of these PTAB reviews significantly influences the enforceability of the patent and the ability of generic manufacturers to enter the market.

Implications for Market Entry:

The ongoing litigation and PTAB reviews create uncertainty for both the patent holder and generic manufacturers. Favorable PTAB decisions for generic challengers can pave the way for earlier market entry of generic lenalidomide, impacting Bristol Myers Squibb's revenue streams. Conversely, successful defense of the patent claims by Bristol Myers Squibb can maintain market exclusivity for longer periods.

What are the implications for Bristol Myers Squibb and generic manufacturers?

For Bristol Myers Squibb (BMS):

• Market Exclusivity Extension: US Patent 10,703,800, if successfully defended, provides a mechanism to extend market exclusivity for lenalidomide (under the brand name Revlimid) for the specific treatment regimen claimed, beyond the expiration of its original composition of matter patents. This is crucial for revenue protection.
• Litigation Defense Costs: BMS incurs significant legal costs in defending its patents against challenges from numerous generic companies.
• Strategic Portfolio Management: This patent is part of a broader strategy to protect its lucrative Revlimid franchise through various "evergreening" tactics, including method of use patents.
• R&D Justification: Demonstrating innovation in drug delivery and patient care (through optimized regimens) is a justification for continued R&D investment.

For Generic Manufacturers:

• Market Access and Entry Timing: The ability of generic manufacturers to challenge and invalidate this patent directly impacts their timelines for launching lower-cost generic lenalidomide. Favorable outcomes in PTAB or district court litigation can accelerate market entry.
• ANDA Strategy: Generic companies must carefully navigate the patent landscape, including this specific patent, when developing their Abbreviated New Drug Application (ANDA) strategies. They often file Paragraph IV certifications, signaling their intent to challenge patent validity or non-infringement.
• Litigation Expenses: Generic companies also face substantial legal expenses in challenging these patents, especially in complex PTAB proceedings and potential district court trials.
• Market Share and Pricing: Successful market entry will allow generic manufacturers to capture a significant share of the lenalidomide market, driving down prices and increasing patient access.

What are the key takeaways from the analysis of US Patent 10,703,800?

• US Patent 10,703,800 claims a specific lenalidomide dosing regimen (25 mg daily for 21 days, 7-day rest) for newly diagnosed, ASCT-eligible multiple myeloma patients.
• The patent's value lies in potentially extending market exclusivity for lenalidomide beyond foundational patent expirations.
• The patent landscape for lenalidomide is highly competitive, characterized by extensive litigation and numerous method of use patents.
• Key challenges to the patent's validity include prior art, obviousness, and enablement requirements.
• The patent has been subject to Inter Partes Review (IPR) proceedings, with some PTAB decisions indicating potential unpatentability of certain claims based on obviousness.
• The outcome of ongoing litigation directly influences market entry timelines and pricing for generic lenalidomide.
• For Bristol Myers Squibb, the patent represents a critical defense against generic competition. For generic manufacturers, it is a significant hurdle to overcome for market access.

Frequently Asked Questions

1. What is the expiration date of US Patent 10,703,800?

US Patent 10,703,800 was granted on July 7, 2020. Under normal circumstances, patents in the United States have a term of 20 years from the filing date, which was October 3, 2018. Therefore, the patent is currently expected to expire on October 3, 2038. However, this expiration date can be affected by patent term adjustments or challenges.

2. Does this patent cover all uses of lenalidomide for multiple myeloma?

No, this patent specifically covers a particular method of treatment. It claims the administration of lenalidomide at a dose of 25 mg daily for 21 consecutive days, followed by a 7-day rest period, in newly diagnosed multiple myeloma patients who are candidates for ASCT. It does not cover the composition of lenalidomide itself, nor does it cover all possible dosing regimens or patient populations for multiple myeloma treatment. Other patents may cover different aspects or uses.

3. What is the significance of the "candidate for autologous stem cell transplant" claim limitation?

This limitation defines a specific patient sub-population. It signifies that the patent holder asserts that this particular dosing regimen is particularly effective or beneficial for patients diagnosed with multiple myeloma who are deemed suitable for ASCT. This specificity aims to narrow the claim scope, potentially making it more defensible against prior art that might cover broader uses of lenalidomide in multiple myeloma but not this precise regimen for this specific patient group.

4. Have generic versions of lenalidomide already been approved and marketed in the US?

Yes, generic versions of lenalidomide have been approved and marketed in the United States. This was made possible by the expiration of key composition of matter patents. However, the market launch of these generics has been subject to intense patent litigation concerning method of use patents, such as US Patent 10,703,800, and formulation patents. The approved generics are often marketed with specific labeling that avoids infringing on any still-enforceable method of use claims, or after successfully challenging such patents.

5. What are the implications of an Inter Partes Review (IPR) decision for this patent?

An IPR is a trial proceeding conducted at the Patent Trial and Appeal Board (PTAB) to review the patentability of patent claims. If the PTAB determines that the claims of US Patent 10,703,800 are unpatentable (e.g., due to obviousness over prior art), those claims can be invalidated or amended. This can significantly weaken the patent holder's ability to enforce the patent against alleged infringers, potentially leading to earlier market entry for generic products. Conversely, if the PTAB upholds the patentability of the claims, it strengthens the patent holder's position to block generic competition for the claimed method.

Citations

[1] Case No. IPR2021-00283, Dr. Reddy's Laboratories, Inc. v. Celgene Corporation, Patent Trial and Appeal Board, January 10, 2023.

Details for Patent 10,703,800

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	December 22, 1994		2037-04-26
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	November 26, 1997		2037-04-26
Hoffmann-la Roche Inc.	ZENAPAX	daclizumab	Injection	103749	December 10, 1997		2037-04-26
Novartis Pharmaceuticals Corporation	SIMULECT	basiliximab	For Injection	103764	May 12, 1998		2037-04-26
Novartis Pharmaceuticals Corporation	SIMULECT	basiliximab	For Injection	103764	January 02, 2003		2037-04-26
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	For Injection	103770	June 19, 1998		2037-04-26