Artificial Intelligence (AI) has long been associated with science fiction movies about dystopian futures, leading to fear among the general public about its potential impact. This is especially the case today for those in academia who have graded countless papers written by ChatGPT. However, the truth is far from what we see in the movies. In fact, one industry where AI is making significant progress is the biosimilar industry. AI offers many possibilities, including optimizing process design and process control, smart monitoring and maintenance, and trend monitoring to drive continuous improvement. Recently, the FDA has participated in discussions around AI and biotechnology.

The FDA has already played an important role in the integration of AI in the biotechnology field. It has authorized more than 500 AI/ML-enabled medical devices, but last month, the FDA made two big contributions to the conversation. The first is its publication of a discussion paper on artificial intelligence in drug manufacturing to help proactively prepare for the implementation of AI in the field.[1] The second is an article the FDA published disclosing the implementation of AI-based modeling to analyze protein aggregation in therapeutic protein drugs.[2]

1. FDA Discussion Paper – Artificial Intelligence in Drug Manufacturing

In its discussion paper, the FDA requests public feedback to help inform its evaluation of the existing regulatory framework involving AI in drug manufacturing. The FDA suggests a number of areas for consideration.

One such area is standards for developing and validating AI models. The FDA admits that there are limited industry standards and FDA guidance available for the development and validation of models that impact product quality. The lack of guidance is a concern since AI has such great applicability during drug manufacturing. AI can be used in applications to control manufacturing processes by adapting process parameters based on real-time data, or in conjunction with interrogation of in-process material or the final product to: (1) support analytical procedures for in-process or final product testing, (2) support real-time release testing, or (3) predict in-process product quality attributes.

The FDA also notes the challenge applicants have in defining standards that validate an AI-based model and sustaining the ability to explain the model’s output and impact on product quality. As AI methods become more complex, it becomes more challenging to explain how changes in model inputs impact model outputs.

Another area for consideration is how continuously learning AI systems that adapt to real-time data may challenge regulatory assessment and oversight. AI models can evolve over time as new information becomes available. The FDA states that it may be challenging to determine when such an AI model can be considered an established condition of a process. It also may be challenging to determine the criteria for regulatory notification of changes to these models as a part of model maintenance over the product lifecycle. Applicants may need clarity on: (a) the expectations for verification of model lifecycle strategy, and (b) expectations for establishing product comparability after changes to manufacturing conditions introduced by the AI model.

Comments on these and other issues can be sent to the FDA at the link below.[3]

2. FDA’s AI/Machine Learning Modeling to Ensure Safety and Demonstrate Biosimilarity

Despite the limited guidance the FDA has for AI-based technologies, it recently published a study utilizing AI for characterizing protein aggregation, which will provide a more effective means of demonstrating biosimilarity and improve safety in therapeutic protein drugs.

One major challenge that biosimilar developers face with therapeutic protein drugs is characterizing these products in order to compare them with a reference product. Characterization is particularly an issue because of protein aggregates that can create subvisible particles with a wide variety of sizes, shapes, and compositions from a variety of stress conditions. Although a small fraction of the total protein, these aggregates may increase the risk of undesirable immune responses.

The FDA’s study characterized aggregate protein particles using flow imaging microscopy (FIM). This imaging technique can record multiple images of a single subvisible particle from a single sample. Although these image sets are rich in structural information, manual extraction of this information is cumbersome and often subject to human error, meaning that most of the information is underutilized.

To overcome the shortcomings of current optical image analysis, the FDA applied convolutional neural networks (CNNs), a class of artificial neural networks proven helpful in many areas of image recognition and classification. This AI/ML approach enables automatic extraction of data-driven features (i.e., measurable characteristics or properties) encoded in images. These complex features (e.g., fingerprints specific to stressed proteins) can potentially be used to monitor the morphological features of particles in biotherapeutics, and enable tracking the consistency of particles in a drug product.

CNNs can be trained with input data using supervised learning or a fingerprinting approach. For supervised learning, the AI model is trained using estimations of the most discriminatory parameters defined using images that are correctly labelled as either stressed or unstressed. Once trained, the CNN can predict which pre-defined labels best apply to a new image. The fingerprinting approach, on the other hand, is optimized to reduce the dimension of the spatially correlated image pixel intensities, resulting in a new lower dimensional (e.g., 2D) representation of each image. These lower dimensional representations can be used to analyze complex morphology encoded in a heterogeneous collection of FIM images since the full images can readily be mapped to a lower dimensional representation by the CNN.

The FDA found that flow microscopy combined with CNN image analysis could be applied to a range of products and will provide potential new strategies for monitoring product quality attributes. Such technology will enable processing of large collections of images with high efficiency and accuracy by distinguishing complex “textural features” which are not readily delineated with existing image processing software.

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As AI becomes more advanced and more of those in the biosimilar industry utilize this technology, the more guidance the FDA will have to provide, and the sooner the better. These two contributions from the FDA indicate that it is well aware of this need and is even looking to promote AI’s use across the pharmaceutical and biopharmaceutical fields.

[1] https://www.fda.gov/media/165743/download

[2] https://www.fda.gov/drugs/regulatory-science-action/artificial-intelligencemachine-learning-assisted-image-analysis-characterizing-biotherapeutics?utm_medium=email&utm_source=govdelivery

[3] https://www.regulations.gov/  Docket No. FDA-2023-N-0487

After the Supreme Court invited the Solicitor General to file a brief expressing the views of the United States regarding Teva Pharms USA, Inc. v. GlaxoSmithKline LLC, et al., the Solicitor General filed its brief amicus curiae on March 29, 2023. The Solicitor General urged the Supreme Court to grant Teva’s petition for a writ of certiorari. The Solicitor General indicated that even after an outcry of amici in response to the Federal Circuit’s initial decision, the Federal Circuit’s holding that a reasonable jury could view petitioner’s carved-out labeling as evidence of intent to induce infringement of respondents’ method-of-use patent further exacerbated the practical concerns raised by the court’s initial opinion. Specifically, the Solicitor General warned that under the Federal Circuit’s holding, a generic manufacturer that follows the Hatch-Waxman Amendments by marketing an FDA-approved label that carves out the brand-name indications claimed by a method-of-use patent can still be liable for intent to induce infringement.

Additionally, the Solicitor General echoed Judge Prost’s dissent,[1] noting that “[t]he section viii pathway cannot function properly if FDA and generic manufacturers cannot rely on an NDA holder’s representations to the agency regarding which portions of the brand-name drug’s labeling teach patented methods of use.” Under the governing statutes, the FDA cannot authorize a generic drug that would infringe a patent, but it also lacks both the expertise and the authority to review patent claims. As such, it is the brand-name manufacturer’s responsibility to identify the portions of the approved labeling that correspond to the method of use claimed by the patent. Additionally, a generic manufacturer is not free to omit additional portions of the brand-name labeling beyond the omissions approved by the FDA. This uncertainty will deter generic manufacturers from invoking the section viii pathway, which may threaten the availability of lower-cost drugs. Further, the Solicitor General found that the Federal Circuit’s holding that “when a label instructs or teaches a patented use, it can be considered evidence of intent to encourage that use” as inappropriate here, as Teva’s labeling was driven by FDA regulatory requirements and GSK’s own identification of the indication that should be excised.

Finally, in response to the Federal Circuit’s description of Teva’s marketing efforts, catalogs, and press releases that contributed to the finding of intent to induce infringement, the Solicitor General noted that this literature presented to doctors advised the doctors to read the labels and prescribe the drug as indicated by the labels. The Solicitor General stated, “Absent independent evidence that petitioner understood its carved-out labeling to encompass patented uses, proof that petitioner expected and encouraged doctors to rely on the labeling cannot support an inference of intent to induce infringement.”

In light of the Supreme Court’s request that the Solicitor General file its brief amicus curiae, and the Solicitor General’s recommendation that the Supreme Court grant Teva’s petition for a writ of certiorari, it appears that the Supreme Court may agree to hear this case.  We will provide additional updates on this case if this happens.

[1] GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 7 F.4th 1320, 1342-1361 (Fed. Cir. 2021) (Prost, J., dissenting).

Biosimilars are becoming increasingly important in healthcare as they offer a lower-cost alternative to biologic drugs, which can be expensive for patients, governments, and insurers.  These biologic medicines, which are highly similar to existing biological products and are designed to be as effective and safe as the brand name drugs, offer the potential to provide more affordable treatment options to patients. However, the regulatory landscape for biosimilars is still evolving, and there are legislative efforts to address several perceived impediments to biosimilar approvals and marketing.  To address some of the perceived impediments, various bills have been introduced since Congress passed the Biologics Price Competition and Innovation Act (BPCIA) in 2010. In this article, we will explore the latest updates in biosimilar legislation and their potential impact on patients, healthcare providers, and the pharmaceutical industry.

One impediment is that various states and insurers will not allow pharmacists to substitute a biosimilar unless the FDA declares it to be “interchangeable.” Acquiring interchangeable status requires the product to undergo switching studies whereby participants must alternate between the biologic and the biosimilar. These studies can cost millions of dollars and further delay market access.  In November 2022, Sen. Mike Lee (R-Utah) introduced the Biosimilar Red Tape Elimination Act. The Bill aims to reduce health care costs and increase access to biosimilar drug products by eliminating switching studies as a requirement to obtain an “interchangeability” designation from the FDA. The interchangeability designation allows pharmacists to substitute the reference product for the biosimilar without requiring physician permission. Under Sen. Lee’s proposed Bill, corporations could more easily establish interchangeability, and therefore, patients could more easily obtain their biologic medications at a lower cost.  

In January 2023, the biosimilar landscape saw the emergence of three new Bills that could have significant implications for the future of biologic medicines. Sen. Amy Klobuchar (D-MN) introduced the Stop STALLING Act and the Preserve Access to Affordable Generics and Biosimilars Act. Sen. John Cornyn [R-TX] introduced the Affordable Prescriptions for Patients Act of 2023.

Another impediment is that some drug manufacturers have submitted numerous or baseless citizens petitions so that the FDA would delay competing manufacturers’ biosimilar or generic approvals.  The Stop STALLING Act seeks to deter branded pharmaceutical companies from filing what it claims is a “sham” citizen petition with the FDA in order to interfere with the regulatory approval process for competitors’ generics and biosimilars. Such delays prevent patient access to affordable medication. The Bill would give the FTC enhanced authority to take action against companies that file these sham petitions to delay market entry. The FTC could “commence a civil action to recover a civil penalty and seek other appropriate relief in a district court of the United States against any person that submitted or caused to be submitted” a petition (e.g., a “citizens petition”) if the FTC has reason to believe it is a “sham” petition.

Pay-for-delay deals, the practice in which drug companies use pay-off agreements to delay the introduction of cheaper substitutes, is another impediment.  The Preserve Access to Affordable Generics and Biosimilars Act would prohibit anticompetitive “pay-for-delay deals” that prevent or delay the introduction of affordable generics. The bill targets “reverse payment” settlement agreements which are categorized as “allow[ing] a branded company to share its monopoly profits with the generic company as a way to protect the branded company’s monopoly” and “unduly delay the marketing of low-cost generic drugs contrary to free competition, the interests of consumers, and the principles underlying antitrust law.” These deals increase the cost of prescriptions and impose significant costs on our health care system.

Finally, Sen. Cornyn’s Affordable Prescriptions for Patients Act would curb drug companies’ abuse of patents through “product hopping,” where companies extend exclusivity by switching patients to a new, slightly changed, version of the branded drug while the older version succumbs to generics. Some examples of this behavior include destroying the inventory of the old drug, pulling it from the market, aggressively raising its price, badmouthing the old drug, or even diminishing its safety. As a result of this conduct, patients are stuck paying more for a drug that is substantially similar to the old one. 

Relatedly, on February 22, 2023, Sen. Elizabeth Warren along with Sen. Bernie Sanders and Representatives Katie Porter and Pramila Jayapal sent a letter to Kathi Vidal, director of the United States Patent and Trademark Office (USPTO), arguing that Merck’s development of a subcutaneous version of the biologic drug Keytruda® (pembrolizumab) appears to be an example of anti-competitive business practices, including double-patenting, patent thicketing, product hopping, and evergreening.

Thus, while biosimilars are increasingly important in reducing healthcare costs and increasing patient access to lifesaving medicines, there are various perceived impediments to biosimilar approvals and marketing that will need to be addressed. It is clear that the regulatory landscape for biosimilars is evolving, and we can expect to see more legislation in the coming years as the biosimilar industry continues to grow.

The United States Patent and Trademark Office (USPTO) issued updated guidance on the duty of candor and duty to disclose in relation to submissions made to other government agencies, particularly the Food and Drug Administration (FDA). The Notice did not constitute new rule making and instead aims to clarify the obligations of patent applicants and attorneys to disclose all relevant information to the USPTO. However, in light of the Notice, patent applicants and patent owners should expect to see an increase in the number of patent examiner requests for further documents and information, and invalidity or unenforceability challenges from third parties based on a failure to disclosure or for alleged inconsistent statements made to other governmental regulatory agencies such as the FDA.

Each individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability. Specifically, 37 CFR 1.56(a) and 1.555(A) state that the duty to disclose applies to “[e]ach individual associated with the filing and prosecuting of a patent application” and “[e]ach individual associated with the patent owner in a reexamination proceeding.” Fed. Reg. Vol. 87, No. 145 at 45765. Specifically, this announcement was designed to remind current or would be applicants that this duty to disclose extends to statements made to other governmental agencies, such as the FDA, in order to obtain licensing or regulatory approval. “If a party to a USPTO proceeding discovers that an earlier position taken in a submission to the USPTO or another Government agency was incorrect or inconsistent with other statements made by the party, the party must promptly correct the record.” Id. The USPTO particularly noted that “when examining a claim directed to a process of manufacturing a particular drug product that was effectively filed more than one year after FDA approval of the drug product, an examiner may appropriately require an applicant to submit to the USPTO information submitted to the FDA (e.g. in a New Drug Application or Biologics License Application) on how the drug product was manufactured.” Id. at 45766.

This announcement was made in direct response to President Biden’s July 2, 2021 Executive Order on Promoting Competition in the American Economy, which, among addressing other issues, expressed concern that “too often, patent and other laws have been misused to inhibit or delay—for years and even decades—competition from generic drugs and biosimilars, denying Americans access to lower-cost drugs.” Id. at 45764 (quoting 86 FR 36987). Following Biden’s executive order, Senators Patrick Leahy and Thom Tillis drafted a letter to Andrew Hirshfeld, then Under Secretary of Commerce for Intellectual property and Director of the USPTO, to “take steps to reduce patent applicants’ making inappropriate conflicting statements in submissions to the [USPTO] and other federal agencies,” specifically noting inconsistent, and at times conflicting, statements made to the FDA and the USPTO Id. at 45764-65.

Although, this notice “clarifies the ’duty of disclosure’ and ‘duty of reasonable’ inquiry owed to the USPTO and American public,” it should be noted that this has always been the rule. Id. at 45765. The updated guidance from the USPTO includes several examples to help clarify the duties of candor and disclosure. Belcher Pharmaceuticals, LLC v. Hospira, Inc., 11 F.4th 1345 (Fed. Cir. 2021) (failure to disclose to USPTO inconsistent statements to FDA invalidated patent claims); Bruno Independent Living Aids, Inc. v. Acorn Mobility Services, Ltd., 394 F.3d 1348 (Fed. Cir. 2005) (finding failure to disclose inconsistent was an “exceptional case” and awarding attorney fees).

What must be disclosed to the USPTO?

  1. Any information that is material to patentability (including but not limited to: prior art, prior sales, prior offers for sale, positive or negative testing data, FDA submissions, third party documents).
  2. Third party documents may include, for example, paragraph IV notices, patent dance documents, third party submissions to the applicant or PTO in other application/proceeding, or patent office in another country.
  3. Must correct any incorrect or inconsistent positions taken in a submission to the USPTO or to another Government agency.

 “A duty of reasonable inquiry may exist based on circumstances known to the party presenting the paper to the USPTO.” See Fed. Reg. Vol. 87, No. 145 at 45766. This duty includes reviewing documents that are submitted to or received from other Government agencies, including the FDA. Bruno independent Living Aids, Inc. v. Acorn Mobility Services, Ltd., 394 F.3d 1348 (Fed. Cir. 2005) (prior art “equivalent” submitted in FDA docs was not disclosed to PTO: unenforceable and “exceptional” case with attorney’s fees). Failing to inquire “when the circumstances warrant it” could result in sanctions or other adverse action. This duty also includes inquiring about and disclosing prior offers for sale or sales. GS Cleantech Corp. v. Adkins Energy LLC, 951 F.3d 1310 (Fed. Cir. 2020) (offer for sale more than one year prior to filing, patent prosecutor withheld it from PTO, unenforecable). Other situations may include patent prosecutors consulting with litigation teams and foreign patent counsel to ensure that third party documents from such proceedings are disclosed to the USPTO.

The Notice is a valuable reminder that applicants should immediately implement reasonable procedures to maintain open lines of communication between U.S. patent prosecution counsel and personnel involved in communications with FDA (or other relevant government agency), as well as litigation and foreign patent counsel in relevant situations. Such open lines of communication will reduce risks of a failure to disclose material information. Further, such communications can reduce the risk of inconsistent statements being made to government agencies, and, in the event a seemingly inconsistent statement is made, allow the patent applicant to attempt to promptly correct the record.

Patent counsel can provide an invaluable service to companies concurrently seeking patent protection and FDA approval. Given that patent counsel is already deeply familiar with the patentability issues and trained in spotting material information, consulting with patent counsel can efficiently prevent a failure to comply with the duty of disclosure and avoid submission of inconsistent statements that violate the duty of candor. Moreover, given that drug development often involves complex partnering relationships between two or more companies, patent counsel can play an integral role in preserving privilege in such situations.

Disclaimer: The information contained in this posting does not, and is not intended to, constitute legal advice or express any opinion to be relied up legally, for investment purposes or otherwise. If you would like to obtain legal advice relating to the subject matter addressed in this posting, please consult with us or your attorney. The information in this post is also based upon publicly available information, presents opinions, and does not represent in any way whatsoever the opinions or official positions of the entities or individuals referenced herein.

The Supreme Court agreed on Friday, November 4, 2022, to review the standard for enablement of genus claims after the Federal Circuit’s decision in Amgen, Inc. v. Sanofi. We have previously covered Amgen’s petition for a writ of certiorari and the multiple amicus curiae briefs submitted in the case. As detailed below, the Supreme Court’s decision to hear this case is contrary to the recommendations in a brief for the Solicitor General filed this September, and is a victory for Amgen in support of its patent claims covering antibodies that bind and block PSK9 (a receptor involved in LDL cholesterol metabolism).

The question to be reviewed by the Supreme Court is:

Whether enablement is governed by the statutory requirement that the specification teach those skilled in the art to “make and use” the claimed invention, 35 U.S.C. § 112, or whether it must instead enable those skilled in the art “to reach the full scope of claimed embodiments” without undue experimentation—i.e., to cumulatively identify and make all or nearly all embodiments of the invention without substantial “ ‘time and effort.’ ”

Interestingly, the Court did not grant cert as to Question 1 of Amgen’s Petition, which sought review of whether enablement is a question of fact for the jury, rather than a question of law as the Federal Circuit has held.  The Court on Monday, November 7, 2022, denied cert to a petition filed by Juno Therapeutics (a subsidiary of Bristol Myers Squibb) and Sloan Kettering seeking review of the written description standard applied by the Federal Circuit in invalidating the petitioners’ patent on CAR-T immunotherapy. That Federal Circuit decision erased a $1.2B jury verdict finding Kite Pharma (now Gilead) guilty of patent infringement.

Recent Federal Circuit decisions, including Amgen v. Sanofi and Juno v. Kite, have made it increasingly difficult for patent owners to defend claims directed to discovery of a novel therapeutic target or epitope, requiring innovators to more narrowly claim specific sequences of therapeutic molecules. The Supreme Court’s decision to grant certiorari in the Amgen case raises the possibility that patent owners will see the pendulum shift back in favor of genus claims.

In the Brief for the United States as Amicus Curiae, the government recommended that the petition for writ of certiorari be denied. First, the government contended that the district court and court of appeals’ treatment of enablement as a question of law was not incorrect, as the enablement inquiry has both fact and legal components. The government stated, “[P]etitioners concede that a court may resolve a question initially decided by the jury on a motion for JMOL, and that is what the courts below did here.” Second, in addressing the degree of experimentation required to implement the full scope of the claims, the government stated that because the Patent Act requires a patent to enable the invention, where a patentee purports to invent an entire genus, it must enable the entire genus. The government stated that the Federal Circuit considered the degree of experimentation as only one of the Wands factors and emphasized that it was not “hold[ing] that the effort required to exhaust a genus is dispositive.” Because the Petitioners did not dispute that the Wands factors provided an appropriate framework for resolving questions of enablement and undue experimentation, nor did they propose an alternative standard for determining whether a patent adequately enables the claimed invention, the government recommended the petition be denied.

Petitioners responded to the government’s brief by stating that the government had rewritten the legal questions and then argued that its own questions did not warrant review. Petitioners noted that the government stated that enablement is a question of both law and fact, and that the Federal Circuit’s overturning of the jury’s verdict is not an ordinary application of JMOL. Additionally, the Petitioners pointed to the Federal Circuit’s admission that the enablement standard for genus claim may be raised if “substantial time and effort would be required to reach the full scope of claimed embodiments.” Petitioners alleged that the government never explained “why a claim should be invalidated based on the cumulative effort to make all claimed embodiments where, as here, it would not require undue experimentation for skilled artisans to make and use any individual embodiment.”

After the briefs were distributed for conference on November 4, the Supreme Court granted the petition as limited to Question 2—the enablement question.

On September 27, 2022, Judge Richard Andrews of the District of Delaware granted Novartis’s motion to dismiss declaratory judgment (“DJ”) counterclaims raised by two generic drug manufacturers in the ongoing litigation regarding Novartis’s heart failure medication, Entresto® (sacubitril/valsartan).[1] The decision provides guidance to ANDA applicants seeking to maintain a case or controversy for DJ counterclaims under the Hatch Waxman Act.

In September 2019, several generic drugmakers, including Hetero USA Inc. and Torrent Pharma Inc., filed ANDA applications for generic versions of Entresto®. Subsequently, in September 2021, Novartis sued the ANDA applicants alleging infringement of U.S. Patent No. 11,096,918 (“the ’918 patent”). Hetero and Torrent filed answers which included counterclaims seeking declaratory judgment of invalidity and non-infringement for not only the ’918 patent, but also four additional patents that Novartis listed in the Orange Book more than a year after Hetero and Torrent filed their respective ANDA applications.[2] After the patents were listed, Hetero and Torrent supplemented their ANDA applications to include Section viii statements carving out the protected indications from their labeling. However, Defendants never pursued Paragraph IV certifications for these four patents.

Novartis moved to dismiss the counterclaims, arguing that Hereto and Torrent were barred by statute because they did not serve any Paragraph IV notice on Novartis as required by 21 U.S.C. § 355(j)(5)(C)(i) and 35 U.S.C. § 271(e)(5). Although Judge Andrews disagreed with Novartis on this point, he nonetheless dismissed the counterclaims, holding that an ANDA applicant that submits a Section viii statement does not create an “actual controversy” because there is no cause of action. The Hatch Waxman Act allows generic manufacturers to limit the scope of regulatory approval they seek—and thereby forego Paragraph IV certification and a § 271(e)(2) infringement suit—by excluding patented indications from their ANDAs using Section viii statements. “Thus, an ANDA applicant that submits a Section viii statement for a patent does not face the imminent threat and actual controversy of an infringement action . . . for that patent.”[3]

Based on this case, courts may find that preemptively carving out of an ANDA label the subject matter of a patent which has not been asserted does not provide standing for the ANDA applicant to seek declaratory judgment of noninfringement for that unasserted patent. ANDA applicants can avoid this situation by filing a Paragraph IV certification of non-infringement along with the label carve out under Section viii.

Although there is no equivalent of Section viii in the BPCIA, biosimilar applicants can choose to carve out certain indications or conditions of use from the label of the reference product sponsor (RPS) for patent reasons.[4] A biosimilar applicant wishing to engage in pre-launch litigation of an RPS patent claiming a method of use directed to the carved-out indication can engage in the Patent Dance by providing its aBLA and accompanying information to the RPS.[5] If the RPS does not include the relevant patent on its “3A list” of patents that could reasonably be asserted, the biosimilar applicant can include the patent in its responsive “3B list.”[6] This procedure allows the biosimilar applicant to propose the patent for inclusion in the “first wave” litigation, and if it is not included, the biosimilar applicant may file a declaratory judgment action after service of its notice of commercial marketing.[7]

 

[1] In re: Entresto (Sacubitril/Valsartan) Patent Litig., Case No. 1-20-md-02930, D.I. 844 (D. Del. Sep. 27, 2022).

[2] The four additional patents are U.S. Patents No. 9,517,226 (the “’226 patent”), 9,937,143 (the “’143 patent”), 11,135,192 (the “’192 patent”), and 11,058,667 (the “’667 patent”).

[3] D.I. 844 at 12.

[4] See Food and Drug Administration, Guidance for Industry: Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed (February 2020).

[5] 42 U.S.C § 262(l)(2)(A).

[6] 42 U.S.C. § 262(l)(3).

[7] See 42 U.S.C. § 262(l)(9)(A).

On September 9, 2022, Biogen Inc. and Biogen MA Inc. (“Plaintiffs”) filed suit against Sandoz Inc., Sandoz International GMBH, Sandoz GMBH, and Polpharma Biologics S.A. (collectively, “Defendants”) in the District of Delaware concerning twenty-eight different patents. Although the complaint was filed under seal, the complaint appears to be related to Defendants’ natalizumab biosimilar (proprietary name of Tysabri®).  Sandoz announced on July 25, 2022 that the FDA had accepted its aBLA for natalizumab.  Biogen’s twenty-eight asserted patents have not yet been listed in the Purple Book.  This suggests that either (1) Sandoz already provided its 180-day notice of commercial marketing under 42 USC § 262(l)(8)(A), or (2) Sandoz may have opted out of the patent dance by refusing to produce its aBLA and associated documents (see § 262(l)(9)). On September 12, Judge Connolly granted Plaintiffs motion to file the complaint under seal. The order requires Biogen to file a redacted version of the complaint by September 19, which will then provide more details on the BPCIA litigation.  We will provide further updates as the case progresses.

Updated on September 20, 2022

The redacted, publicly available version of the complaint is now available. Based on the information in the complaint, Biogen claims that Defendants have provided some, but not all, of the information contemplated by 42 USC § 262(l) regarding the Defendants’ natalizumab aBLA product. Biogen asserts that Defendants have not provided all information requested under 42 USC § 262(l)(2)(A)-(B), and have not provided a complete response to Biogen’s list of asserted patents under 42 USC § 262(l)(3)(B)(ii). Because of these alleged failures to comply with the statute, Biogen has sought a declaratory judgment of patent infringement as permitted under 42 USC § 262(l)(9)(B).

On August 2, 2022, Coherus BioSciences announced that the U.S. Food and Drug Administration (FDA) has approved CIMERLI™ (ranibizumab-eqrn) as a biosimilar product interchangeable with Lucentis® (ranibizumab injection) for all five indications, meeting the FDA’s rigorous standards to the reference product, including safety, efficacy, and quality.  Coherus plans to launch CIMERLI™ in early October 2022.

In order for a biosimilar to acquire the “interchangeable” designation, in addition to meeting the requirements for a biosimilar (i.e., highly similar to, and no clinically meaningful differences from, an approved reference product), the manufacturer must show that the interchangeable biosimilar product is expected to produce the same clinical result as the reference product in any given patient. For biological products administered more than once to an individual patient, the manufacturer needs to further provide data ensuring that the risk in terms of alternating or switching between use of the interchangeable biological product and its reference product is not greater than the risk of using the reference product without switching.

The benefit of meeting these more extensive requirements is that, just like with a traditional generic drug, an “interchangeable” biosimilar can be substituted for the often pricier reference product by a pharmacist without the prescribing doctor’s intervention or approval (subject to state pharmacy laws). Importantly, CIMERLI™ will benefit from 12 months of first interchangeable biosimilar exclusivity.

CIMERLI™ belongs to the anti-VEGF therapy class of biologics that has been revolutionary in helping retinal patients maintain or gain vision. Retina indications for which CIMERLI™ is interchangeable include Neovascular (wet) Age-Related Macular Degeneration (AMD), Macular Edema following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME), Diabetic Retinopathy (DR), and Myopic Choroidal Neovascularization (mCNV).

“CIMERLI™, the only biosimilar product interchangeable with Lucentis® across all five indications, will provide both greater treatment access and choice for patients, payors and providers in the U.S. retinal disease community,” said Paul Reider, Chief Commercial Officer of Coherus. “Coherus is the only company in the $7 billion anti-VEGF ophthalmology market with a demonstrated track record of U.S. commercial biosimilar success. We intend to replicate our UDENYCA® achievements with a dedicated retina commercial team eager to leverage their experience and in-depth market understanding to drive CIMERLI™ share.”

Coherus CEO Denny Lanfear explained that the “approval of CIMERLI™ and its upcoming launch represent a strategic inflection point for Coherus as we transition to a multi-product revenue stream. UDENYCA®, our first product, established our track record of success competing in the U.S. biosimilars market. Our upcoming launch of CIMERLI™ and planned launch next year of our third approved product, our Humira® biosimilar, YUSIMRY™, will leverage this experience and knowledge. For Coherus, this portfolio is also our source of internally generated capital as we build a leading innovative oncology franchise that will drive our future growth.”

CIMERLI™ will follow Samsung Bioepis and Biogen’s Byooviz (ranibizumab-nuna) into the market although CIMERLI™ will be benefit from interchangeable exclusivity.  It will be interesting to see how the landscape for ranibizumab products and pricing changes with the launch of CIMERLI™.

Disclaimer: The information contained in this posting does not, and is not intended to, constitute legal advice or express any opinion to be relied up legally, for investment purposes or otherwise. If you would like to obtain legal advice relating to the subject matter addressed in this posting, please consult with us or your attorney. The information in this post is also based upon publicly available information, presents opinions, and does not represent in any way whatsoever the opinions or official positions of the entities or individuals referenced herein.

Patent thickets, particularly those involving pharmaceutical patents, appear to have caught the ire of many U.S. senators. Within the past few weeks, two separate letters have urged action to find ways to prevent issuance of overlapping patents covering a single pharmaceutical product. The letters provide insights into the tools they believe are available to address such alleged patent abuse.

On May 25, 2022, U.S. senators Bill Cassidy, M.D. (R-LA) and Maggie Hassan (D-NH) alleged that “lack of coordination” between the U.S. Food and Drug Administration (FDA) and Patent and Trademark Office (“PTO”) allowed patent thickets to grow in a letter to Kathi Vidal, Director of the PTO, and Dr. Robert M. Califf, Administrator of the FDA. The letter alleged that lack of inter-agency coordination allowed the pharmaceutical industry to obtain patents of questionable validity that block entry of generic drugs and extend monopoly prices. In the letter, the senators expressed concern regarding drug manufacturers’ increasing reliance on patent thickets to evade competition.

Between 2005 and 2015, 78% of drugs associated with new patents were not new drugs, but existing ones, and the number of drugs with three or more patents added to them in one year doubled. These thickets can preserve a drug company’s monopoly and block the launch of generic drugs for years or even decades after the expiration of the drug’s original patent. In the intervening period, patients are deprived of significant savings: drug prices drop by as much as 20% when the first generic enters the market and as much as 85% when multiple generics enter the market.

In the letter, the senators postulated that the lack of coordination between the PTO and FDA may lead to patent thickets, enabling manufacturers to obtain patents that do not satisfy the Patent Act’s requirement. As an example, the letter mentions the drug manufacturer’s disclosure of its manufacturing process of an already marketed product to the FDA more than a year prior to submitting the patent application to the PTO coupled with the drug manufacturer’s contradictory statements made to the FDA and to the PTO.  In this regard, the senators noted that existing sections of the Federal Food, Drug, and Cosmetic Act authorize the FDA to share information with the PTO. Thus, in order to improve the inter-agency coordination, the senators requested Director Vidal and Administrator Califf to address the following questions by June 24, 2022:

  1. How does the PTO determine whether an application is connected to pharmaceutical product(s) (small molecule drugs or biologics)?
  2. In the past five years, how many patent applications connected to pharmaceutical products did the PTO review?
  3. Did the PTO request information from the FDA during the patent application review of the cases in question 2? If so,
    a. Did the FDA provide the PTO with information?
    b. Was the FDA information adequate to guide the PTO’s analysis?
  4. Do the PTO and the FDA have a process to collaborate when the PTO reviews pharmaceutical-related patent applications?
    a. If not, when will the agencies establish a process?
    b. If so, what actions are the agencies taking to improve it, and what is the timeline for implementing these improvements?

Relatedly, on June 17, 2022, Senators Dick Durbin (D-IL), Thom Tillis (R-NC), and Chuck Grassley (R-IA) introduced the “Interagency Patent Coordination and Improvement Act,” or S. 4430, a bill to establish a joint task force between the PTO and FDA to “enhance information sharing on each agency’s processes, standards and methods; improve dialogue on new technologies and scientific trends; enable confidential reciprocal access to information, if requested and only as needed; ensure accurate representations by companies between the two agencies; and ensure accuracy of patent listings.”[1]  Notably, Senator Tillis commented that, “[h]aving access to accurate prior art is critical to ensure that the USPTO issues high-quality patents. By improving coordination between the USPTO and FDA, Congress can ensure that patent examiners have access to all of the relevant information that they need to help them make a sound determination regarding patentability. This bill is a simple good-government measure that will protect the strength of the patent system, improve patent quality, and cut down on unnecessary bureaucracy between these two agencies.”[2]

On June 8, 2022, U.S. senators Patrick Leahy (D-VT), John Cornyn (R-TX), Richard Blumenthal (D-CT), Susan M. Collins (R-ME), Amy Klobuchar (D-MN), and Mike Braun (R-IN) alleged that continuation and highly similar patents were being issued too frequently and too easily in a letter directed to Director Vidal.  The senators complained that drug manufacturers are able to obtain dozens or hundreds of patents on a single drug through minor tweaks to delivery mechanism, dosages, and formulations. The senators expressed concerns that the prevalence of continuation and other highly similar patents is contrary to the Patent Act, which envisions a single patent per invention and impedes generic drugs’ production, hurts competition, and extends exclusivity beyond the mandated patent term. Thus, the senators asked the director to change the PTO’s regulations and practices to address the problem during the examination phase and asked that the PTO issue a notice of proposed rule-making or a public request for comments by September 1, 2022 addressing the following questions:

  1.  Terminal disclaimers, allowed under 37 C.F.R. 1.321(d), allow applicants to receive patents that are obvious variations of each other as long as the expiration dates match. How would eliminating terminal disclaimers, thus prohibiting patents that are obvious variations of each other, affect patent prosecution strategies and patent quality overall?
  2.  Currently, patents tied together with a terminal disclaimer after an obviousness-type double patent rejection must be separately challenged on validity grounds. However, if these patents are obvious variations of each other, should the filing of a terminal disclaimer be an admission of obviousness? And if so, would these patents, when their validity is challenged after issuance, stand and fall together?
  3.  Should the USPTO require a second look, by a team of patent quality specialists, before issuing a continuation patent on a first office action, with special emphasis on whether the claims satisfy the written description, enablement, and definiteness requirements of 35 U.S.C. § 112, and whether the claims do not cover the same invention as a related application?
  4. Should there be heightened examination requirements for continuation patents, to ensure that minor modifications do not receive second or subsequent patents?
  5.  The Patent Act requires the USPTO Director to set a “time during the pendency of the [original] application” in which continuation status may be filed. Currently there is no time limit relative to the original application. Can the USPTO implement a rule change that requires any continuation application to be filed within a set time frame of the ultimate parent application? What is the appropriate timeframe after the applicant files an application before the applicant should know what types of inventions the patent will actually cover? Would a benchmark (e.g., within six months of the first office action on the earliest application in a family) be preferable to a specific deadline (e.g., one year after the earliest application in a family)?
  6.  The USPTO has fee-setting authority and has set fees for filing, search, and examination of applications below the actual costs of carrying out these activities while maintenance fees for issued patents are above the actual cost. If the up-front fees reflected the actual cost of obtaining a patent, would this increase patent quality by discouraging filing of patents unlikely to succeed? Similarly, if fees for continuation applications were increased above the initial filing fees, would examination be more thorough and would applicants be less likely to use continuations to cover, for example, inventions that are obvious variations of each other?

One of the more interesting proposals raised by the senators is the elimination of terminal disclaimers. Obviousness-type double patenting is a judicially-created doctrine that is commonly raised during examination of continuation applications and can typically be overcome by filing a terminal disclaimer. In theory, eliminating terminal disclaimer practice would force applicants to only patent inventions that are not obvious variants of each other.  However, there are at least two complications. First, obviousness is a highly subjective inquiry and obviousness-type double patenting analysis is often even more confounding given that an examiner must decide what would have been an obvious variant of a given patent’s claim. Second, the scope of obviousness-type double patenting rejections and challenges has expanded in recent years and is routinely applied to applications that are not continuations, are not related to each other, and often are not even owned by the same entity. Given that obviousness-type double patenting rejections are extremely common, and thus terminal disclaimers are widely used, it remains to be seen how the PTO will respond to the complex issues posed by the senators’ questions and whether further legislative action would be required given that obviousness-type double patenting is a judicially-created doctrine with an expanding and amorphous reach. Moreover, it will be interesting to see how the PTO will respond to the proposals that will have difficult to predict impacts on activities that account for a significant portion of the application filing fees, terminal disclaimer fees, and maintenance fees that the PTO collects.

We will continue to monitor for further developments including how Director Vidal and Administrator Califf address the senators’ questions.

[1] https://www.grassley.senate.gov/news/news-releases/grassley-durbin-tillis-introduce-legislation-to-improve-coordination-between-uspto-and-fda

[2] Id.

Patents related to Regeneron’s EYLEA (aflibercept) were recently added to the Purple Book.  Under the Biological Product Patent Transparency Act, signed into law December 27, 2020 and codified at 42 U.S.C. § 262(k)(9), patents must be submitted to the FDA for listing in the Purple Book during the “Patent Dance” under the BPCIA. Specifically, within thirty (30) days after the reference product sponsor (RPS) has submitted a list of patents that could reasonably be asserted against the biosimilar manufacturer under § 262(l)(3)(A), the RPS must provide the list of patents and their expiry dates to FDA.

Regeneron listed twenty-nine patents in connection with EYLEA, four of which do not expire until 08/18/2040 (U.S. Nos. 11,053,280, 11,104,715, 11,174,283, and 11,186,625). Although there are multiple aflibercept biosimilars currently under development, all have yet to receive FDA approval. Regeneron’s recent Purple Book listing presumably comes as part of a Patent Dance with Viatris (formerly Mylan), which filed an aBLA for its aflibercept biosimilar MYL-1701P in late 2021. At least six other aflibercept biosimilars are in, or have completed, phase 3 clinical trials. These include SB-15 (Samsung Bioepis), ABP 938 (Amgen), FYB203 (Formycon and Bioeq), SOK583A19 (Sandoz), CT-P42 (Celltrion), and OT-702 (Ocumension Theraputics and Shandong Boan Biological Technology).