The § 505(b)(2) regulatory pathway gives a smaller pharmaceutical company, a start-up company even, the opportunity to submit and obtain FDA approval of a new drug application (NDA) without breaking the bank. A 505(b)(2) NDA may rely heavily on data from an already-marketed drug product and information in published literature to demonstrate the safety and efficacy of the proposed product. This drastically cuts down on R&D and clinical study costs, and can provide an entryway to the “branded drugs” side for a pharmaceutical company more used to operating on the generic side. Once a 505(b)(2) NDA is approved, patents covering new features of the approved drug could be listed on the FDA’s “Orange Book” and serve to block entry of bioequivalent generic products for years and years to come.
The Tension between § 505(b)(2) FDA Approval and Patent Prosecution
Because data from an old product are used in this regulatory approval process, the old product must be similar enough in important aspects to the new proposed drug for such data to be relevant to the new drug in terms of demonstrating safety and efficacy to the FDA. On the other hand, to obtain a patent that covers the new drug, the 505(b)(2) NDA sponsor would have to argue in the patent office that some useful features of the new drug are not only different from, but non-obvious over, all prior art knowledge including the old drug, so as to be patentable. This generates a tension.
This tension can result in a finding of inequitable conduct by a court, as we see in the recent Federal Circuit opinion in the Belcher v. Hospira case, 2021 WL 3889810 (Fed. Cir. Sept. 1, 2021). Such a finding not only renders the entire patent-in-suit unenforceable, it can also potentially engender “infectious unenforceability” on related patents including future patents, and, if other facts align, even antitrust liability due to “sham litigation,” i.e. asserting a patent known to be unenforceable to prolong a market monopoly illegally.
Some Lessons from the Belcher Opinion
Belcher submitted a 505(b)(2) NDA on injectable l-epinephrine formulation (with very limited new data), using a prior Sintetica product as reference. The in-process pH value is important to minimize degradation of such a product. Sintetica used a 2.8-3.3 pH range. Initially, Belcher wanted to use a new 2.4-2.6 pH range, presumably to generate patentable IP. However, the FDA expressed concerns on the new range, precisely because there were no data on its effect on the product. Here, we see one example of the tension between getting FDA approval without new studies and data, on the one hand, and obtaining a patent based on differentiating the approved product with the prior art, on the other hand.
In Belcher’s case, instead of running studies to show that the 2.4-2.6 pH range resulted in a stable product—and, as an added benefit, to show that the new pH range could result in an improvement or “unexpected results” in the product—the company worked with an FDA consultant, and decided to use the 2.8-3.3 pH range. This strategy worked at the FDA, and Belcher got approval. Lost in the shuffle, but dredged up in litigation, was the fact that Belcher’s NDA described the 2.8-3.3 pH range as “old,” presumably to contrast with the new 2.4-2.6 pH range before its abandonment.
Meanwhile, at the patent office, Belcher presented a piece of prior art teaching a wider 2.2-5.0 pH range, but argued that a 2.8-3.3 range was “critical” for product stability. Neither the Sintetica product nor other prior art teaching the 2.8-3.3 range was presented to the PTO. Belcher got its patent claims with the pH 2.8-3.3 limitation. Hospira, the later ANDA filer, challenged the patents and argued invalidity and inequitable conduct. The courts found for Hospira, including that the patent is unenforceable due to inequitable conduct during patent prosecution, i.e. the concealment of the relevant prior art including the Sintetica product by Belcher’s Chief Science Officer coupled with a finding of his intent to deceive the patent office.
It is rare for a patent challenge to prove inequitable conduct. Usually, such a claim would falter because it is very hard to prove, by “clear and convincing evidence,” that a single individual or multiple individuals working together knew about a reference, knew that it was material to patentability, and then made a deliberate decision to withhold it. In other words, it could be difficult to show that someone who owed a duty of candor to the patent office had a specific intent to deceive it. Intent must be found in an individual’s mind, not in a corporation in general. Mistakes are not intent. Miscommunication within an organization, for example, could be used as evidence of a lack of deceptive intent.
Considerations for the 505(b)(2) Sponsor in Patent Prosecution
We present a hypothetical scenario here. Suppose a pharmaceutical company filed a 505(b)(2) NDA and someone working there who handled the FDA regulatory approval process knew and appreciated the importance of a prior art reference, but that individual did not have a responsibility for patent prosecution, which was handled by an outside law firm and an in-house liaison. Suppose the individual handling FDA application sent the reference to the patent prosecution liaison, but forgot to explain why it was important. Perhaps he thought it should be obvious to anyone why the reference was important to patentability. However, the liaison did not have the technical expertise to realize how important the reference was, mistook it as “cumulative,” and never sent it to the patent prosecutor. As a result, nobody actually had any intent to deceive the patent office.
And given the nature of the 505(b)(2) application, it necessarily relies on past literature to support the view that certain safety and efficacy studies are not needed. The very nature of the (b)(2) product approval may be predicated on the basis that the (b)(2) product is safer, more efficacious, solves an unmet medical need, etc. The literature that supports a possible distinction between the reference (predicate) standard may be the very reason why that literature should be submitted to the PTO during examination. R&D personnel involved in the early development may collect literature to support the (b)(2) development. Such R&D personnel may also become inventors, who definitely have the duty to disclose relevant and material literature to the PTO.
In the Belcher case, in contrast, the CSO was proven to be “a key player” and had a “central role” for both the FDA approval process and patent prosecution. He was involved in drafting the patent application in question, product development, and the drafting of the NDA. When a single individual could be proven to have known about material prior art references, understood their materiality from the teachings of the 2.8-3.3 pH range, decided to withhold the references from the patent office, and made seemingly contradictory statements to the FDA and the patent office (because he was directly involved in both processes) regarding whether the same pH range had been “old,” or new and “critical.” When all the evidence converge on a single individual, it is much easier to infer a deceptive intent.
How can we help you?
As we see, a 505(b)(2) NDA sponsor should be mindful of the tension between the FDA approval process and any related patent prosecution, and take steps early on to minimize the risk of a difficult outcome of having a patent found unenforceable, or even allegations of antitrust violation. Upadhye Tang LLP represents 505(b)(2) sponsors in strategy counseling and litigation. Contact Yixin Tang at email@example.com or 312-598-2611 for more information.
About Upadhye Tang LLP
Upadhye Tang LLP is an IP and FDA boutique firm concentrating on the pharmaceutical and medical device spaces. We help clients with navigating the legal landscape by helping on counseling and litigation. Clients call us to help move drug and device approvals along and to represent them in IP and commercial litigation. Call Yixin Tang at firstname.lastname@example.org or 312-598-2611; or Shashank Upadhye, 312-327-3326, or by email: email@example.com, for more information.
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