Elysium filed its petition requesting Inter Partes Review of the 8,383,086 (Pharmaceutical or '086) Patent on July 17, 2017.
ChromaDex (technically Steptoe on behalf of Dartmouth, but I'll just say "ChromaDex" or "Steptoe" throughout) filed its preliminary response on November 3, 2017.
The Patent Trial and Appeal Board (PTAB) granted Elysium's petition and explained its reasoning on January 29, 2018.
I have been assuming that if we gave Steptoe four months or more to think about it, they would create some utterly devastating arguments against Elysium's weird position that the known effects of buttermilk prevent anyone from patenting a pharmaceutical composition that delivers nicotinamide riboside to replenish NAD.
We were not disappointed.
Throughout this vexing litigation I have maintained that ChromaDex was getting its money's worth out of their lawyers -- and so was Elysium from its lawyers (even if I do not approve of their true profession, they are nonetheless impressive practitioners).
But Steptoe has really shown the way in this document, which you can read here:
It's actually easy to be right when the facts are on your side, which they obviously are for Steptoe. The hard part is to make the argument so simple, clear, and compelling that even an overworked, underpaid, distracted PTAB panel that churns these things out can immediately see the true nature of the question and avoid being misled by the opposition's inevitable red herrings, a boatload of which is due to wash up on August 22nd.
Steptoe has achieved that level of clarity.
The second thing I like about this Final Response is that it is not only aimed at the PTAB Panel, but at the US Court of Appeals for the Federal Circuit, which has appellate jurisdiction over the matter. No matter the PTAB Panel's inclinations, Steptoe clearly outlines what constitutes reversible error and why Elysium's position, if embraced below, likely will not get a warm reception on appeal. As Sun Tsu says, first win the war, then fight it.
Overview
The essence of ChromaDex's argument is this:
The ’086 patent claims require a pharmaceutical composition containing nicotinamide riboside as the active agent. The asserted prior art, Goldberger et al. (Ground 1) and Goldberger and Tanner (Ground 2), discloses milk and buttermilk, respectively. Petitioner has not established that either milk or buttermilk is a pharmaceutical composition containing nicotinamide riboside as the active agent. Because all claims of the ’086 patent require the same pharmaceutical composition containing nicotinamide riboside as the active agent, Petitioner has failed to establish that the prior art anticipates any claim of the ’086 patent.
That argument applies to all five claims.
ChromaDex adds that Claim 2 is also valid for another reason, which is that the NR in the '086 patent is isolated, and the NR in milk is not.
Finally, ChromaDex points out that even if the active agent claim construction were rejected, Claim 5 still specifies that the formulation replenishes NAD, which milk might not (according to Elysium's own expert). Therefore, claims 2 and 5 represent separate, independent, extremely strong arguments.
Active Ingredient
But let's look more closely at the active ingredient issue, because that argument, which relates to all five claims, if successful, results in a complete shutout of Elysium's petition.
This is what the PTAB wrote in their initial decision instituting trial:
Claim 1 recites a “pharmaceutical composition comprising nicotinamide riboside . . . formulated for oral administration.” Claim 3 reads “[t]he pharmaceutical composition of claim 1, wherein the formulation comprises a tablet, troche, capsule, elixir, suspension, syrup, wafer, chewing gum or food.” Petitioner contends that the term “pharmaceutical composition” should include food products. As support, Petitioner points to the language of dependent claim 3, which further limits the pharmaceutical composition of claim 1 to a Markush grouping that includes food. Patent Owner offers no construction for the term “pharmaceutical composition” other than to argue that milk is not a pharmaceutical composition. We agree with Petitioner that, as used in claim 1, the term “pharmaceutical composition” includes food products. Not only is this construction consistent with the dependent claim 3 it is supported by the Specification of the ’086 patent, which states: “For oral therapeutic administration, the compound can be combined with one or more carriers and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, foods and the like.” (citations omitted)
To rebut, Steptoe starts by pointing out that the inventor of this '086 Patent, Dr. Charles Brenner, discovered the NRK pathway, and
...that oral pharmaceutical formulations of nicotinamide riboside as the active agent could be used to treat conditions that are connected to NAD+ biosynthesis...In light of the discovery that nicotinamide riboside is an effective active agent, the ’086 patent claims oral pharmaceutical compositions containing nicotinamide riboside. Contrary to Petitioner’s arguments, the ’086 patent does not cover any composition that happens to include nicotinamide riboside. Instead the ’086 patent claims cover oral compositions specifically formulated with nicotinamide riboside as the active agent.
So that's the claim construction that wins the whole case.
Is a "pharmaceutical composition comprising nicotinamide riboside" just anything that happens to have NR in it, or does the NR have to be an active ingredient in the formulation, as opposed to just incidentally present?
Steptoe needs to show not only that this is a sensible definition, but that it is the RIGHT definition -- the one that was intended and already contextually present in the patent and just needs to be recognized.
Steptoe next points out that all five claims refer to NR implicitly as an active agent in the patented formulation.
The patent needs to be understood from the standpoint of a skilled practitioner in the art, rather than from the standpoint of bleacher bums like me who actually don't know anything about biochemistry. A person of ordinary skill in the art of the '086 patent, according to Steptoe, would be a professor of biochemistry familiar with pharmacokinetics.
THAT skilled practitioner, says Steptoe, "would understand that the ’086 patent is directed to nicotinamide riboside, and specifically, to its use as an active agent in the claimed pharmaceutical compositions."
By contrast, Elysium proposes no meaningful definition for the term "pharmaceutical composition" and instead focuses only on the physical forms the claimed composition may take (e.g., tablet capsule, syrup, etc.). In doing so, Elysium
ignores the disclosure of the ’086 patent itself and the specification’s focus on nicotinamide riboside compositions. Patent Owner proposes that the Board construe the phrase “pharmaceutical composition comprising nicotinamide riboside” consistent with the way a person of ordinary skill in the art would understand that phrase, namely as “a composition containing nicotinamide riboside as the active agent.”
Steptoe than points out that the patent specification repeatedly refers to a "nicotinamide riboside composition" or a "nicotinamide treatment" to confirm that a professor of biochemistry would understand that the specification was describing "a pharmaceutical composition in which nicotinamide riboside is the active agent, rather than just an inactive excipient."
Indeed, Steptoe continues, the essence of a pharmaceutical is that it contains an active ingredient. Not only does a biochemistry professor know this, but it is also in the dictionary.
The phrase "active agent" is actually used in the portion of the specification dealing with carriers, noting that the thing the carrier is carrying is an "active agent."
Elsewhere, in the claimed compositions, the patent uses the phrase "subject compound" and "active compound," which obviously refer to nicotinamide riboside.
Must a Carrier Carry?
The PTAB in its decision instituting trial rejected both parties' proposed definitions of "carrier," and instead drew a definition from the patent itself:
a liquid or solid filler, diluent, excipient, or solvent encapsulating material, [that] is involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
That is a mouthful, but, Steptoe points out, the PTAB's definition of "carrier" requires that there be a thing carried, and that thing would be the active ingredient or subject compound. So the proposed definition of "pharmaceutical composition" is in harmony with the actual definition of "carrier."
But What About Tablets, Capsules, and Elixirs?
Steptoe pours more water on Elysium's proposed definition: The phrase from claim three listing tablet, capsule, elixir, et al, "does not define the composition, but rather identifies some of the specific forms the composition...can take when used for oral therapeutic administration."
Really, it says that in the patent:
For oral therapeutic administration, the compound can be combined with one or more carriers and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, food, and the like.
"The very next sentence in the specification," says Steptoe,
"confirms that such compositions must include the 'active compound' and that 'the amount of active compound in such compositions is such that an effective dosage level will be obtained...In other words, even if a composition takes the form of food, such food would not be necessarily considered a 'pharmaceutical composition' of the '086 patent unless the composition also included the active compound nicotinamide riboside."
"Contrary to this teaching," Steptoe continues, Elysium's "proposed interpretation would lead to the absurd result that any food would qualify as a 'pharmaceutical composition' under the '086 patent."
Why does Steptoe say that Elysium says that? Because
"[Elysium']s expert, Dr. Bauer, confirmed that under [Elysium's] interpretation 'any food would qualify' as a pharmaceutical composition of the '086 patent, without exception. This result is particularly nonsensical given that [Dr. Bauer] also understands that pharmaceutical compositions generally should 'be interpreted to always mean something that doesn't harm the molecule being administered.'" (citations omitted)
It sounds like Steptoe had their way with Dr. Baur in the deposition. They also got him to agree that the "active agent" in the patent would be NR, and that NR is the "active agent" in claim 1, and that NR was the "active agent" in the patent.
Steptoe then notes that ignoring all of the active agent language in the patent would be error because claims have to be considered in the context of the surrounding words.
Another Contradiction
Moreover, Elysium's approach would also result in the patent's claims being construed to cover milk, which cannot be right, because milk was explicitly disclosed as a prior art source of the active agent nicotinamide riboside. Steptoe then cites a Federal Circuit case from last September that reverses the PTAB for giving a disputed term an "unreasonably broad" interpretation "in the face of the otherwise different description in the specification."
Steptoe concludes:
Petitioner’s proposed interpretation of the claimed pharmaceutical compositions should be rejected because it does not account for the understanding that first and foremost, the pharmaceutical composition must contain the specified active agent, which in the ’086 patent is nicotinamide riboside...This understanding, which is reflected in Patent Owner’s proposed construction, is consistent with the interpretation of a person of ordinary skill in art in light of the entire disclosure of the ’086 patent.
If you have enjoyed the last few pages, I heartily urge you to read on past page 16 in the Response, where Steptoe reminds the PTAB why it already rejected Elysium's definition of "isolated" in Claim 2 as isolating the milk from the cow, and not nicotinamide riboside from the milk.
And you will also enjoy Steptoe's tying up the pharmaceutical composition argument:
[The 1928] article discussing the administration of a variety of foodstuffs to dogs and the ability of the foodstuffs, if any, to prevent blacktongue, does not disclose any pharmaceutical compositions containing nicotinamide riboside as the active agent...Goldberger et al. does not disclose nicotinamide riboside, let alone nicotinamide riboside as the active agent in a pharmaceutical composition.
And revisiting Dr. Baur's testimony:
Petitioner’s arguments regarding claim 1 are a result of reading out the claim’s requirement for the active agent (i.e., nicotinamide riboside) and boil down to the illogical conclusion that all food, without limitation or other characteristics, would qualify as a pharmaceutical composition. [Dr. Bauer] confirmed as much, and further testified that (1) all milk qualifies as a pharmaceutical composition, “unless it has actually spoiled”; and (2) chewing gum, “on its own,” qualifies as a pharmaceutical composition “based on it being recited in the dependent claim”. [Dr. Baur] further stated that a prior art reference disclosing a child drinking milk would be sufficient to anticipate claim 1 of the ’086 patent. These conclusions bear no relationship to, and contradict, the teachings of the ’086 patent. (citations omitted)
The logical flaw Steptoe identifies in Elysium's argument is that the patent teaches that a pharmaceutical composition can take the form of food, but does not teach, contrary to Elysium, that all food is a pharmaceutical composition.
In fact, says Steptoe, "a person of ordinary skill in the art would readily understand that the ’086 patent requires more than just food on its own and that nicotinamide riboside must be more than just an inactive excipient."
Was Therapeutic NR Disclosed in 1929?
Are we done yet? No! Steptoe still has left in its quiver its most stinging argument! Page 22:
Dr. Baur concedes that the 1929 article "does not even disclose whether the milk contained nicotinamide riboside," and Elysium relies on a separate paper to establish that NR is naturally present in milk. But that separate paper fails to establish whether any of the NR in milk is therapeutically active since the NR in milk is bound to another molecule. Indeed, the NR in milk might have been degraded by bacteria -- in other words, there might not even have been any NR present in the milk used in the experiments underlying the 1929 article.
Claim 5
We'll tarry just a moment on Claim 5, which adds the requirement that the composition increase NAD+ biosynthesis. Even Dr. Baur conceded that there is no evidence in the 1929 article that drinking milk increased NAD+, in part because milk contains additional NAD+ precursors, including nicotinamide and tryptophan. So not only is there no disclosure of an NAD+ increase in 1929, but even if an increase were hypothesized there would be no way to know what to attribute it to.
The rest is just the same.
Conclusion
Steptoe has presented a convincing defense of Claim 1 -- which by itself rescues all five claims, because the other four claims incorporate Claim 1 -- and has shown that Elysium's position is illogical, unsupported by the patent's language, and violates the governing standards for claim construction.
Even if you didn't buy all that, Steptoe has shown an even stronger defense for claim 5, eviscerating the factual evidence that Elysium had offered in support of its challenge.
And the PTAB's prior ruling essentially disposes of the challenge to claim 2.
There is one important implication that I want to call out. We have been slightly concerned about the construction of "isolated" in Claim 2 as requiring 25% solution, because it would seem to suggest that diluted NR formulas might not infringe that claim.
However, if the PTAB agrees that Claim 1 covers a composition in which NR is an active ingredient, then even compounds with lower percentages of NR would still likely be infringing, as long as NR was an active ingredient.