Bortezomib - USA

On Jul 17, 2017 Federal circuit reversed the district court’s finding and upholds the validity of patent on Bortezomib.

Millennium Pharmaceuticals, Inc. is the exclusive licensee of U.S. Patent No. 6,713,446 (“the ’446 Patent”), issued March 30, 2004 and assigned to the United States. Millennium developed the patented product for treatment of oncology disease, particularly multiple myeloma and mantle cell lymphoma. The product has the brand name Velcade®. ANDA filers (collectively “Sandoz”) filed abbreviated new drug applications (“ANDAs”), admitting infringement and seeking to invalidate various claims of the ’446 Patent. Based on the litigation that ensued, the district court held that claims 20, 31, 49, and 53 of the ’446 Patent were invalid, leading to this appeal.

The ’446 Patent describes the chemical compound Dmannitol N-(2-pyrazine)carbonyl-L-phenylalanine-Lleucine boronate. The compound is described as a boronate ester of bortezomib (a boronic acid) and D-mannitol (a hydroxy compound). The lyophilized compound “D-mannitol N-(2- pyrazine)carbonyl-L-phenylalanine-L-leucine boronate” was claimed in Claim 20.

The district court held that the claims were obvious because they were the inherent result of an allegedly obvious process, viz., lyophilizing bortezomib in the presence of the bulking agent mannitol. Millennium argued that a person of ordinary skill would avoid lyophilization in developing a formulation involving bortezomib because “bortezomib was known to be unstable even in the dry state as a freestanding solid compound.” The court was not persuaded by this argument and instead relied on the testimony of Sandoz’s witness, Dr. Repta, to find that, as of the ’446 Patent’s priority date, lyophilization “was well-known in the field of formulation” and that it was considered an obvious alternative “when a liquid formulation provided limited success.” The district court received testimony from the inventor and others that the formation of this new compound was not expected or intended when they conducted the lyophilization. There was no contrary evidence. Nonetheless, the district court held the claims invalid on the ground of obviousness, agreeing with Sandoz that “Millennium conceded as a matter of law that the ester is the ‘natural result’ of freeze-drying bortezomib with mannitol.” The court reasoned that the “natural result” of a chemical procedure is inherent in the procedure, and thus the product thereof “would have been obvious to a person of ordinary skill,” in the words of § 103. On the evidence of objective indicia of obviousness, the district court found that Millennium did not establish unexpected results because it did not compare the claimed invention to a glycerol ester of bortezomib. The court also rejected long-felt need as objective evidence of non-obviousness, stating that “the lyophilized mannitol ester of bortezomib did not solve any problem having persisted over a long period of time without resolution by the prior art.”

Federal circuit said that, recognizing our obligation to give deference to a district court’s greater familiarity with the record and authority to reach factual conclusions therefrom, we conclude that the district court erred in its evaluation of obviousness. In the case at bar, the question is whether a person of ordinary skill, seeking to remedy the known instability and insolubility and to produce an efficacious formulation of bortezomib, would obviously produce the D-mannitol ester of bortezomib, a previously unknown compound.  The prior art contains no teaching or suggestion of this new compound, or that it would form during lyophilization. Sandoz identifies no reference or combination of references that shows or suggests a reason to make the claimed compound. No reference teaches or suggests that such a new compound would have the long-sought properties of stability and solubility, and sufficiently dissociate to release bortezomib at an effective rate in the bloodstream, all critical to effective use for treating multiple myeloma.

The D-mannitol ester of bortezomib is a new compound with distinct chemical properties. We consider whether the prior art “would have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success.” Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1292 (Fed. Cir. 2012); see also Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 752 F.3d 967, 973 (Fed. Cir. 2014). The parties agree that bortezomib is the proper lead compound for this analysis. It is not disputed that the Velcade® compound provided unexpected properties, solving the problems that accompanied bortezomib. The district court clearly erred in its obviousness analysis. There is no teaching or suggestion in the references to produce the claimed mannitol ester. No reference shows or suggests ester formation at freeze-drying conditions, or that any such ester might solve the problems of instability and insolubility of the free acid while dissociating rapidly in the bloodstream. No reference provides a reason to make the mannitol ester of bortezomib.

Sandoz argues that lyophilization was generally known in formulating pharmaceutical products. It states that bulking agents were known for use in lyophilization, and that mannitol was a known bulking agent. All true. However, the prior art does not teach or suggest that lyophilization of bortezomib in the presence of mannitol would produce a chemical reaction and form a new chemical compound, or provide a reason to make this specific new chemical compound, or that this new compound would solve the previously intractable problems of bortezomib formulation. Although mannitol was a known bulking agent, and lyophilization was a known method of drug formulation, nothing on the record teaches or suggests that a person of ordinary skill should have used mannitol as part of a synthetic reaction to make an ester through lyophilization. Sandoz failed to show that it was obvious to use mannitol to make an ester during lyophilization, or that the ester would solve the problems experienced with bortezomib.

The district court also clearly erred in its determination that lyophilizing bortezomib with mannitol to form an ester was a “suitable option from which the prior art did not teach away.” Millennium offered persuasive evidence that the chemical modification of bortezomib would have been unattractive to a person of ordinary skill for fear of disturbing the chemical properties whereby bortezomib functions effectively as an anti-cancer agent; in particular, a person of ordinary skill would have noted that the ester blocks a portion of the bortezomib molecule. We agree with Millennium that a person of ordinary skill would have avoided creating an ester with mannitol because several different esters, each with different chemical and possibly biological properties, could have formed.

The district court also clearly erred in its consideration of inherency. “A party must . . . meet a high standard in order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis.” The district court stated that Millennium “conceded as a matter of law that the ester is the ‘natural result’ of freeze-drying bortezomib with mannitol.” Sandoz argues that although lyophilization in the presence of mannitol produced an unexpected result, the result was “inevitable” and thus “inherent,” and thus not “inventive.” No expert testified that they foresaw, or expected, or would have intended, the reaction between bortezomib and mannitol, or that the resulting ester would have the long-sought properties and advantages.

We conclude finally that the district court clearly erred in its examination of the objective indicia of unexpected results and long-felt need. We conclude that the district court should have treated bortezomib as the closest prior art compound, and acknowledged the unrebutted evidence that the D-mannitol ester of bortezomib exhibited unexpected results compared with bortezomib, including unexpectedly superior stability, solubility, and dissolution. The district court clearly erred in attributing Velcade®’s commercial success to bortezomib alone, as bortezomib is not a viable commercial product and had been denied FDA approval because of its instability. The D-mannitol ester was responsible for Velcade®’s successful results, for the D-mannitol ester is necessary to provide the required solubility and stability.

CONCLUSION: We conclude that the Sandoz group of defendants did not establish the obviousness of the asserted claims of the ’446 Patent by clear and convincing evidence. The district court’s judgment of invalidity is reversed, and judgment is entered in favor of Millennium as to the Sandoz defendants.