A Crisis on Patenting of “Ready-to-Use” Oral Liquid Formulations: Azurity Pharms.,Inc. v. Alkem Lab’ys Ltd

A. Patented technology

Enalapril had been used to treat high blood pressure (hypertension) long before the claimed invention. ¹⁹ Enalapril was initially approved as tablets for oral administration, but the tablet form was inconvenient for children or elderly patients to consume. ²⁰ To provide a better form of enalapril, Silvergate invented Epaned^® Kit, consisting of an enalapril powder and a liquid for a pharmacist to make an enalapril liquid by mixing the powder with the liquid. ²¹ The way to administer Epaned^® Kit is known as reconstitution. ²²

Silvergate continued to improve oral administration of enalapril and finally created a “ready-to-use” (or “RTU”) enalapril liquid. ²³ The claimed invention was developed for patients who cannot swallow pills. ²⁴ The claimed invention also reduced the risk of error or contamination during the dispensing of Epaned^® Kit’s powders. ²⁵

As the district court Azurity Pharms., Inc. acknowledged, to design a liquid dosage form, the major concern is the chemical stability of a drug in a solution. ²⁶ Enalapril can undergo hydrolysis when it is mixed with water. ²⁷ To prevent enalapril from degrading, the pH of an enalapril solution is the key factor. ²⁸ An oral liquid formulation of enalapril must contain a buffer to control the pH of the enalapril solution. ²⁹

When the claimed invention was under development, a certain level of chemical stability was required to make a ready-to-use liquid of enalapril “stable for at least 12 months to account for distribution time.” ³⁰ Additionally, under the FDA’s “Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products” (November 2003) (hereinafter, “Stability Testing Guidance”), for drug substances intended to be stored in a refrigerator, an applicant for drug approval must submit 12 months of stability data for a new drug substance or drug product stored at refrigerated temperature (5 ± 3°C) or 6 months of stability data at an elevated temperature (25 ± 2°C). ³¹ The FDA then used an index “significant change for a drug product” to assess whether any further stability studies are needed, and one definition of “significant change” was“[a] 5 percent change in assay from [the drug’s] initial value.” ³²

The claimed invention provided a liquid formulation that “maintains about 95% w/w or greater of the initial enalapril amount at the end of a storage period of at least 12 months at about 5 ± 3°C.” ³³ The specification of the 621 Patent disclosed that the ingredients of such a liquid formulation included enalapril or enalapril maleate, a sweetener, a buffer, a preservative, and water. ³⁴ While examples of each ingredient were also disclosed in the specification, ³⁵ for purposes of the obviousness issue, the scope of the claimed invention was defined by the disputed claims.

B. Asserted claims

Nine asserted claims were involved: claims 16, 18, 22, 23, and 28 of the 482 Patent and claims 4, 7, 17, and 18 of the 621 Patent. ³⁶ For infringement analysis, the district court chose claim 4 of the 621 Patent as illustrative. ³⁷ But, all disputed claims of the 621 Patent were dependent on claim 1 which recites:

A stable oral liquid formulation, consisting essentially of:

i)

about 0.6 to about 1.2 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;

ii)

a buffer to maintain the pH of about 4.5 or below, wherein the buffer concentration is about 5 mM to about 20 mM;

iii)

a preservative, wherein the preservative is a paraben or a mixture of parabens; and

iv)

water;

wherein the formulation optionally comprises a sweetener, a flavoring agent, or both;

wherein the formulation is stable at about 5 ± 3°C. for at least 12 months; andwherein the stable oral liquid formulation has about 95% w/w or greater of the initial enalapril amount and about 5% w/w or less total impurity or related substances at the end of the given storage period. ³⁸

Claim 4 defined “buffer” as comprising “a citrate, a phosphate, a citrate/phosphate, an acetate, a glycinate, an amino acid, or a tartrate buffer.” ³⁹ Claim 7 provided that “the buffer maintains the pH at about 3.3.” ⁴⁰ In claims 17 and 18, the lengths of the stability of the claimed formulation at 5 ± 3°C were alleged to be at least 18 months and 24 months, respectively. ⁴¹

Claims 16, 18, 22, 23, and 28 of the 482 Patent were all dependent on claim 14, while claim 16 further depended on claim 15, which was also a dependent claim of claim 14. ⁴² Claim 14 recited:

An oral liquid formulation, comprising: i)

about 0.6 to about 1.2 mg/mL enalapril or a pharmaceutically acceptable salt or solvate thereof;

ii)

a buffer comprising a mixture of citric acid and sodium citrate, wherein the buffer is present at a concentration between about 5 mM and about 20 mM in the oral liquid formulation;

iii)

about 1 mg/mL of a preservative, wherein the preservative is a paraben or a mixture of parabens; and

iv)

water;

wherein the formulation maintains about 95% w/w or greater of the initial enalapril amount at the end of a storage period of at least 12 months at about 5 ± 3°C. ⁴³

Following claim 15, which further added a sweetener to the formulation of claim 14, claim 16 specified the sweetener as sucralose. ⁴⁴ Claim 22 set the pH of the claimed formulation to about 3.3. ⁴⁵ Claim 23 required the claimed formulation to maintain “about 95% w/w or greater of the initial enalapril amount at the end of a storage period of at least 18 months at about 5 ± 3°C.” ⁴⁶ Claim 28 narrowed the concentration range of the buffer from about 10 mM to about 20 mM. ⁴⁷ Lastly, claims 16, 22, 23, and 28 of the 482 Patent were slightly different from the disputed claims of the 621 Patent, but claim 18 was special: claim 18 recited a negative limitation excluding mannitol from the claimed formulation. ⁴⁸

The district court noted that both parties “did not dispute that the individual claimed ingredients—enalapril, water, citrate buffers, paraben preservatives, sweeteners, and flavors—were known before its invention.” ⁴⁹ Thus, the district court framed the dispute as before the priority date of the disputed patents, March 18, 2016, “whether it would have been obvious how to combine those ingredients into a liquid that would be stable for as long as the claims require—12 to 24 months.” ⁵⁰

III. ANALYSIS OF THE DISTRICT COURT’S DECISION

A. Legal standard for determining obviousness

The obviousness inquiry is a mixed question of law and fact. ⁵¹ While the “ultimate judgment of obviousness is a legal determination[,]” ⁵² the Supreme Court in Graham v. John Deere Co. has required a court to four factual findings: “(1) the scope and content of the prior art; (2) the differences between the claims and the prior art; (3) the level of ordinary skill in the art; and (4) objective considerations of nonobviousness.” ⁵³ The objective considerations of non-obviousness are known as secondary considerations, such as “commercial success, long felt but unsolved needs, failure of others, etc.” ⁵⁴

Following KSR Int’l Co. v. Teleflex Inc., 550U.S. 398 (2007), the district court in stated that “[t]he obviousness inquiry is ‘flexible’ and ‘functional.’” ⁵⁵ So, the district court opined that it “can take account of the inferences and creative steps that a [person of ordinary skill in the art (POSA)] would employ.” ⁵⁶ However, the district court cautioned that “analysis based on hindsight is forbidden.” ⁵⁷ The district court emphasized that “[a]n invention is not obvious merely because it is ‘sufficiently simple to appear obvious to judges after the discovery is finally made.’” ⁵⁸

Since all individual claimed ingredients were admitted prior art, the district court noted that “[a] patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” ⁵⁹ Contrarily, the district court embraced an approach that a defendant must show “by clear and convincing evidence that a skilled artisan would have had reason to combine the teaching of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success from doing so.” ⁶⁰ In addition, the district court pointed out that “motivation must be viewed from the perspective of the prior art.” ⁶¹

B. Legal issues and undisputed facts

The district court focused its obviousness analysis on two questions: “whether a POSA would have expected, before [the claimed] invention, that enalapril in water could be as stable as the asserted claims require” and “whether it would have been obvious to use the particular combination of ingredients recited in the claims.” ⁶²

To answer these questions, the district court identified what had been undisputedly known before the claimed invention: (1) all claimed ingredients; (2) manufacture of a liquid dosage form of enalapril by mixing enalapril with water; (3) enalapril liquids including the same buffers, preservatives, sweeteners, and flavors as recited in the asserted claims, such as, for example, Azurity’s Epaned Kit containing enalapril in the claimed concentration, a citrate buffer, sweeteners, and paraben preservatives. ⁶³ On the other hand, the district court recognized an undisputed fact that “the prior art did not disclose any liquid formulation of enalapril known to be stable for a year or more at refrigerated temperature.” ⁶⁴

Ultimately, the district court found that the defendant “has proven by clear and convincing evidence that the asserted claims would have been obvious to a POSA as of March 18, 2016.” ⁶⁵

C. Reasoning

In determining that the defendant “has proven by clear and convincing evidence that the asserted claims would have been obvious to a POSA as of March 18, 2016[,]” the district court took a six-step approach. ⁶⁶

First, the district court discussed “whether a POSA would have reasonably expected that enalapril in water could be as stable as the claims require—that is, at least 95% stable at refrigerated temperature after 12, 18, or 24 months.” ⁶⁷ The district court opined that “the prior art did confer a reasonable expectation that mixing enalapril with water and adjusting the pH to about 3 could result in a drug that was highly stable for a long period of time.” ⁶⁸ Thus, the district court held that the defendant “has proven by clear and convincing evidence that the prior art would have led a POSA to expect success in making a long-term stable enalapril liquid.” ⁶⁹

Second, the district court examined whether “a POSA would be motivated to make an enalapril liquid as stable as the claims require.” ⁷⁰ The district court identified two motivations: “the requirements of distribution time and the FDA’s requirements regarding shelf-life.” ⁷¹ In finding “a motivation to measure stability with a 95% threshold[,]” the district court specifically pointed to the FDA’s Stability Testing Guidance “defin[ing] a ‘significant change’ as, among other things, ‘[a] 5 percent change in assay from [the drug’s] initial value.’” ⁷² In addition, the district court accepted a view that “a formulator making a ready-to-use liquid would want it to be as stable as the product already on the market—[Azurity’s Epaned Kit]—which was 24 months.” ⁷³ Therefore, the district court held that “a POSA would have been motivated to make an enalapril formulation as stable as the claims require.” ⁷⁴

Third, the district court decided whether “it would have been obvious to a POSA ‘how’ to make an enalapril liquid as stable as the claims require.” ⁷⁵ The district court’s analysis relied primarily on a finding that “[t]he prior-art literature strongly conveys that pH drives the stability of enalapril in water and does not suggest that any other variable should be adjusted.” ⁷⁶ This finding led the district court to opine that “[a] formulator would have been immediately guided to focus on adjusting a single variable, the pH.” ⁷⁷ The district court further adopted a view that the “optimization [to achieve the claimed stability] “would have been ‘easy’ through ‘routine experimentation’ [because the] variable was known, the target range (about 3) was known, and the method of adjusting and testing was known.” ⁷⁸

Besides, the district court took into consideration that “a formulator would not have needed to wait years for the experimental formulations to degrade” because the formulator would have used accelerated stability studies as one source in the literature teaches. ⁷⁹ As a result, the district court held that the defendant “has proven by clear and convincing evidence that a POSA would have been able to make a liquid formulation that was long-term stable at refrigerated temperature through routine application of the known method of adjusting the formulation and testing for stability.” ⁸⁰

Fourth, because noticing that “[s]ome of the asserted claims require that the formulation have a pH within a certain range” and that “[t]he narrowest of these limitations requires that the pH be ‘about 3.3[,]’” the district court asked whether “the asserted claims remain obvious when these [pH] limitations are included.” ⁸¹ The district court acknowledged that “[a] POSA seeking to develop a liquid formulation of enalapril would review published literature and conclude that the pH at which enalapril was most stable in water was about 3.” ⁸² But, the district court found that “a POSA would have expected success in optimizing stability through pH adjustment and would have been able to achieve the claimed stability through ‘ordinary skill and common sense’ rather than ‘innovation.’” ⁸³ Hence, the district court concluded that the defendant “has proven by clear and convincing evidence that the pH limitations of the asserted claims would have been obvious in combination with the other limitations.” ⁸⁴

Fifth, the district court examined whether “the particular formulation Azurity claimed would have been obvious, including the particular combination of all claimed ingredients.” ⁸⁵ The district court considered “the [claimed] invention as a whole” to evaluate “whether a POSA would have been motivated to combine ingredients known in the prior art.” ⁸⁶ The district court found that the traditional process of formulation provided “a motivation to combine elements needed to meet the target properties of the drug” and “a motivation to combine these ingredients with the stability and pH limitations.” ⁸⁷ The district court reasoned that the prior art taught: (1) “enalapril could be mixed with water”; (2) “those liquids should use pH at which enalapril is stable”; (3) “a buffer could be used to maintain the pH”; (4) “enalapril liquids should include sweeteners and preservatives necessary for liquids that are stored in a bottle and orally administered to children”; (5) “the particular choices of buffers, sweeteners, and preserves claimed were individually known and—more importantly—known to be usable with enalapril.” ⁸⁸

The district court also addressed the obviousness issues concerning specific choices of claimed ingredients: buffers, preservatives, and sweeteners. ⁸⁹ The district court started with the choice and concentration of the claimed buffers. ⁹⁰ The district court found that “[t]he need to make the drug stable would have provided a motivation to combine such a buffer with the other claim limitations.” ⁹¹ The holding was based on one prior publication showing that “a formulator would have selected a buffer made from sodium citrate and citric acid” which “can be used at a pH near 3” and that “determining an appropriate buffer concentration for the target pH would have been routine.” ⁹² Regarding preservatives and sweeteners, the district court relied on Azurity’s patent and the labeling of Epaned Kit to opine that “Azurity’s choice of preservative (parabens) and sweetener (sucralose) were known and known to work with enalapril.” ⁹³ Thus, the district court concluded that it would have been obvious to choose the claimed preservative and sweetener to combine with the other claim limitations. ⁹⁴

The district court further discussed negative limitations requiring some claims-in-dispute not to contain mannitol or silicon dioxide. ⁹⁵ While recognizing that Azurity’s patent taught that mannitol and silicon dioxide can be stabilizing agents in enalapril liquids, the district court adopted an approach that “a formulator would start with a target product profile and add those ingredients required to meet it.” ⁹⁶ By crediting one expert testimony that “a formulator working in this way would simply not introduce mannitol because it is rarely used in liquids[,]” the district court held that the absence of mannitol would have been obvious. ⁹⁷ The district court applied the same reasoning to silicon dioxide. ⁹⁸

Finally, the district court considered three factors of secondary considerations of nonobviousness proposed by Azurity: unexpected results, failure of others, and long-felt but unresolved need. ⁹⁹ Regarding unexpected results, while acknowledging that “whether it would have been unexpected as of March 2016 that an enalapril formulation using the claimed ingredients would have been stable[,]” the district court stated that “published studies suggested it was likely enalapril could be stable long-term.” ¹⁰⁰ Regarding the failure of others, the district court observed that none of those prior art references cited by the patentee aimed at achieving long-term stability of enalapril liquids. ¹⁰¹ As for long-felt but unresolved need, the district court found that Azurity did not prove that by the filing date, there was a need to replace Epaned Kit by a ready-to-use enalapril liquid. ¹⁰²

As a result, the district court concluded that because “secondary considerations of nonobviousness are only minimally probative,” the defendant “has proven by clear and convincing evidence that the asserted claims would have been obvious to a POSA as of the filing date.” ¹⁰³

IV. IMPLICATIONS

A. Future patenting of “ready-to-use” oral liquid formulations

The obviousness inquiry under Azurity Pharms., Inc. may block the patenting of “ready-to-use” oral liquid formulations that consist of known excipients. The district court’s approach may render four types of limitations unable to be non-obvious features.

1. Stability limitations

The district court recognized that before March 18, 2016, “it was known in the art that stability is a critical part of the development of an oral liquid.” ¹⁰⁴ This recognition indicates that in terms of an oral liquid formulation claim, it may be obvious to combine ingredient limitations and stability limitations.

The disputed claims in Azurity Pharms., Inc. contain two types of stability limitation. The first type recites a storage period with a refrigerated temperature, while the second type recites the degrading of an active ingredient during a certain period. These stability limitations merely reflect the stability data required by the FDA. The FDA’s stability requirements lead to the district court’s finding of motivation to make an enalapril liquid long-term stable. Thus, this finding implies that “FDA-required stability” limitations would have been obvious in an oral liquid formulation claim.

2. pH limitations

The district court noted both that “[t]he chemical stability of many drugs in solution may be improved by maintaining the pH of the solution in a particular range” and that “[b]uffers are used to maintain pH[.]” ¹⁰⁵ This holding indicates that a buffer limitation with a range of pH values would have been obviously included in an oral liquid formulation claim.

However, the question is whether a specific pH or pH range would have been obvious. Two significant notions in Azurity Pharms., Inc. are relevant. The first notion is “[o]ptimizing a known variable within a known range is a more straightforward task than the open-ended problem of finding some combination of ingredients that achieves stability.” ¹⁰⁶ The second notion is that “[d]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” ¹⁰⁷ If courts follow Azurity Pharms., Inc., the answer is more likely to be yes.

3. Excipient limitations

The district court acknowledged that “the process of formulation provides a motivation to combine elements needed to meet the target properties of the drug, such as combining a preservative (needed for a drug stored in a multi-use container) with a sweetener (needed for a drug administered orally to children).” ¹⁰⁸ This opinion indicates that limitations reciting common excipients would have been obviously included in an oral liquid formulation claim.

However, the question is whether specific excipients would have been obviously selected for an oral liquid formulation. Azurity Pharms., Inc. suggests that any excipients listed in prior publications related to oral liquid formulations may be chosen without accompanying stability data to verify the likelihood of success.

4. Concentration limitations

The district court accepted a notion that “determining an appropriate buffer concentration for the target pH would have been routine.” ¹⁰⁹ This opinion suggests that a buffer limitation with a concentration value or range would have been obviously included in an oral liquid formulation claim because adjusting the concentration of a chosen buffer to meet the target pH is routine. It is especially true when citric acid and sodium are used because as the district court has found, the literature discloses “example concentrations of citric acid and sodium citrate that can be used to make a buffer suitable over a pH range from 2.5 to 6.5[.]” ¹¹⁰