In the Hatch-Waxman patent infringement case Amgen, Inc. v. Sandoz Inc., Civ. Action No. 3:18-cv-11026, Judge Shipp of the District Court of New Jersey held in favor of Amgen in part and for Defendants in part.

Background

Amgen sued Dr. Reddy’s Laboratories, Sandoz, and Zydus Pharmaceuticals for infringement of five patents: U.S. Pat. Nos. 7,427,638 (“the ’638 patent”), 8,455,536 (“the ’536 patent”), 10,092,541(“the ’541 patent”), 7,893,101 (“the ’101 patent”), and 8,093,283 (“the ’283 patent”). The asserted patents relate to using stereomerically pure apremilast and crystal forms thereof to treat psoriasis. Amgen sells oral apremilast tablets under the name Otezla^®, the “Show More of You” tablets, as touted in the Otezla^®television commercials.

The ’638 Patent

The district court found that the ’638 patent was not shown to be invalid. Defendants had stipulated to infringement, so judgment was entered in favor of Amgen.  Score 1 for Amgen.

Asserted claims 3 and 6 respectively read:

[t]he pharmaceutical composition of claim 2 wherein said pharmaceutical composition is suitable for oral administration to a patient.

[t]he pharmaceutical composition of claim 5 wherein the amount of stereomerically pure [apremilast] is from 10 mg to 200 mg.

The primary reference relied upon by Defendants for their obviousness challenges was U.S. Patent No. 6,020,358, a Celgene patent with inventors common to the ’638 patent. The reference patent discloses seventeen examples, all of which are racemic mixtures, including a racemic mixture of 50% apremilast and 50% of its enantiomer. The reference patent states “[b]oth the racemates of these isomers and the individual isomers themselves … are within the scope of the present invention.” Furthermore, the prior patent asserted that:

The racemates can be used as such or can be separated into their individual isomers mechanically as by chromatography using a chiral absorbant. Alternatively, the individual isomers can be prepared in chiral form or separated chemically from a mixture by forming salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, and then freeing one or both of the resolved bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of >95%.

Id. at *23-24 (internal citation omitted). 

Defendants contended that it would have been obvious to resolve the racemate comprising apremilast. In assessing the obviousness of apremilast, Defendants contended that a lead compound analysis was not applicable. The district court agreed, noting the Federal Circuit’s direction with respect to analyzing obviousness of purified and racemic compounds:

Where a claimed composition is a purified form of a mixture that existed in the prior art and “if the prior art would provide a person of ordinary skill in the art with reason to believe [it had desirable properties], the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified.”

Amgen at * 21 (quoting UCB, Inc. v. Accord Healthcare, Inc., 890 F.3d 1313, 1323 (Fed. Cir. 2018).

[I]f it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, or if the prior art would provide a person of ordinary skill in the art with a reason to believe that this is so, the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified.

Amgen at *26 (quoting Aventis Pharma Deutsch/and GmbH v. Lupin, 499 F.3d 1293, 1301 (Fed. Cir. 2007)).

The district court found that the Defendants failed to meet their burden to show that the prior art would have provided a person of ordinary skill in the art (“POSITA”) with the motivation to resolve  the racemate into its enantiomers, or that a POSITA would have had reason to believe “that the desirable properties of [the racemate] derived in whole or in part from the apremilast isomer.” Id. at *27. The district court also found that Defendants did not show that a POSITA would have had a reasonable expectation of success of resolving the enantiomers. In particular, the court rejected the argument that there is always a motivation to separate a racemate simply because it’s a mixture. Id. at *28. Amgen’s expert stated that to do so without any information about the racemate would be an “unacceptable” waste of effort, time, and resources. Id. Moreover, resolving a racemic mixture is “a difficult process based on trial-and-error experimentation.” Id. at *29.

The district court distinguished the present case from Aventis, where, unlike here, “the prior art … provided the POSA with sufficient reason to investigate the claimed stereoisomer because the prior art taught that there were substantial differences in its potency compared to the other stereoisomer. Id at *32. The district court found the present case more like Forest Laboratories, Inc. v. lvax Pharmaceuticals, Inc., 438 F.Supp.2d 479, 492 (D. Del. 2006), aff’d 501 F.3d 1263, 1269 (Fed. Cir. 2007). The district court found that, as in Forest:

with limited publicly available data to a POSA in 1999 or 2002 on the biological effects of the [racemic] example compounds, the POSA would have had little reason or motivation to attempt to separate the compounds enantiomers - let alone a reason to try to separate or synthesize the enantiomers of [the racemate].  That is especially so given the unpredictable “trial and error” nature of resolving racemic compounds.

Id. at *33 (internal citation omitted).

Objective evidence of unexpected results further supported Amgen’s position on nonobviousness. The record established both that apremilast demonstrated unexpected improvements over the racemate and “over other PDE4 inhibitors in terms of efficacy and tolerability.” Id. at *35-36. Amgen established a sufficient nexus between “the unexpected potency and side-effect profile of apremilast” and the asserted claims. In particular, the evidence established “that apremilast’s unexpected potency over the [prior art] racemic mixture derives from its separation from the other enantiomer[.]” This was consistent with the stipulated claim construction: “[A] composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound, wherein that one stereoisomer is (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyIethyl]-4-acetylaminoiso-indoline-1,3-dione.” Id. The court also credited evidence of long-felt, unmet need (nexus presumed because Amgen showed that the objective evidence was tied to a specific product and that product was the invention disclosed and claimed), failure of others, industry skepticism (as shown by the concern expressed with apremilast having a structure related to thalidomide), and commercial success.

The court also rejected Defendants’ argument that the claimed enantiomer was anticipated by the racemate disclosed in the prior patent. Citing UCB, the district court held that “[t]he knowledge that enantiomers may be separated is not ‘anticipation’ of a specific enantiomer that has not been separated, identified, and characterized.” Id. at *47. The district court concluded that the prior patent was not enabled as to separation of the enantiomers. Id. at *48.

The defendants also alleged that the ’638 patent was invalid for obviousness-type double patenting over a commonly owned patent drawn to a crystal form of apremilast, the ’283 patent. But Amgen showed, and the district court agreed, that the only reason the ’638 patent expired after the ’283 patent was due to “two statutorily authorized time extensions [patent term adjustment and patent term extension] [that] were properly calculated and awarded[.]” Id. at *55, citing Novartis AG v. Ezra Ventures, LLC, 909 F.3d 1367, 1372-75 (Fed. Cir. 2018). “The ’283 Patent is not a proper ODP reference for the ’638 Patent because the difference in expiration dates between the ’638 and ’283 Patents arises solely from two statutorily authorized time extensions: a patent-term adjustment under 35 U.S.C. § 154(b) and another under 35 U.S.C. § 156.” Id. at *56. The court also asserted that, “[e]ven if the ’283 Patent were a proper ODP reference for the ’638 Patent the Court would exercise it equitable discretion not to apply the doctrine of ODP under the circumstances of this case because the difference in expiration date between the ’638 and ’283 Patents is not the result of prosecution gamesmanship or any improper conduct by Celgene.” Id. (citations omitted).

The ’536 Patent

The district court held that asserted claim 6 of the ’536 patent was not shown to be invalid. Defendants stipulated to infringement, and judgment was entered in favor of Amgen. Score 2 for Amgen.

Claim 6 reads:

[t]he method of claim 1, wherein the stereomerically pure compound comprises greater than about 97% by weight of (+) isomer based on the total weight percent of the compound.

The district court concluded that there was no anticipation by the same reference asserted against the ’638 patent. Id. at *57. The general nature of the disclosure of the prior art was not sufficient to anticipate the specific enantiomer of apremilast.

Additional references were added to the obviousness allegation, but the district court found that the references did “not make claim 6 of the ’536 patent obvious” at the time of the invention:

Once again, to invalidate the ’536 Patent for obviousness, Defendants must demonstrate that “a person having ordinary skill in the art would have had ‘reason to attempt to make the composition’” known as stereomerically pure apremilast to treat psoriasis and “a reasonable expectation of success in doing so.” … For the reasons discussed above regarding the ’638 Patent, the Court finds that Defendants have failed to demonstrate that with the limited public data available to a POSA in 2002 on the feasibility of treating psoriasis with any of the [prior art] compounds, the POSA would have had a reason or motivation to attempt to separate or synthesize the compounds’ enantiomers, let alone a reason to try and separate or synthesize the enantiomers of Example 12 to invent such a treatment.

Id. at *60. In addition, the court found that the objective evidence weighed in favor of nonobviousness.

The ’541 Patent

Defendants did meet their burden of showing that the ’541 patent was invalid.  Score 1 for the Defendants.

Asserted claim 2 reads:

 [a] method of treating a patient with stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, wherein the patient is suffering from psoriasis, the method consisting of: (a) administering to a patient stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione in an initial titration dosing schedule consisting of (i) 10 mg in the morning on the first day of administration; (ii) 10 mg in the morning and 10 mg after noon on the second day of administration; (iii) 10 mg in the morning and 20 mg after noon on the third day of administration; (iv) 20 mg in the morning and 20 mg after noon on the fourth day of administration; (v) 20 mg in the morning and 30 mg after noon on the fifth day of administration; and (b) on the sixth and every subsequent day, administering to the patient 30 mg in the morning and 30 mg after noon of stereomerically pure(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione. 

According to the Defendants, the prior art disclosed a fixed dosing titration schedule for apremilast up to 60 mg per day within 6 days. Id. at *62. Based on the evidence presented, the district court found that “a twice-daily, six-day, fixed apremilast dosing schedule, initiating treatment at 10 mg and increasing toward a 30 mg target dose in 10 mg increments is rendered obvious by the prior art.” Id. at *67. A POSITA would have been motivated to look to a 6-day titration schedule to increase patient compliance. Id. at *69. No objective evidence of nonobviousness was submitted.

The ’101 Patent

Amgen did not meet its burden of showing Zydus infringed the ’101 patent, so a judgment of non-infringement was entered for Zydus. DRL and Sandoz had stipulated to infringement of the ’101 patent and failed in their invalidity arguments, so a judgment of infringement was entered in favor of Amgen. Score ½ for Amgen and ½ for Defendant Zydus.

Asserted claim 1 reads: [a] form B crystal form of [apremilast]

which is enantiomerically pure, and which has an x-ray powder diffraction pattern comprising peaks at about 10.1, 13.5, 20.7, and 26.9 degrees 2θ.

Asserted claim 15 recites a solid pharmaceutical composition comprising the crystal form of any one of the claims 1 and 2 to 13.

Zydus’s proposed ANDA product and its active pharmaceutical ingredient (“API”) admittedly includes Form A apremilast. Form A is different from Form B apremilast in claims 1 and 15 of the ’101 patent. Id. at *72. The district court determined that Amgen did not conclusively show the presence of Form B in Zydus’ product. Id. at *76.

The ’283 Patent

The district court held that the ’283 patent was not shown to be invalid. Zydus had stipulated to infringement, so judgment was entered in favor of Amgen.^[1]  Score 3 for Amgen.

Asserted claim 2 of the ’283 patent recites “[t]he crystal form of claim 1, wherein the crystal form is Form A, which has an X-ray powder diffraction pattern comprising peaks at about 8.1, 14.4, 17.4, 23.6, and 25.1 degrees 2θ.”

Claim 1 recites “[a]n unsolvated crystal form of [apremilast]

which is enantiomerically pure, wherein the crystal form is Form A, which has an X-ray powder diffraction pattern comprising peaks at 8.1, 14.4, 17.4, 23.6 and 25.1 degrees 2θ, or Form F, which has an X-ray powder diffraction pattern comprising peaks at about 8.1, 15.6, 17.3, and 25.4 degrees 2θ.

Claim 27 of the ’283 patent is an independent claim that recites: “[a] solid pharmaceutical composition comprising the crystal form of claim 2.”

The district court concluded that Zydus failed to show that a POSITA would have had a reasonable expectation of success in obtaining Form A as of the priority date of March 27, 2008, noting that “crystallization and polymorphism are highly unpredictable” and at the time of the prior art, a POSITA would not have even known that Form A exists. Id. at *88-89.

Zydus’ inherent anticipation argument failed because there was no evidence that the prior art ever produced Form A, let alone “necessarily and inevitably” produced Form A. Id. at *90-91. In fact, the evidence showed the prior art process resulted in Form B. Id. at *91.  Score 4 for Amgen.

Take-Aways

Crystal forms are complicated and unpredictable, which can be determinative when considering obviousness and inherent anticipation. However, such arguments might have an undersirable effect on written description support of certain claims!

Different crystal forms may have different physicochemical properties that can be claimed. These elements can impact patentability/validity arguments as well as infringement arguments. For example, characterizing information such as IR, Raman, NMR, X-ray, DSC, density, cell parameters, melting point, color, and intensity, recited in a claim may be considered elements of the claim that will need to be proven to show infringement.

Infringement of the asserted claims of the ’101 patent drawn to Form B was not established in this case. One of the asserted claims recited an x-ray powder diffraction pattern comprising peaks at about 10.1, 13 .5, 20.7, and 26.9 degrees. The patent drafter and prosecutor should at least consider whether fewer peaks, clearly distinguishing over other known forms, could be recited.

In terms of patentability/validity, it may be difficult to establish obviousness of a particular crystal form of a salt over a salt not having that particular crystal form. And inherent anticipation requires any property to be “necessary and inevitable.” In terms of particular crystal salts, the patent applicants/owners may be able to establish that unpredictability is an argument for no inherent anticipation and nonobviousness over a salt not having that particular crystal form

For patent drafters, consider whether the solid state crystal form is in the composition after formulation. Think about the manner in which API is formulated into the compositions. What crystal form, if any, is administered during the method of treating? In other words, consider what may have happened to the API during formulation.

Consider characterizing crystal forms by various, suitable, and sufficient experimental parameters, with which the particular crystal forms can be characterized and distinguished over other forms known in the art. To that end, consider including the experimental conditions used to produce the new crystal forms and to obtain any experimental measurements (e.g., the wavelength of the X-ray source in the case of XRPD, the disc material in the case of IR, and the heating rate in the case of DSC) in the specification. Consider providing a discussion of potential technical advantages of the claimed crystal forms, if there are any. Crystal forms may require considerations involving balancing the ability to prove patentability/validity against the proving infringement in litigation. Think through the pros and cons of the following types of claims, for example:

• Claim(s) that simply refer to the unique crystal form(s).

• Claim(s) having some characterization data that uniquely identifies the crystal form(s).

• Claims drawn to process(es) of making the unique crystal form(s)

Consideration of Section 112(f) means plus function claims might be useful as well.  See, e.g., Ex parte Gleave, No. 2012-004973 (2014). For instance, in a claim to a combination of crystal compound/salt and carrier for treating cancer, the drafter and/or prosecutor might try a claim resembling the following:

A pharmaceutical formulation comprising:

1. means for treating cancer, and

2. a pharmaceutical carrier.

By using a linking table to a specific active ingredient crystal, the claim could, in the language of 112(f), be construed to cover the corresponding structure, material, or acts described in the specification (i.e., the specific crystal disclosed) and equivalents thereof. 112(f) equivalents would be literal equivalents, not equivalents under the doctrine of equivalents.

FOOTNOTE

^[1] Zydus was the only defendant involved with respect to the ’283 patent.

Stacy Lewis, a law clerk with Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, also contributed to this article.