How a Dosage Regimen Patent for RRMS Treatment May Satisfy the Written Description Requirement—A Lesson from Novartis Pharmaceuticals Corp. v. Accord Healthcare,Inc.

A. Patent-in-suit

The ’405 Patent is titled “S1P Receptor Modulators for Treating Relapsing-Remitting Multiple Sclerosis.” ²⁷ The ’405 Patent was a divisional application of current U.S. Patent No. 8,741,963 (’963 Patent). ²⁸ The ’405 Patent claims a method of using fingolimod, in free form or in a pharmaceutically acceptable salt form, to treat RRMS patients, ²⁹ while the ’963 Patent claims a method for using the same substance to treat neoangiogenesis-associated MS patients. ³⁰

S1P means “sphingosine 1-phosphate,” a natural lysophospholipid that is present at high nanomolar concentrations in serum. ³¹ The ’405 Patent describes S1P receptor modulators as sphingosine analogues, such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives. ³² The specification further identifies “FTY720, i.e. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form” as “Compound A” and points to its hydrochloride salt as an experimental prodrug used in an Experimental Autoimmune Encephalomyelitis (EAE) experiment and a clinical trial. ³³

EAE is often a mouse-based animal model of multiple sclerosis in clinical and pathological aspects. ³⁴ Other animals (such as rats, guinea pigs, rabbits, and nonhuman primates) may be used for EAE experiments. ³⁵ EAE requires external immunization to develop MS-like symptoms inside a tested animal, and it uses adjuvant-containing known antigens to activate the innate immune system via pattern recognition receptors. ³⁶ Here, the ’405 Patent discloses use of female Lewis rats that were injected with Freund's adjuvant containing guinea pig spinal cord tissue to trigger immunization. ³⁷ The Novartis I court referred to the disclosed EAE experiment as the “EAE model.” ³⁸

The Novartis I court referred to the clinical trial as the “Prophetic Trial.” ³⁹ The Novartis I court found that the disclosed trial was not an actually performed clinical trial but a prophetic trial which merely describes “how a drug would be administered and how a patient given that drug should be monitored in a clinical trial.” ⁴⁰

The ’405 Patent has six claims, where claims 1, 3, and 5 are independent claims and share the same body. ⁴¹ Claim 1 recites:

A method for reducing or preventing or alleviating relapses in Relapsing-Remitting multiple sclerosis in a subject in need thereof, comprising orally administering to said subject 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form, at a daily dosage of 0.5 mg, absent an immediately preceding loading dose regimen. ⁴²

Claim 3 recites a method of treating RRMS. ⁴³ Claim 5 recites a method of slowing progression of RRMS. ⁴⁴

The issue of the written description requirement related to the phrase “at a daily dosage of 0.5 mg, absent an immediately preceding loading dose regimen.” ⁴⁵ The Federal Circuit characterized the disputed phrase as two limitations: the 0.5 mg daily dose limitation (or daily dosage limitation) and the no-loading-dose negative limitation (or no-loading-dose limitation). ⁴⁶ The daily dosage limitation represents “at a daily dosage of 0.5 mg,” while the no-loading-dose limitation stands for “absent an immediately preceding loading dose regimen.” ⁴⁷

B. Legal standard

A specification has adequate written description of the claimed invention if it “reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date[.]” ⁴⁸ Courts will perform “an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art.” ⁴⁹ In addition, written description is a question of fact. ⁵⁰ When a district court is on bench trial to resolve a written description issue, the Federal Circuit will review the finding under the clear error standard. ⁵¹ That is, such a finding will not be overturned unless the Federal Circuit has “a definite and firm conviction that a mistake has been made.” ⁵²

It should be noted that the ’405 Patent claims a priority based on a U.K. Patent Application No. 0612721.1 filed on June 27, 2006. ⁵³ HEC's arguments focused on whether the U.K. application supported that the inventors possessed the claimed invention in 2006. ⁵⁴ However, the Federal Circuit found that the defendants relied merely on the ’405 Patent's specification. ⁵⁵ Because recognizing that the U.K. application covered the portion of the ’405 Patent's specification supporting the written description requirement, the Federal Circuit did not look into the U.K. application. ⁵⁶

C. Novartis I decision: daily dosage limitation

HEC argued that the specification of the ’405 Patent did not support 0.5 mg daily dose as being effective to treat RRMS, which was rejected by the Novartis I court. ⁵⁷ The argument targeted the data shown from the EAE model and the Prophetic Trial. ⁵⁸

First, HEC asserted that the lowest dose (0.3 mg/kg per week) used in the EAE model would not support the 0.5 mg/day dose in humans. ⁵⁹ However, the Novartis I court found that in the specification, the content related to the EAE model “provides further written description for the 0.5 mg/day limitation.” ⁶⁰ Specifically, the Novartis I court pointed out that the “EAE model describes a dosage of 0.3 mg/kg per week as effective to ‘fully block[ ] disease-associated angiogenesis and completely inhibit[ ] the relapse phases.’” ⁶¹

In addition, the Novartis I court found no error in the district court's crediting the plaintiff's expert opinions together concluding that the EAE model would lead to the choice of 0.5 mg daily dose in humans. ⁶² Though, HEC criticized these expert testimonies as “undisclosed mathematical sleights of hand,” ⁶³ the Novartis I court worried that taking HEC's view would violate its precedents by overlooking the perspective of the ordinary skilled in the art and relying merely on “literal description of every limitation.” ⁶⁴

Secondly, HEC contended that because the Prophetic Trial adopted three daily doses (0.5, 1.25, and 2.5 mg), it would not sufficiently support the 0.5 mg/day dose limitation. ⁶⁵ However, the Novartis I court held that the “disclosure of two other dosages does not detract from the written description of the claimed dose.” ⁶⁶ The Novartis I court also emphasized that no “disclosures of dosage ranges in other areas of the specification lead away from the claimed dose.” ⁶⁷

Thirdly, HEC alleged that no “blaze marks” appeared in the specification to direct the ordinary skilled in the art to the selection of 0.5 mg daily dose. ⁶⁸ But, the Novartis I court clarified that blaze marks are necessary in “cases where the specification describes a broad genus and the claims are directed to a single species or a narrow subgenus[.]” ⁶⁹ Contrarily, as the Novartis I court mentioned, blaze marks “are not necessary where the claimed species is expressly described in the specification, as the 0.5 mg daily dosage is here.” ⁷⁰ The Novartis I court reasoned that the specification “does not contain the laundry-list-type disclosures” that “require guidance to direct a skilled artisan to the claimed species[.]” ⁷¹

In addition, the Novartis I court held that “the literal description of the 0.5 mg/day dose in the Prophetic Trial” was not diminished by other disclosure of “larger ranges of potential doses for S1P receptor modulators, e.g., 0.1 to 100 mg/day doses[.]” ⁷² The Novartis I court pointed out that “smaller dosage ranges, such as 0.5–30 mg/day, are disclosed for fingolimod hydrochloride.” ⁷³ Therefore, the Novartis I court opined that “[e]ven if blaze marks were required in this case, the Prophetic Trial and 0.5–30 mg/day dosage range would provide a skilled artisan more than sufficient guidance to direct them to the claimed 0.5 mg/day dose.” ⁷⁴

Finally, the Novartis I court held that HEC's argument concerning efficacy of the claimed 0.5 mg/day dose was baseless. ⁷⁵ The Novartis I court noted that the disputed claims did not require efficacy and that the EAE model supported the efficacy of 0.5 mg/day dose. ⁷⁶ Therefore, the Novartis I court concluded that no clear error existed in the district court's holding because the holding was “supported by the specification and ample expert testimony interpreting that specification.” ⁷⁷

The Novartis II court did not review the Novartis I court's holding concerning the 0.5 mg daily dose limitation, ⁷⁸ so the dosage limitation still satisfies the written description requirement.

D. Novartis II decision: no-loading-dose limitation

The Novartis II court held that the no-loading-dose negative limitation did not meet the written description requirement, ⁷⁹ while the Novartis I court found the same limitation valid. ⁸⁰ Both the Novartis II and Novartis I courts agreed that nothing in the ’405 Patent's specification expressed the limitation “absent an immediately preceding loading dose regimen.” ⁸¹ However, the Novartis II and Novartis I courts adopted different approaches to the case law concerning a negative limitation to reach different conclusions. ⁸²

While the Novartis I court merely and expressly rejected a proposition that “silence alone cannot serve as a basis for a negative limitation,” ⁸³ the Novartis II court went further to lay out a framework for examining a negative limitation. ⁸⁴ First, the Novartis II court stated that “[f]or negative claim limitations, like the no-loading-dose limitation at issue here, there is adequate written description when, for example, the specification describes a reason to exclude the relevant [element]” by either “expressly listing the disadvantages of using [the] element” or “distinguish[ing] among the element and alternatives to it.” ⁸⁵

Secondly, while clarifying that “[s]ilence is generally not disclosure,” the Novartis II court acknowledged that “a negative limitation need not be recited in the specification in haec verba[.]” ⁸⁶ However, the Novartis II court emphasized that “there generally must be something in the specification that conveys to a skilled artisan that the inventor intended the exclusion, such as a discussion of disadvantages or alternatives.” ⁸⁷ Thirdly, the Novartis II court offered some evidentiary rules concerning a negative limitation with silent disclosure. ⁸⁸ While observing that “a written description's silence about a negative claim limitation is a useful and important clue and may often be dispositive,” the Novartis II court pointed out a possibility that “the written description requirement may be satisfied when a skilled artisan would understand the specification as inherently disclosing the negative limitation.” ⁸⁹ One example is that “the record established that in a particular field, the absence of mention of a limitation necessarily excluded that limitation[.]” ⁹⁰ On the other hand, “testimony from a skilled artisan as to possibilities or probabilities that the recited element would be excluded would not suffice[.]” ⁹¹ Ultimately, the Novartis II court concluded that “a patent owner could establish that a particular limitation would always be understood by skilled artisans as being necessarily excluded from a particular claimed method or apparatus if that limitation is not mentioned[.]” ⁹²

With this approach, the Novartis II court went on to examine the district court's crediting expert testimony surrounding a particular sentence in the specification: “Initially patients receive treatment for two to six months.” ⁹³ The Novartis II court considered the disputed sentence as “speak[ing] to the initial length of treatment, not the dosage with which treatment begins.” ⁹⁴

Unlike the district court, the Novartis II court found the disputed sentence unable to support the no-loading-dose limitation. ⁹⁵ The Novartis II court started with reviewing the plaintiff's expert testimonies. ⁹⁶ Considering whether these testimonies were “inconsistent with the plain text of the specification and therefore carrie[d] no weight,” the Novartis II court accepted one expert's testimony and objected to another expert's testimony. ⁹⁷ Consequently, the Novartis II court relied on that accepted expert's testimony and found that the specification disclosed “neither the presence nor absence of a loading dose.” ⁹⁸ The Novartis II court further acknowledged that the silence about loading doses did not “support a later-added claim limitation that precludes loading doses.” ⁹⁹

Next, the Novartis II court observed that the district court combined the disclosure of a daily dosage and the silence on no loading doses to find the disclosed exclusion of a loading dose. ¹⁰⁰ The Novartis II court detailed three errors the district court made regarding that combined finding. ¹⁰¹

The first error was the district court's misconception that “a patent is presumed ‘complete’” to “contain all of the necessary information about the [patent].” ¹⁰² However, the Novartis II court clarified that “[a] patent is not presumed complete such that things not mentioned are necessarily excluded” because its case law “presume[s] only that a patent has adequate written description, not that it is complete.” ¹⁰³

The second error was that “the disclosure of a daily dosage” was found to “amount to a disclosure that there can be no loading dose[.]” ¹⁰⁴ The Novartis II court looked to the prosecution history and found that the disputed claims were allowed “only after the applicants added the no-loading-dose limitation.” ¹⁰⁵ Thus, the Novartis II court opined that “[i]f reciting ‘daily dosage’ without mentioning a loading dose necessarily excluded a loading dose, there would have been no reason for the applicants to add the no-loading-dose limitation.” ¹⁰⁶

Finally, the third error was that some expert testimony focused on “where in the specification the patentee would have mentioned a loading dose if they intended a loading dose to be included.” ¹⁰⁷ The Novartis II court noted that “the question is whether the patentee precluded the use of a loading dose[,]” not “whether the patentee intended there to be a loading dose[.]” ¹⁰⁸ In addition, the Novartis II court found no evidence showing that the “silence regarding a loading dose” would mean “to necessarily exclude a loading dose.” ¹⁰⁹ Contrarily, the Novartis II court pointed out that “all the experts agreed that loading doses are sometimes given to MS patients.” ¹¹⁰

In conclusion, the Novartis II court held that “[t]he district court's finding that the no-loading-dose limitation meets the written description requirement was clearly erroneous.” ¹¹¹ Therefore, the rehearing was granted, and the disputed claims were found invalid. ¹¹²

A. Daily dosage limitation

A daily dosage limitation is a common limitation used in treatment claims. ¹¹³ For instance, in Merck & Co., Inc. v. Teva Pharmaceuticals USA, Inc., disputed claim 23 of U.S. Patent No. 5,994,329 (’329 Patent) recited: “[a] method for treating osteoporosis in human comprising orally administering about 70 mg of alendronate monosodium trihydrate, on an alendronic acid basis, as a unit dosage according to a continuous schedule having a dosing interval of once-weekly.” ¹¹⁴ Another example is in Acorda Therapeutics, Inc. v. Roxane Laboratories, Inc., where disputed claim 1 of U.S. Patent No. 8,354,437 (’437 Patent) read:

A method of increasing walking speed in a human multiple sclerosis patient in need thereof comprising orally administering to said patient a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a time period of at least two weeks, wherein said 10 milligrams of 4-aminopyridine twice daily are the only doses of 4-aminopyridine administered to said patient during said time period. ¹¹⁵

Unlike the ’405 Patent, the ’329 Patent and ’437 Patent were not challenged under the written description requirement. ¹¹⁶ The ’437 Patent includes EXAMPLE 5 illustrating a Phase 2, double-blind, placebo-controlled, parallel group, 20-week treatment study in 206 MS patients (some of which took a 10 mg dose) and showing efficacy data (e.g., Timed 25-Foot Walk). ¹¹⁷ On the other hand, the ’329 Patent discloses preclinical animal-based experimental data, and it also described several dosage regimens claimed to be used for treatment without showing efficacy data. ¹¹⁸ The ’329 Patent is as prophetic as the ’405 Patent. ¹¹⁹

The ’437 Patent is more likely to satisfy the written description requirement because of the disclosed efficacy data. ¹²⁰ However, the Federal Circuit in University of Rochester v. G.D. Searle & Co., Inc. has cautioned that “[w]e of course do not mean to suggest that the written description requirement can be satisfied only by providing a description of an actual reduction to practice.” ¹²¹ Under University of Rochester, “[c]onstructive reduction to practice is an established method of disclosure[.]” ¹²² Thus, a disclosure of prophetic trials may be enough to meet the written description requirement.

Novartis I may provide guidance for drafting a daily dosage limitation. First, a treatment claim should avoid an “effective”-like term as associated with the claimed dosage. ¹²³ Instead, a claim should recite specific purposes of the treatment, such as “reducing or preventing or alleviating RRMS” in the preamble. ¹²⁴

Secondly, a claimed dosage must be specified in the specification rather than mentioned in a range of doses. ¹²⁵ Otherwise, “blaze marks” must be placed in the specification to “direct[] an investigator of ordinary skill in the art to the claimed species from among a forest of disclosed options[.]” ¹²⁶

Lastly, in terms of RRMS, EAE information must be described in the specification. ¹²⁷ Dosages administered to tested animals need to be specified. Particularly, those dosages amounting to therapeutic effects must be identified. ¹²⁸ Additionally, it is better to include how a therapeutic dosage for tested animals may be used to estimate or predict a therapeutic dosage for humans. ¹²⁹ Otherwise, expert testimony in litigation may control whether a claimed dosage meets the written description requirement. ¹³⁰

B. No-loading-dose limitation

While the disputed no-loading-dose negative limitation was held invalid under the written description requirement, the Novartis II court contended that it did not “create a heightened standard for negative claim limitations.” ¹³¹ Rather, the Novartis II court clarified that “[w]hile silence will not generally suffice to support a negative claim limitation, there may be circumstances in which it can be established that a skilled artisan would understand a negative limitation to necessarily be present in a disclosure.” ¹³²

The Novartis II decision does not foreclose a dosage regimen claim with a “no loading dose” limitation. The question is whether the specification can show something “that conveys to a skilled artisan that the inventor intended the exclusion, such as a discussion of disadvantages or alternatives.” ¹³³ Therefore, a specification must disclose disadvantages or alternatives to what is excluded in a claim, such that the claimed negative limitation may satisfy the written description requirement.

Unfortunately, the applicant of the ’405 Patent would not have included information of no loading doses due to the nature of the invention. “Loading doses” were administered to healthy subjects for pharmacokinetic (PK) or pharmacodynamic (PD) studies of FTY720. ¹³⁴ In fact, the purpose of administering loading doses is to expedite steady-state blood levels. ¹³⁵ On the other hand, for efficacy studies on RRMS patients with FTY720, loading doses were not used. ¹³⁶ Thus, it is understandable for the ’405 Patent's applicant not to include “no loading doses” as part of the described dosage regimen.

After Novartis II, the practical question for patenting RRMS treatments through dosage regimen claims is what description can show disadvantages or alternatives to “loading doses.” FTY720 has a very long half-life in humans from six to nine days. ¹³⁷ As Klemens Budde et al. have commented, “[t]ypical of long half-life drugs, the use of a loading dose of FTY[720] would be useful if the clinical setting requires rapid attainment of therapeutic drug levels[.]” ¹³⁸ Therefore, a specification may describe embodiments indicating that if rapid attainment of therapeutic drug levels is required, loading doses may be administered before a regular daily dosage regimen.

C. Prosecution concerns

The Novartis II court worried that if silence means disclosure, “then every later-added negative limitation would be supported so long as the patent makes no mention of it.” ¹³⁹ Actually, the disputed negative limitation in the ’405 Patent was added before the examiner started to review the application and issued a non-final rejection. ¹⁴⁰

When the ’405 Patent was filed on April 21, 2014, original claim 1 recited:

A method for reducing or preventing or alleviating relapses in Relapsing-Remitting multiple sclerosis in a subject in need thereof, comprising orally administering to said subject a daily dosage of 0.5 mg of a S1P receptor modulator, wherein said S1P receptor modulator is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, or a pharmaceutically acceptable salt thereof. ¹⁴¹

The negative limitation “absent an immediately preceding loading dose regimen” was added via a filing of preliminary amendment. ¹⁴² While the applicant did not explain any reason for this voluntary amendment, ¹⁴³ the idea of adding the negative limitation may come from the prosecution history of the ’963 Patent.

During the prosecution of the ’963 Patent, the applicant added a limitation “absent an immediately preceding loading dose regimen” into pending claims when it filed a request for continued examination (RCE) on February 18, 2013. ¹⁴⁴ This then-newly added limitation successfully helped overcoming an obviousness rejection under 35 U.S.C. § 103 in view of a PCT (Patent Cooperation Treaty) application (International Publication No. 2006/058316 A1, hereinafter, :Kovarik application”). ¹⁴⁵ The Kovarik application was filed by the same applicant. ¹⁴⁶

The Kovarik application was also a basis of an obviousness rejection during the prosecution of the ’405 Patent. ¹⁴⁷ But, relying on the disputed negative limitation, the applicant successfully overcame the rejection. ¹⁴⁸ Although back then the applicant asserted that no new matter was added and the examiner did not object to that assertion, ¹⁴⁹ Novartis II indicates that the disputed negative limitation as a new matter should have been a basis for a rejection under 35 U.S.C. § 112(a). ¹⁵⁰

The written description requirement prevents an applicant from adding “new matter” into pending claims. ¹⁵¹ To add the disputed negative limitation without raising a new matter issue, the applicant would have filed a continuation-in-part (CIP) application. A CIP application contains “a portion or all of the disclosure of an earlier application together with added matter not present in that earlier application.” ¹⁵² Thus, the applicant would include the negative limitation in the claims and relevant description in the CIP specification.

Finally, it should be noted that “[s]ubject matter that arises for the first time in the CIP application does not receive the benefit of the filing date of the parent application.” ¹⁵³ However, that is not a concern here because the Kovarik application had already existed before the 2006 priority. Hence, if the ’405 Patent had been granted from a CIP application, the outcome of Novartis II would have been different.