Two New Issued Qsymia Patents: Where Does Vivus Stand Now?
Vivus’ Qsymia patent portfolio has been highly scrutinized since the drug was first approved in July 2012. The portfolio consists of two patent families: the first family, which names Dr. Thomas Najarian as the sole inventor, contains issued patents that are scheduled to expire in 2020; and the second family contains two newly issued U.S. patents (US Patent Nos. 8,580,298 and 8,580,299) that are not scheduled to expire until 2028 plus nearly a year of patent term adjustment. Being that the new patents were filed almost ten years after the original Qsymia patents, Vivus may face significant challenges enforcing valid claims from its new patents in light of its own earlier patents and a decade of new prior art. These challenges and Vivus’ potential strategies for mitigating these risks are the subject of the present report.
What is the “new” subject matter claimed in the ‘298 and ‘299 patents?
The newly issued patents stem from a patent application (12/135,953) filed in June 2008 to inventors Thomas Najarian, Peter Tam and Leland Wilson – none of which are still employed by the company. The ‘953 application was abandoned in favor of continuation-in-part applications (US Patent Application Nos. 12/481,540 and 12/481,548), which issued as US Patent Nos. 8,580,298 and 8,580,299, respectively, on November 12, 2013.
These patents do not claim priority to the earlier filed Najarian applications, so they are susceptible to prior art that published before their June 2008 filing date, including the original Najarian patents. In simple terms, in order to be found patentable, the claims in the new application need to be patentably distinct from the earlier Najarian patents and any other prior art that predates June 2008. As the prosecution history from the new patents shows, this is a difficult strategy to execute without undermining the validity and enforceability of the earlier Najarian patents. But it seems this was a risk the company was willing to take.
Throughout the prosecution of the new patents, Vivus changed the content and scope of the pending claims a number of times – beginning with claims directed to compositions covering the specific features of controlled release topiramate (the ‘953 application), methods for effects weight loss using very low dose phentermine (2-8 mg) in combination with topiramate (the ‘298 patent), and methods for effecting weight loss by administering controlled release and non-controlled release topiramate according to an escalating dosing regimen (the ‘299 patent).
Ultimately, Vivus had to introduce narrow elements to the claims in an attempt to differentiate the claimed inventions from the prior art. Some of the narrow features found in the issued claims, include
- the specific, approved low dosages of phentermine and controlled release (CR) topiramate found in Qsymia (e.g., phentermine between 2-8 mg and controlled release (CR) topiramate between 15-50 mg)
- the dosage ratio of phentermine to CR topiramate (16%) found in Qsymia
- the pharmacokinetic features (Cmax, Tmax and AUC) of Qsymia
- the characteristics of patients receiving Qsymia (e.g., BMI greater than 30 kg/m2 and the presence of a condition associated with obesity)
- the duration of treatment (e.g., at least two years)
- the formulation mechanism (e.g., a matrix core has a delayed release coating comprising ethyl cellulose and polyvinyl pyrrolidone, and a polymeric filler comprising microcrystalline cellulose)
It is not a bad strategy for a patent holder to seek narrow claims to enforce its patent rights. However, the claims still need to be valid and enforceable, while still being regularly infringed, for the strategy to work. Below I discuss why I think Vivus’ strategy may fail.
Prior art referenced in the below discussion
- (D1) US 2004/002462 (Najarian); Published: January 1, 2004; Issued as US Patent No. 7,056,890; cited in earlier IDS
- (D2) WO 2006/063078 (Elan Corp; Jenkins et al) Published: June 15, 2006; cited in earlier IDS [corresponds to US 20060121112 A1, which published on 8 June 2006]
- (D5) Vivus 8-K Disclosure (Exhibit 99.1): Conference Call Transcript; VVUS – Q3 2007 Earnings Conference Call; Event Date: November 9, 2007; cited in an IDS that was submitted on November 8, 2013; as of the publication of this report, the IDS has yet to be signed off on by the examiner
- (D6) Vivus Advisory Committee Briefing Document (AdCom) submitted to the FDA on February 22, 2012; does not appear to be in any of the IDS’s
- (D7) Vivus Quarterly SEC Filing 10-Q; May 8, 2007; does not appear to be in any of the IDS’s
(See the “Catalog of the Most Relevant Prior Art” section at the end of this report for a detailed listing of the prior art content.)
Potential problems with the new patent family (the “2028 Patents”)
* Likely anticipated (not novel) with no likely remedy outside the U.S. – when the claims of a patent are found to be anticipated they are no longer valid because none of the features of the claims are novel; in light of D1, D2 and D5 I would argue there are no novel features found in the claims with the possible exception of the very specific formulation details found in claims 7, 8 and 9 of the ‘298 patent (although the European examiner of the corresponding European applications rejects similar claims based on D1); many of the details of Qsymia’s formulation and specific dosages were first disclosed in a Vivus press release and during a company conference call (D5) before the second family of patents was first filed; while D1 and D2 describe phentermine and CR topiramate dosage ranges down to 5 mg, D5 discloses the specific dosages found in approved Qsymia and claimed in the ‘298 and ‘299 patents; D1 and D2 are strong obvious references for dosages (see below discussion), while D5 is spot on novelty art; however, it is likely the inventors of the ‘298 and ‘299 will try to swear behind D5 (i.e., declare they were in possession of the invention prior to the conference call); this may remedy the problem in the U.S. where the option of swearing behind is offered, but in most patent jurisdictions outside of the U.S. (e.g., Europe), inventors are not afforded this opportunity; a transcript of the conference call (D5) was submitted as part of a third-party observation filed with the European Patent Office (EPO) against European Patent Application Nos: 09763480.2 and 09763479.4; the challenges can be viewed here and here)
* Likely obvious in light of significant prior art – in order for a patent claim to be valid, the new features in the claim, when taken together, need to be non-obvious in view of the prior art; in my opinion, any claim elements from the ‘298 and ‘299 patents that may be considered novel or new are clearly obvious (an opinion shared by the European examiner in view of D1 and D2); below is a discussion of why the features found in the claims are, in my opinion, obvious (in addition to being anticipated):
i. regarding the claimed dosages, D5 is spot on novelty prior art since it lists the very dosages Vivus is trying to protect in its new family of patents; assuming the inventors swear behind D5 in the U.S., D1 and D2 are still available to demonstrate the claimed dosages and ratio are obvious since they both disclose phentermine and CR topiramate dosage ranges down to 5 mg (see Iron Grip Barbell v USA Sports) across a range of fixed dosage ratios, including 16% (see claim 27 from Najarian US Application No. 20060234952)
ii. regarding the claimed specific pharmacokinetic (PK) parameters, it seems the patents claim the PK features of controlled release topiramate (lower Cmax while maintaining the AUC); this is merely a description of any controlled release formulation, so unless Vivus is claiming it’s the first inventor of controlled release formulation technology (which it is not), there does not appear to be anything inventive here
iii. regarding the claimed patient characteristics and the duration of treatment, it is obvious those in need of weight loss medications are the obese and D1 discloses administering the CR topiramate with phentermine for up to 18 months (which falls within the claimed ranges of the new patents)
iv. regarding the claimed formulation mechanics, both D1 and D2 teach ways for mixing CR topiramate with phentermine; these mechanisms were all well known in the art at the time of the Vivus filing
* Surprising and unexpected results –in order to overcome a finding of obviousness, Vivus needs to demonstrate the once-a-day formulation yields surprising or unexpected results (e.g., in the form of improved efficacy or side effects); in my opinion, the only thing that is arguably surprising about the once-a-day formulation is the lower bioavailability (e.g., Cmax and AUC) of phentermine in the presence of controlled release topiramate, however, this is finding is not convincing for the following reasons:
A. irrelevant – Vivus does not provide clinical evidence why this finding is important; the shapes of the phentermine PK curves – whether in the presence of controlled release and non-controlled release topiramate – are the same; while the shapes of the curves are the same, the area under the curve (AUC) is lower in the presence of controlled release topiramate, so one needs to administer more drug to get the same effect when phentermine is combined with CR topiramate; while this is an odd result, it does not seem to have a beneficial therapeutic effect – in fact you could argue (as the European examiner does) that the effect is detrimental since more phentermine needs to be administered
B. inherently anticipated by Elan application – Elan already describes the once-a-day formulation in its patent application (which was abandoned after it was found obvious) so any properties phentermine has in the presence of controlled release topiramate seem to be inherently anticipated
Any other arguments about the dosages, dosage ratio, pharmacokinetic (PK) parameters, combination formulation or treatment duration lack the necessary evidence to demonstrate surprising or unexpected results over the extensive prior art. Which begs the questions:
What is surprising or unexpected about the once-a-day formulation versus the twice-a-day formulation (prior art)? Nothing (except for a detrimental effect on the bioavailability of phentermine).
Consider this revelation from the conference call (D5): Peter Tam stated the once-a day-formulation “has the exact dosing, timing and exposure relative to the twice-a-day formulation used in the phase II study”; the phase II study was based on the twice-a-day formulation described in the Najarian patents (see page 36 of Vivus’ 10-Q dated May 8, 2007); in fact, Dr. Najarian came up with the dosages and administration scheme used in the phase II trials; therefore, it should not be surprising that the once-a-day formulation works as described in the Najarian patent (and the Elan application); if there is evidence to the contrary (e.g., efficacy or side effect data from the once-a-day formulation versus the twice-a-day formulation), the company has not produced it for the patent examiner to consider; instead, we have to rely on the company’s statements to the FDA that the side effect profile is consistent with the monotherapy or merely dose-dependent – again, offering nothing surprising or unexpected
From Vivus’ AdCom submitted to the FDA on February 22, 2012:
“Top dose QNEXA (phentermine 15 mg and topiramate 92 mg) contains half of the maximum daily dose of phentermine and approximately one-fourth of the maximum daily dose of topiramate. As such, the side effects of QNEXA therapy are expected to be consistent with those described in the approved labeling for phentermine and topiramate, albeit at a severity consistent with lower doses.” (page 73)
* Extensive prior use – from the conference call we also learn that Dr. Najarian had already treated 10,000 patients with combinations of topiramate and phentermine as a practicing doctor at his Los Osos, California weight lost clinic – presumably in a manner similar to the phase II trials he designed (e.g., administering phentermine in the morning and topiramate in the evening); after learning the once-a-day formulation was designed to mirror the dosing, timing and exposure of the drug combination used in the phase II trials, this extensive prescribing history stands squarely as critical prior art – the details of which (dosages, formulations, safety and outcomes) have never been disclosed to the USPTO; also Dr. Najarian’s years of prescribing the drug combination at his weight loss clinic likely constitutes a public prior use of the invention (unless medical use is exempt under some hidden public use doctrine that I’m not aware of)
* May be found unenforceable – the company may find some or all of its patent claims unenforceable due to inequitable conduct (a scenario discussed in earlier reports for the first patent family); applicants and patent practitioners have a duty to disclose material information to the USPTO; the 2007 conference call was not disclosed to the patent office until I emailed it to Vivus’ patent counsel, Mintz Levin; see the email here; however, the examiner did not have time to consider the contents of the conference call (as indicated by the still unsigned 1449 form in the file history); the conference call is significant because, among other things, it contains statements made by Peter Tam that contradict later statements found in his September 27, 2013 declaration; for example, in the declaration, Mr. Tam states, “Importantly, the pharmacokinetics profile of the claimed unit dosage forms surprisingly permits 24 hour coverage of phentermine and topiramate (thereby suppressing appetite and enhancing satiety throughout the day).” (See page 4, section 7); on the conference call, he described the PK-PD profile as, “Pharmacokinetics and pharmacodynamic studies have confirmed that the final formulation of Qnexa is comparable with the twice-a-day formulation that was used in the Phase II study conducted at Duke University.” (Seep page 3, Tam comments, paragraph 3).
Is it surprising that the formulation did what the inventors expected?
The formulation was designed to perform exactly how the combination is described in the prior art; for further evidence, see the company’s February 2012 AdCom (which was never included in an IDS):
“The Phase 3 clinical trial program was designed to assess the safety and efficacy of a single-capsule, extended-release formulation containing immediate-release phentermine and extended-release topiramate, and was designed to mimic the time-sequenced daily dosing of the individual components studied in study OB-201.” (page 5)
Another area of potential inequitable conduct that I’ve already identified from the first family that also likely affects the second family is the idea of prosecuting the two families in parallel while making statements about the lack of enabling disclosure in the first family.
First, in its December 2012 Response to the Final Rejection, Vivus argues Dr. Najarian does not teach or suggest a controlled release topiramate formulation that provides a comparable AUC but lower Cmax (see page 6 of the Response from the 12/481,540 application). This is the PK effect of any controlled release formulation, and controlled release topiramate formulations are the subject of the pending claims submitted on March 22, 2012 in US Application No. 12/683,353 from the first family. Judges do not like when patent practitioners say an application does not teach or suggest something (in order to get claims allowed in their client’s other application), while still trying to get claims to the same subject matter they just said is not enabled in the original application.
A more glaring example of this occurs when Vivus argues the Najarian patents teach away from topiramate dosages below 50 mg and arguably below 200 mg, while still pursuing claims to topiramate at dosages as low as 5 mg (see claim 85 of the pending claims submitted on March 22, 2012 in US Application No. 12/683,353). For the “teaches away” statement, see page 7 of the February 2012 Response After Non-Final Action for US Patent Application No. 12/481,540:
“Because Najarian teaches an optimized daily maintenance dosage of topiramate that is so significantly greater than the daily maintenance dosages of the instant claims, the ordinarily skilled artisan would not modify, and particularly, would not decrease the daily maintenance dosage of topiramate below the 200 mg taught by Najarian with any reasonable expectation of predictable results or success…In fact, Najarian teaches away from the daily maintenance dosage of topiramate of less than 50 mg…”
You cannot do this and expect to maintain enforceable patents – or at the very least maintain credibility with a judge.
* Inventorship – it’s a bit unusual for a CEO and VP of corporate development to be named an inventors of a complicated drug formulation patent – as is the case on the second patent family with Leland Wilson and Peter Tam; from the conference call, we learn that the once-a-day formulation was “developed with outside consulting experts as well as a company that has broad expertise in controlled-release formulation development” (see page 11); yet no one outside of the company is named as an inventor; what specific features from the claims did Mr. Tam and Mr. Wilson contribute? If the only difference between the claims and the prior art is a very technical specific aspect of the formulation, then it is hard to believe a CEO and an MBA came up with it (in other words, did they come up with a specific formulation that is not already described or obvious in light of D2, which is devoted largely to specific CR formulations of topiramate in combination with phentermine?); if it was a general idea, like merely combining CR topiramate with IR phentermine by any means known in the art, then it is not an invention (since this is described in D1 and D2); if and when the inventors swear behind conference call as a reference in the U.S., the details of their inventive contributions may become clearer (or less clear); in the meantime, it appears either there’s nothing inventive about actually developing the formulation (otherwise the outside consulting experts need to be named as inventors – for at least some of the dependent claims), or Vivus may be obscuring the inventorship picture perhaps to avoid a royalty payment; while I have no specific insights here relating to inventorship, it is an area litigators are likely to focus
* Narrow claims – in light of the extensive prior art, any claims that survive may be very narrow in scope; for example, the claims may be limited to the specific formulation details (e.g., topiramate in a controlled release polymeric core coated in immediate release phentermine); it is not a bad strategy for patent holders to seek the narrowest claims possible that are still likely to be regularly infringed; however, if too narrow, a drug claim can be designed around such that generic drug still achieves the required bioequivalency necessary for approval; also, although many of the limitations found in the claims are also on Qsymia’s label, there are some discrepancies (e.g., relating to duration of treatment and BMI requirements) that generics may take advantage of by either introducing a skinny label (e.g., seek approval for a generic version of Qsymia with a narrower label that does not infringe the claims) or arguing there are instances when patients and doctors do not infringe using their generic product (see Commil v Cisco (Fed. Circ. 2013)); an example of a skinny label might include slightly modified versions of the higher dosages of Qsymia (e.g., greater than 8 mg phentermine and 50 mg topiramate)
Potential problems with the old patent family (the “2020 Patents”)
As a reminder, the problems plaguing the 2020 patents still exist, and I believe the company will have a difficult time enforcing these patents because they are likely to be found invalid, unenforceable or not infringed by the courts. I have supported this position through exhaustive research, which I’ve published in this blog, in press releases and a third party observation filed in Europe. In my opinion, the problems with the 2020 patents minimally include the following:
* Likely obvious – both of the components of Qsymia, phentermine and topiramate, were previously known to cause weight loss, therefore, it was obvious to combine the two drugs as an anti-obesity combination, especially in light of an earlier patent filed by Susan McElroy that describes the same combination for weight loss; further, it is my opinion that the 2020 patents lack the surprising and unexpected results (e.g., clinical evidence) necessary to overcome an obviousness challenge.
* Likely not enabled – the 2020 patents lack the necessary enabling disclosure relating to Qsymia’s dosages, formulation and titration that the company admits are required to differentiate Qsymia from its generic components; Vivus’ own patent counsel provides written admissions during the prosecution of the 2028 patents that the 2020 patents fail to teach topiramate dosages below 50 mg and arguably below 200 mg
* May be unenforceable due to inequitable conduct – there are multiple instances of potential inequitable conduct throughout the prosecution of the 2020 patents, including statements by the Applicant to the USPTO regarding Qsymia’s side effect profile that are not consistent with later statements to the FDA, misstatements to the USPTO by Vivus’ former patent counsel about the lack of prior art (McElroy), and more recently statements made by Vivus’ current patent counsel during prosecution of the 2028 patents that are at odds with issued claims from the 2020 family
* Ownership uncertainty – without evidence to the contrary, it seems both Harvard Medical School and Endo Health Solutions should likely have rights to the 2020 patents since Dr. Najarian was employed by both institutions when he allegedly made all or part of the Qsymia “invention”; either demonstrating Vivus is not the proper owner of the patent or seeking a license from Harvard or Endo might offer a quick way around the 2020 patents
A final note on the 2020 patents: In a letter published by Vivus shareholder Clinton Group, the shareholder defends the strength of the earlier patents and cites an unnamed law firm that specializes in intellectual property as the basis for its opinion. While I publish this blog anonymously, I also support all of my conclusions with explicit reasoned arguments and exhaustive research that is cited throughout my reports. I also don’t charge $800 per hour for my services. The Clinton Group letter only includes the naked conclusions and the law firm remains anonymous. I for one would like to know which law firm stands behind the strength of the 2020 patents so others can factor in this information when seeking legal advice from patent firms.
Where does Vivus stand now in terms of its Qsymia’s patent portfolio?
I believe Vivus and its patent counsel, Mintz Levin, recognized the difficulty the company is likely to have enforcing the 2020 patents and adopted an aggressive patent prosecution strategy to get new patents outside of the earlier Najarian patent family – plus the new patents offer the obvious benefit of extending Qsymia’s patent coverage an additional nine years until 2029.
I commend the company and Mintz Levin for getting the new patents issued, but it was done so without critical prior art (e.g., the 2007 conference call and Dr. Najarian’s 10,000 patient prescribing history) being properly considered by the examiner. When this prior art is considered side-by-side with the declaration from Peter Tam, the contradictions and inconsistencies in Vivus’ arguments become quite apparent and the materiality of the conference call is hard to question.
It wasn’t until I sent an email that explained the contents of the conference call to the company’s patent counsel, Mintz Levin, that the company felt compelled to submit an information disclosure statement (IDS) disclosing the conference call and the above linked email to the USPTO. The inclusion of these documents in an IDS indicates that Vivus and its patent counsel believe both documents are material to patentability. However, since the IDS was submitted days before the scheduled issuance of the new patents, it does not appear the examiner had the opportunity to consider these references. Thus, the company is left in a strange situation: it has issued patents that are not presumed valid over references it deems material.
There are some ways Vivus can try to remedy the situation. It can file a request for Supplemental Examination, a fairly new procedure that offers the Applicant another round of prosecution so the US Patent & Trademark Office (USPTO) can consider, reconsider, or correct information believed to be relevant to the patent. In this case, if the USPTO determines the reference is material and unresolved (it has 3 months to make this determination), the patent gets kicked into an ex-parte reexamination process. In a best case scenario for Vivus, during ex-parte reexamination the Office determines the contents of the conference call do not change the patentability of the invention and the claims remain issued as is, or the PTO determines the reference does not raise a substantial new question of patentability and the patent is immunized from allegations of inequitable conduct without going through reexamination.
As is often the case with patent matters, the only real resolution regarding validity will not come until the patents are litigated. Vivus could opt not to file a request for Supplemental Examination and delay any determination until litigation, however, in my opinion, this makes a determination of inequitable conduct more likely for the patents. Patent holders are eligible to file a request for Supplemental Examination anytime during the period of enforceability of the patent in question, so Vivus may opt to wait (pending its business objectives) before trying to remedy any uncertainty.
Antitrust note: Should Vivus or its affiliates attempt to enforce Qsymia patents in cases where the courts find that inequitable conduct has occurred during patent prosecution and Vivus’ patents were thereby fraudulently listed in the FDA’s Orange Book, there could be potential antitrust risk. If this is indeed the case, let it be noted that the allegations of inequitable conduct relating to the second family of patents were first raised by the originator Robert Diggs in this report and the earlier email to Mintz Levin.
Third Party Challenges in the U.S.
There are a number of post grant strategies for prosecuting Orange Book listable patents, and patent challengers (e.g., generics) are increasingly taking advantage of these strategies. While these can cost more than $15K to file, it is certainly cheaper than ANDA litigation and resolution can come much faster.
- Ex Parte Reexamination (anytime after grant); can be triggered by the applicant by submitting a request for supplemental examination as described above; can also be filed by anonymous third parties; no discovery allowed
- Inter Partes Reexamination (after 9 months of grant); discovery is allowed
- Post Grant Review (within 9 months of grant); broad grounds for challenging available (101, 102, 103 and 112); discovery is allowed
Regardless if any of the above strategies are used, the patents will likely end up in ANDA litigation if generics deem the market attractive enough (which they always seem to do…)
* ANDA litigation – at the time of publication of this report, an ANDA had still not been approved by the FDA (for reasons that are unclear to me); clearly generics have invested some resources determining ways to manufacture Qsymia (see Ranbaxy’s US Patent Application No. 13/848476, which was filed before Qsymia was approved and appears to disclose ten different ways for making Qsymia); assuming ANDA applicants file a paragraph IV certification, they now must also explain why they do not infringe the new patents, or why the new patents are invalid or unenforceable; Vivus is still entitled to a 30-month stay once it files its infringement suit; Delaware typically begins trials in 22-24 months; trials only last 5-10 days and a decision is usually reached within 3 months
Foreign Rights for the Second Family
The ramifications of the D5 reference (the conference call) for Vivus’ foreign patent rights are more clear cut (versus its U.S. rights). For second family applications filed outside of the U.S., the conference call can likely be cited as an anticipation and inventive step reference since it describes the specific dosages and formulation for the once-a-day formulation of Qsymia, which is largely the subject matter of the pending applications. Unlike the U.S., inventors cannot swear behind a reference in most foreign jurisdictions therefore it stands as a strong prior art reference without an apparent remedy.
I took the opportunity to introduce the contents of the conference call to the European Patent Office as part of a pair of prior art challenges filed against two pending Vivus applications from the second patent family (European Application Nos: 09763480.2 and 09763479.4). The challenges (which can be downloaded here and here) allege the applications are not patentable in view of the Qsymia details disclosed during conference call. A press release with more background around the challenges can be viewed here. With Vivus’ 2020 patent family only filed in the U.S., Europe, Canada and Australia, and the pending European application from this family (European Patent Application No: 07011472.3) also the subject of an earlier-filed third party challenge, it’s not clear how the company can come up with a convincing ex-U.S. patent strategy for potential partners.
A closer look at Mr. Tam’s declaration from the ‘298 and ‘299 patent prosecution?
* In the declaration submitted by Peter Tam to the USPTO on Sep 16, 2013 explaining why Vivus’ new patent applications are allegedly patentable over the earlier Najarian patent, Mr. Tam states:
“Additionally, the cited reference [the Najarian 7,056,890 patent] does not teach or suggest a combination of phentermine and topiramate at this fixed claimed ratio [16%] to mitigate dose-related side effects.” [page 5, section 8]
First, Example 1 of the ‘890 patent describes administering 15mg of phentermine in combination with 100mg of topiramate for a 15% ratio of phentermine to topiramate. Does the 1% difference between the Najarian ratio and the later claimed 16% ratio mitigate dose-related side effects? Also, while the amount of topiramate is periodically increased throughout the course of the treatment described in Example 1 of the ‘890 patent, is there evidence that fixing the ratio at 16% produces a therapeutic difference (e.g., improved side effect profile) versus the dosing regimen described by Dr. Najarian? If so, Vivus has not, to my knowledge, produced this data.
Also in the declaration, Mr. Tam stresses the importance of dosage ranges and dosage forms:
“The specific formulation and specific dosage ranges and dosage ratio of the combination of phentermine and topiramate (as required by the claims provided in the accompanying Amendment and Reply) are not taught or suggested by the cited reference [the Najarian ‘890 patent]. More importantly, the dosage forms providing phentermine as immediate release and topiramate as controlled release…provides superior and unexpected properties by dramatically improving tolerability by reducing the adverse side effects of both phentermine and topiramate…” [page 3, section 7]
Again, is there evidence that extended release topiramate offers surprising and unexpected results versus non-extended release topiramate? Does extended release topiramate produce a therapeutically significant difference versus the preferred topiramate dosing embodiments provided in the ‘890 patent? From the ‘890 patent:
“In a preferred embodiment, topiramate is taken later in the day than the phentermine. Preferably, the patient takes the topiramate just before supper or later in the evening. Topiramate is best given later in the day because the drug can be sedating. In other embodiments, the topiramate is given BID (e.g., twice daily), TID (three times daily) or QID (four time daily).” [Col 13, lines 38-44]
Also, given that the half-life of topiramate is 21 hours after a single dose and steady state is reached in about four days, does extended release topiramate offer any clinical utility after about a week?
Catalog of the Most Relevant Prior Art
(D1) The Najarian patent (which published as US 2004/002462 on January 1, 2004) discloses the following:
* (paragraph 10) a drug combination for effecting weight loss which involves treating a subject with a sympathomimetic agent (phentermine) in combination with an anticonvulsant sulfamate derivative (topiramate)
* (paragraphs 11, 52 and 55) methods for treating at least one side effect associated with obesity, including hypertension, diabetes or glucose intolerance and insulin resistance, hyperlipidemia, and sleep apnea
* (paragraph 12) kits including the pharmaceutical compositions of the present invention are also featured (e.g., kits including the compositions packaged in a daily dosing regimen)
* (paragraph 13) a combination therapy that enables a reduction in the effective dosage of each drug administered and minimizing the potential side effects of each individual drug (a statement that is removed in later filed continuation-in-part applications from the same family)
* (paragraph 32) phentermine or topiramate may be prescribed at a dose as low as 5 mg daily; phentermine daily dosage include 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, and 55 mg, with the preferred dose range of about 5-15 mg daily (paragraph 41)
* (paragraph 32) administering an ongoing daily dose given to a patient, typically after gradually increasing (titrating) the daily dose from an initial, low dosage, over an extended time period, e.g., on the order of several weeks; the dosage of topiramate is increased gradually at the outset of the therapy in order to reduce the chance of undesirable side effects associated with higher doses of the drug, for example, topiramate is administered at a dose of 25 mg daily for about the first 5-7 days (e.g., 6 days) of treatment, at a dose of about 50 mg daily for the next 5-7 days (e.g., 6 days), at a dose of 100 mg daily for about the next 6-8 days (e.g., 7 days) and about 100-150 mg daily for the next 20-26 days (paragraph 43)
* (paragraph 33) a single physically discrete dosage form having each of the active ingredients of the combination treatment (e.g., a single dosage form having anticonvulsant and sympathomimetic agent)
* (paragraphs 34, 42 and 44) administering phentermine in the morning and topiramate later in the day
* (paragraph 45) pharmaceutical compositions (e.g., for oral administration) comprising phentermine and topiramate in a single pharmaceutical formulation to increase patient compliance
* (paragraph 46) pharmaceutical composition including phentermine in an immediate release form and further includes topiramate in a controlled release formulation
* (paragraph 46) preferred controlled release formulations include delayed release granules, matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed therethrough), and granules within a matrix
* (originally filed claim 31) a dosage form comprising a core containing the topiramate and a coating containing the phentermine
* (paragraph 47) a sustained release form can be formulated in such a way as to provide an effective dose of topiramate (e.g., provide a physiologically effective blood level) over a 4, 8, 12, 16 or 24 hour period
* (paragraph 52) the combination therapies can be administered until the patient has achieved a weight loss of 5-10%, 10-15%, 15-20%, or 20-25% of their initial body mass
* (paragraph 58) specific combination dosages of 15 mg phentermine and 100 mg topiramate are described, which equal a 15% ratio; other dose ranges include 8 mg phentermine and 50 mg topiramate, which equal a 16% ratio (paragraph 32)
* (paragraph 59) the weight reduction effect of topiramate will continue for as long as 18 months on the medication
(D2) Elan Patent Application (WO 2006/063078) which published on June 15, 2006 discloses the following:
* (page 4, lines 4-8 and lines 10-16; page 12, lines 2-7) once-a-day, controlled release oral dosage forms of topiramate at dosages as low as 5 mg; phentermine in dosages of 5-15 mg
* (page 8, lines 14-17) a delayed-release component comprising from about 5 mg to about 250 mg of topiramate which is released in the body at about 6 hours, about 9 hours, about 12 hours or about 18 hours (Tmax) after the release of the immediate-release component
* (page 10 line 10 – page 11 line 3) a multiparticulate modified-release composition comprising a therapeutically effective amount of the controlled-release form of topiramate in combination with a sympathomimetic agent, namely phentermine
* (page 11, lines 5-10) the sympathomimetic agent has anorexient properties or is anorectic without loss of efficacy or without adverse or undesirable side effects to a subject or patient at therapeutically effective doses when prescribed in combination with topiramate
* (page 11 line 21 – page 12 line 7) combination therapy comprising immediate release phentermine and controlled release topiramate for bringing about weight loss while simultaneously enabling a reduction in the effective dosage of each drug administered and minimizing the potential side effects of each individual drug
* (page 14, lines 16-22) methods for treating at least one additional effect associated with obesity
* (page 18, lines 14-16) the use of a modified-release matrix material
(D5) Excerpts from the November 9, 2007 Vivus Conference Call:
* Qsymia patient characterization description: Page 2, Leland Wilson comments, paragraphs 2-4:
Mr. Wilson describes the EQUIP study which will include “morbidly obese patients; that is, patients with a BMI equal to or greater than 35” (paragraph 2) and the CONQUER study which “will study obese patients with a BMI of 27 or greater with serious co-morbidities, including hypertension, dyslipidemia and Type II diabetes” (paragraph 3). He adds, “Together, these pivotal studies will encompass the population of obese patients who are at greatest risk and in the greatest need of effective therapy.”
* Patient description: Page 2-3, Leland Wilson comments:
“We have also developed and fully scaled up production for a unique, once-a-day formulation of Qnexa. The Phase II studies were conducted with a twice-a-day formulation. This new once-a-day formulation will improve compliance and potentially reduce side effects by reducing peak plasma levels while maintaining the same drug exposure as the twice-a-day dose regimens used in the Duke University Phase II trial. All necessary PK/PD studies to bridge the results to the Phase II study have been completed.”
* Dosage and formulation discussion: Page 3, Peter Tam comments, paragraphs 1-2:
“As Lee mentioned, we have developed a proprietary, once-a-day formulation of Qnexa. Formulation consists of immediate-release phentermine and controlled-release topiramate.
In the Phase III program, three different dosage strengths will be tested. Full-strength Qnexa contains 15 milligrams immediate-release phentermine and 92 milligrams of controlled-release topiramate. Mid-dose Qnexa contains 7.5 milligrams of immediate-release phentermine and 46 milligrams controlled-release topiramate. Low-dose Qnexa contains 3.75 milligrams of phentermine and 23 milligrams of controlled-release topiramate.”
* PK-PD profile discussion: Page 3, Peter Tam comments, paragraph 3:
“Pharmacokinetics and pharmacodynamic studies have confirmed that the final formulation of Qnexa is comparable with the twice-a-day formulation that was used in the Phase II study conducted at Duke University. The once-a-day formulation reduces peak plasma concentration [Cmax] and delays the time to maximum plasma concentration [Tmax] while maintaining equivalent total exposure [AUC]. We believe the once-a-day proprietary formulation administered in the morning will make it easier for patients to comply with dosing regimen.”
* Dr. Najarian prescription history: Page 4, 2nd full paragraph:
“Dr. Najarian, the inventor of this combination treatment, has always maintained based on his 10,000 patient experience that phentermine reduces the cognitive and neuropsychiatric side effects of topiramate. We for the first time provided evidence documenting this effect in our double-blind, randomized trial at Duke University.”
* Titration: Tam Q&A, page 7, paragraph 3 of Mr. Tam’s response to Mike King:
“Now, with regard to the titration, the program is designed in such a way to allow patients dosing flexibility. So for example, if somebody is randomized at a high dose and found the dose to be difficult to tolerate, they certainly have the flexibility to dose titrate downward. That is how topiramate is currently being used in the real world. And that is the program that we believe will be — will represent how the product will be used, and certainly, the dosing flexibility will improve tolerability going forward.”
Equivalence to twice-a-day formulation Tam Q&A, page 10:
Peter Tam — Vivus – SVP, Product & Corporate Development
“The Qnexa, the final formulation that we are testing in Phase III is what we believe is the commercial formulation. It has the exact dosing, timing and exposure relative to what was done in the Phase II study.”
* Inventorship uncertainty – Page 11:
Jeff Goater — Cowen & Company – Analyst
Just a quick question on the once-daily formulation. Was that something that was developed in-house, or was there a third party involved and might there be a small royalty owed?
Peter Tam — Vivus – SVP, Product & Corporate Development
It’s yes and no. It is developed with outside consulting experts as well as a company that has broad expertise in controlled-release formulation development. And no, there are no royalties tied to this formulation because everything is owned by Vivus based on the agreement that we’ve set forth with this formulation company.
* Co-morbidities: pages 14-15
Mike King — Rodman & Renshaw – Analyst
Can, okay. And then just in terms of the other benefits in CONQUER, Peter, they — things like dyslipidemia, weight, circumference, etc., do you think you have enough time on therapy or at 56 weeks to show a meaningful benefit? Or maybe asked the question differently, when should we start to see its clinical benefit in terms of resolution of hypertension, dyslipidemia, (technical difficulty) replicate themselves?
Peter Tam — Vivus – SVP, Product & Corporate Development
That is a very interesting question, Mike. And we have some really strikingly positive data which we believe the uniqueness of this combination will provide almost immediate effects on many of these co-morbidities. So that is one.
Certainly, in a 56-week study, we are confident that we will be able to show statistically and clinically meaningful benefit for these co- morbidities. We saw improvements in these co-morbidities in a fairly healthy population in the Phase II study that was conducted at Duke University. And certainly, with a sicker population that is a group of patients with more room for improvement, if you will, we will be able to see a good differentiation between active drug and placebo for these co-morbidities. Does that answer your question?
(D6) Vivus AdCom submitted February 22, 2012 to the FDA; once-a-day formulation is the same as the twice-a-day formulation; page 5:
“The Phase 3 clinical trial program was designed to assess the safety and efficacy of a single-capsule, extended-release formulation containing immediate-release phentermine and extended-release topiramate, and was designed to mimic the time-sequenced daily dosing of the individual components studied in study OB-201. The QNEXA formulation was designed so that peak exposure of each drug was separated by 7 to 8 hours with peak phentermine exposure in the morning and peak topiramate exposure near late afternoon/evening. The delivery of the topiramate component later in the day was expected to provide peak drug exposure for afternoon/evening hunger.”
* Vivus AdCom submitted Feb 2012 to the FDA; obvious dose-dependent side effect profile; page 73:
“Top dose QNEXA (phentermine 15 mg and topiramate 92 mg) contains half of the maximum daily dose of phentermine and approximately one-fourth of the maximum daily dose of topiramate. As such, the side effects of QNEXA therapy are expected to be consistent with those described in the approved labeling for phentermine and topiramate, albeit at a severity consistent with lower doses.”
(D7) Vivus Quarterly SEC 10-Q; May 8, 2007; twice-a-day dosing regimen used in the Qsymia phase II study was determined by Dr. Najarian; page 36:
“Our Phase 2 study was a single center trial conducted at Duke University in only 200 patients. The twice-a-day dose and timing of the administration of the active ingredients was determined by the inventor through the treatment of patients in his private practice.”