VIVUS Qsymia Patents: Appearance of Ongoing and Systematic Inequitable Conduct before the USPTO by Vivus and its Attorneys

by bobbydiggs

Robert Diggs Deeper: What is the Role of Current Vivus Patent Counsel Mintz Levin?

This report focuses on three areas where Vivus and its attorneys have apparently made misleading or untrue statements, and/or failed to disclose information that is material to the patentability of the Qsymia patents:

First and most recently, Mintz Levin has submitted a series of arguments in a second, later filed family of patents on Qsymia, which substantially undermine the enablement of Vivus’ first set of Qsymia patents.  Enablement is required for patentability in the US and is the extent to which a patent application teaches how to make and use the claimed invention.  I am unable to find where these harmful arguments have been disclosed to the patent examiner for the first set of Qsymia patents.

Second, previous patent counsel, Dianne Reed, and the inventor on the first set of Qsymia patents, Dr. Najarian, made statements  to the USPTO about the side effect profile of the combination of phentermine and topiramate being significantly reduced in comparison to the side effects from the individual components.  Vivus later made statements to the FDA that were at odds with this supposed finding of reduced side effects.  It appears that neither Vivus nor any of its outside counsel, including Mintz Levin has corrected the record on this point.

Third, previous patent counsel, Dianne Reed, appears to have mischaracterized the state of the art in 1996-1999 stating “the only reference in the 1996-1999 time frame describing the combination of phentermine with a second weight loss drug actually teaches away from the present invention”, when in fact the McElroy patent from 1999 taught the same combination of phentermine and topiramate as Qsymia, the invention being referenced.  While the McElroy patent was disclosed to the USPTO, this mischaracterization of the art probably left the examiner with the wrong impression of the prior art.  It appears that neither Vivus nor any of its outside counsel, including Mintz Levin has corrected the record on this point.

* Why is a Duty of Disclosure, Candor and Good Faith to the USPTO Necessary?

Many aspects of the American legal system are based on adversarial proceedings.  Two parties who disagree about something present competing arguments to a judge who decides the matter.  Each party is there to explain its position, but also as a knowledgeable interest participant that can keep that other side honest.  In determining whether a US patent gets issued there is no adversarial system, the patent applicant is merely corresponding with the Patent Office and its examiners.  If the patent applicant fails to be honest and forthcoming then it is unlikely that the patent examiner will have enough information and resources to discover the truth and weaker, less reliable patents would be the result.

* What is the Duty of Disclosure, Candor and Good Faith to the USPTO?

According to US Federal Regulation 37 C.F.R. 1.56  (a) “A patent by its very nature is affected with a public interest. The public interest is best served, and the most effective patent examination occurs when, at the time an application is being examined, the Office is aware of and evaluates the teachings of all information material to patentability. Each individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section. The duty to disclose information exists with respect to each pending claim until the claim is cancelled or withdrawn from consideration, or the application becomes abandoned….”

* What Needs to be Disclosed to the USPTO?

According to US Federal Regulation 37 C.F.R. 1.56 (b)

“…information is material to patentability when it is not cumulative to information already of record or being made of record in the application, and

(1) It establishes, by itself or in combination with other information, a prima facie case of unpatentability of a claim; or

(2) It refutes, or is inconsistent with, a position the applicant takes in:

(i) Opposing an argument of unpatentability relied on by the Office, or

(ii) Asserting an argument of patentability.

A prima facie case of unpatentability is established when the information compels a conclusion that a claim is unpatentable under the preponderance of evidence, burden-of-proof standard, giving each term in the claim its broadest reasonable construction consistent with the specification, and before any consideration is given to evidence which may be submitted in an attempt to establish a contrary conclusion of patentability.”

* Who has a Duty of Disclosure, Candor and Good Faith to the USPTO?

According to US Federal Regulation 37 C.F.R. 1.56 (c)

“Individuals associated with the filing or prosecution of a patent application within the meaning of this section are:

(1) Each inventor named in the application;

(2) Each attorney or agent who prepares or prosecutes the application; and

(3) Every other person who is substantively involved in the preparation or prosecution of the application and who is associated with the inventor, with the assignee or with anyone to whom there is an obligation to assign the application.”

Inequitable Conduct Evidence and Arguments

Below are three examples where I believe Vivus and its patent counsel have failed to meet their Duty of Disclosure, Candor and/or Good Faith to the USPTO.

1. Vivus Admissions: Low Dose Topiramate Is Not Taught

In attempts to secure a new second round of patents on Qsymia, outside of the original Najarian patent family, attorneys representing Vivus at Mintz Levin have submitted written admissions to the USPTO during the prosecution of the pending second round cases (US Patent Application Nos. No. 12/481,540 and 12/481,548) that the original family of Najarian patents fail to teach topiramate dosages below 50 mg and arguably below 200 mg, leaving vulnerable at least two and perhaps all four of Vivus’ marketed formulations of Qsymia. Yet the pending and issued claims in this Najarian patent family clearly embrace doses of topiramate lower than 200 mg or even 50 mg, and the claim from the first family of patents are the only issued claims the company has to Qsymia.

All of this creates a tension that is evident when the company’s patent counsel tries to obtain narrow claims to Qsymia issued in a later filed, second round patent that focuses more specifically on the doses, formulations and titration regimes of the commercial product while the company’s own first round patent (“the Najarian patent”) is being cited against them as prior art. In an effort to overcome the Najarian patent as prior art, Vivus’ counsel argues the Najarian patent does not teach low doses of topiramate.  However when simultaneously pursuing broad claims that include low doses of topiramate in a pending Najarian patent application, Vivus’ counsel does not see a problem presenting these broad claims to the USPTO or failing to tell the patent examiner that this first round patent fails to teach the low doses.

This contradiction lies at the heart of potential inequitable conduct challenges that Vivus and Mintz Levin seem likely to face when the Qsymia patents are litigated.

Below are some of the damaging lack of enablement statements made by Vivus’ patent counsel:

As stated supra, provided the disclosure of Najarian, the ordinarily skilled artisan would readily recognize that the statement cited by the Examiner is so broad as to be uninformative regarding the derivation of the specific daily maintenance dosages for topiramate, as recited by the pending claims [15-50 mg topiramate]. Najarian defines a “maintenance dose” as “an ongoing daily dose given to a patient” that typically follows a ramp-up or drug titration period. Furthermore, as noted by the Examiner, Najarian teaches that a maintenance dose for topiramate is “at least 50 mg daily”. The ordinarily skilled artisan reading Najarian, as a whole as is required, would readily recognize that an effective daily maintenance dose of topiramate cannot be less than 50 mg. In fact, the ordinarily skilled artisan would regard a daily maintenance dose of 50 mg of topiramate as the minimum possible effective dosage, and then turn to the working examples provided by Najarian to optimize the treatment regime. [emphasis added] (See pages 6-7 from the February 2012 Response After Non-Final Action for US Patent Application No. 12/481,540).

Later in the same response to the USPTO, Vivus’ patent counsel tells the Examiner that one should not expect 15-50 mg of topiramate to be efficacious for inducing weight loss. It is stated very clearly here:

Provided the disclosure of Najarian, considered in its totality, the ordinarily skilled artisan would have no reasonable expectation of predictable results or success by using the claimed low dosages of topiramate [15-50 mg] because the skilled artisan would expect such low dosages to be ineffective…

As described supra, the ordinarily skilled artisan would not expect the claimed low dosages of topiramate to be efficacious for inducing weight loss. This low dose of topiramate recited by the instant claims provides unexpected and superior properties by further decreasing the likelihood of adverse side effects observed with higher dosages of topiramate. [emphasis added] (See pages 7-8 from the February 2012 Response After Non-Final Action for US Patent Application No. 12/481,540.)

Vivus’ patent counsel goes even further when, on page 7 of the same response, they explain that Example 2 of the Najarian patent teaches administering up to 400 mg of topiramate (median dose 200 mg); therefore, the topiramate doses of the currently pending claims fall well below the teachings of the Najarian patent.

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… [emphasis added]

One could argue that these statements constitute patent suicide undermining the only patent claims that have been issued to a commercial product. So, perhaps it is not surprising that, based on my review of the available prosecution history, the attorneys at Mintz Levin are not in a rush to notify the USPTO in the first round Najarian patent family of their feelings on the teaching of doses of topiramate below 200 mg or 50 mg.  Also note that the same Mintz attorneys are prosecuting the still pending Najarian patent applications, so it is hard to imagine that there is a disconnect or honest oversight among the team at Mintz in its failure to update the USPTO. Yet this inconsistency remains today: in the still pending Najarian patent application, the Mintz attorneys are arguing for claims to doses of topiramate between 5-1000 mg and to doses of phentermine between 5-60 mg for the treatment of sleep apnea in an obese patient (see the most recently submitted pending claim 85 in U.S. Patent Application No. 12/683,353 filed in March 2012). Meanwhile at the USPTO, the two patent families have different Examiners so it is understandable why the USPTO has failed to identify the contradictions, and why there is a need for the Duty of Disclosure, Candor and Good Faith.

2. Statements made by Dr. Najarian and his patent counsel (Diane Reed) during prosecution that overstate, in absolute terms, the improved side-effects from combining topiramate with phentermine.

Next lets look at statements made by Dr. Najarian and his patent counsel, Diane Reed, to USPTO during the prosecution of U.S. Application No. 09/593,555 (from the Najarian patent family). First is the introductory statement that accompanied the  Applicant’s declaration:

Applicant submits herewith a Declaration under 37 C.F.R. §1.132 (the “Declaration”) that shows that the combination of a sympathomimetic agent such as phentermine with an anticonvulsant sulfamate derivative such as topiramate, provides for the desired weight loss.  Further, the Declaration also shows that unpleasant side effects are observed when phentermine and topiramate are administered alone, but not when administered in combination. [emphasis added] (See page 4 of the response dated July 16, 2002 for U.S. Application No. 09/593,555.)

…and here is the declaration from Dr. Najarian:

In these same patients, over and over, I surprisingly found that the addition of a sympathomimetic agent such as phentermine greatly diminished the side effects of topiramate.  Further, this allowed patients who, previously, could not tolerate topiramate, to be able to take topiramate in combination with phentermine.  I have also had patients who previously had difficulty tolerating phentermine when administered alone as a weight loss treatment because it was too stimulating and caused insomnia, even when taken in the morning as a single dose.  These same patients could tolerate phentermine when combined with topiramate, since both drugs nicely cancel out each other’s side effects. [emphasis added] Declaration from Inventor Najarian (Section 10. A.), filed July 2002 during prosecution of U.S. Application No. 09/593,555).

These statements leave the reader believing that combining topiramate with phentermine doesn’t just diminish the side effects, but they actually disappear. Yet, when the company later submitted its Advisory Committee Briefing Document (AdCom) to the FDA in February 2012 seeking approval for Qsymia, suddenly the side effect profile is consistent with topiramate and phentermine when administered alone. Below are two statements made by Vivus in its AdCom document:

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. (See AdCom document (filed February 22, 2012), page 73, first paragraph.)

The safety and tolerability profile of QNEXA demonstrated in the clinical development program is consistent with the known adverse effects of the approved component agents when used as monotherapy for various indications. Adverse effects observed with phentermine and topiramate monotherapy, which inform current labeling, were generally observed in subjects treated with doses higher than those studied in the QNEXA clinical development program. (See AdCom document (filed February 22, 2012), page 156, “9.2 Risks of Treatment” section.)

Based on my review of the Qsymia prosecution history, I have not found where the company or its patent counsel have updated the USPTO as to the true and accurate side effect profile. This seems to be a classic example of talking out of both sides of your mouth to accomplish two different goals, which would clearly not be allowed under USPTO rules.

3. Characterizing the Prior Art: Failure to Mention the McElroy Patent

The Applicant’s former patent counsel also misinformed the patent examiner about the lack of prior art (McElroy) disclosing the combination of topiramate with phentermine to treat obesity – despite almost certainly being aware of McElroy’s existence and its materiality (see the Najarian Assignment).

Even if, hypothetically, there were no warnings regarding phentermine combination therapy, one of ordinary skill in the art would still have been led away from combining phentermine with a second weight loss drug, insofar as the only reference in the 1996-1999 time frame describing the combination of phentermine with a second weight loss drug actually teaches away from the present invention as well.  See the attached publication by Bradley et al. (Appendix B), which summarizes a study on using phentermine in combination with bupropion hydrochloride for weight loss.  Not only did the second drug fail to increase weight loss relative to phentermine alone, it actually reduced phentermine’s efficacy! Page 18 of 22 of the May 18, 2005 response to an office action in the case of Application No. 10/454,368 that issued as US Patent No. 7,056,890

The most important piece of prior art is conveniently forgotten when Vivus’ patent counsel is making critical arguments to overcome an obviousness rejection. Yet, I do not believe for a second that the materiality of the McElroy patent was “forgotten” since it is featured prominently in the earlier executed assignment agreement between Dr. Najarian and Vivus. It is not the responsibility of USPTO Examiners to find and remember every piece of prior art in a case. Instead, it is the duty of the Applicant and his or her counsel to put the relevant facts in front of the Examiner and to characterize those facts honestly.

Conclusions: What Does All of This Mean?

If it is found that Vivus (the Assignee), Dr. Najarian (the Applicant) or patent counsel representing the Assignee or Applicant intentionally mislead the USPTO on an issue, or in this case multiple issues, material to the patentability of the alleged invention, the entire patent family may be found unenforceable due to inequitable conduct under 35 USC 282(1). In the present case, the missteps, omissions and contradictions described above when taken together become a compelling body of evidence. I believe most judges would view this evidence as a pattern of misconduct justifying a decision that all of the currently issued US patent claims to Qsymia are unenforceable.

In the meantime, a link to the blog has been emailed to the three Mintz Levin attorneys listed in the prosecution documents of Vivus’ Qsymia patents as well as three members of firm management. The email explains that the linked blog contains information that may be material to the prosecution of Vivus’ Qsymia patents and they may feel a need to disclose some or all of it to the USPTO.