Tuesday, November 24, 2015

The Cleveland Clinic Foundation v. True Health Diagnostics: Judge Denies Preliminary Injunction Based on Likelihood That Diagnostic Testing Method Is Patent Ineligible

On December 18, 2015, in The Cleveland Clinic Foundation v. True Health Diagnostics, LLC, a district court judge in Ohio issued an order denying the Cleveland Clinic Foundation’s (“CCF’s”) Motion for Temporary Restraining Order and Preliminary Injunction after concluding that CCF had failed to establish a likelihood of success on the merits.  In particular, the court found that CCF had “fail[ed] to make a clear showing that the patents-in-suit” are directed towards patent eligible subject matter.  This is yet another example of the challenges facing the developers of diagnostic tests in the wake of Mayo v. Prometheus.

The patents at issue in the case, U.S. Patent No. 7,223,552 (“the ’552 patent”); U.S. Patent No. 7,459,286 (“the ’286 patent”); and U.S. Patent No. 8,349,581 (“the ’581 patent”), relate to methods of analyzing Myeloperoxidase (“MPO”) biomarkers in a patient’s blood sample to predict a patient’s potential for heart disease, by comparing the level of MPO found in the patient’s blood sample with levels of MPO in control subjects to see if the patient has elevated levels of MPO.  MPO is an enzyme released by white blood cells when an artery wall is damaged or becomes inflamed, and its presence is thus an early symptom of many types of cardiovascular disease (“CVD”).

Applying the Mayo/Alice two-step test for patent eligibility, the court concluded that “it appears that the correlation between MPO levels and cardiovascular disease is more akin to a law of nature,” and that, “[m]easuring a sample of blood or blood product1 appears to be a “’well-understood, routine and conventional activity’ known in the scientific community.”  As a consequence, at least “at this point in the litigation,” the court was “not convinced that plaintiff has demonstrated that the patents-in-suit contain ‘an element or combination of elements’ sufficient to satisfy step two of the Mayo/Alice test.” The court rejected CCF’s argument that its patents require “measurement of a closed set of specific bodily samples” and, therefore, that its patents apply a “phenomenon in a combination of steps that has never been done before.”

Interestingly, the judge’s Order denying preliminary relief expounds in great detail on the important role the patents played in allowing CCF to translate the patented discovery into a successful commercial product.   It describes how in 2009, CCF launched HeartLab as the exclusive licensee of the patents to commercialize MPO testing.  CCF and HeartLab reportedly invested millions of dollars in their effort to build the MPO testing market, which has involved conducting ongoing medical and scientific studies, application for FDA approvals, and establishment of Medicare reimbursement status for MPO testing.  In addition, they “have focused considerable effort on developing stringent manufacturing and quality standards and also invested in educational programs about MPO testing.”

To illustrate the success of CCF’s and HeartLab’s efforts to develop and commercialize MPO testing, the Order notes that at its “inception, HeartLab had eight employees who performed only a few hundred MPO tests. It now has 140 employees who will perform hundreds of thousands of MPO tests in 2015.”

Thursday, November 19, 2015

Endo v. Actavis: Court Adopts Magistrate's Recommendation Finding Drug Method of Use Claims Facially Invalid Under 35 USC 101

In a September 28, 2015 post I reported on Endo v. Actavis, wherein a magistrate judge’s Report and Recommendation from a magistrate judge in the District of Delaware recommending invalidation of a drug method of treatment patent for patent ineligibility on a motion to dismiss under Rule 12(b)(6).  The magistrate judge essentially found the claim to be highly analogous to method of treatment claims found to be patent ineligible by the Supreme Court in Mayo v. Prometheus, and in my post I explained why the decision was consistent with my long-standing concern that an expansive interpretation of the literal language of Mayo threatened the validity of drug method of use claims in general.

In a November 17, 2015, Order Adopting Report and Recommendation, the district court judge hearing the case adopted the magistrate judge’s recommendation in its entirety and dismissed Endo’s Counts relating to infringement of U.S. Patent No. 8,808,737 (the '"737 patent"), finding the patent to be “facially invalid.”

 The district court judge rejected several arguments made by Endo in support of patent eligibility of the claims.

Of particular significance to the patentability of method of use claims in general, Endo argued “that the Magistrate Judge's reliance on the similarities between the '737 patent's representative claim and the claim involved in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 132 S. Ct. 1289 (2012), was in error because the claim at issue in Mayo did not require that anyone act upon or apply the method in a tangible way, while claim 1 of the '737 patent actually requires that the lower dose be administered.”  As I mentioned in my previous post, many of us have held out hope that even post-Mayo a method of treatment claim that explicitly recites administration of the drug to a patient would remain patent eligible.  The district court judge, however, agreed with the magistrate judge’s conclusion that “limitations at issue in Mayo do in fact mirror the analogous limitations of Claim 1 of the '737patent.” 

The court considered the following side-by-side comparison of the language of the Mayo and Endo claims: "indicates a need to [increase/decrease] the amount of said drug subsequently administered to said subject"(Mayo) vs. "orally administering to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief"(Endo), and concluded that the “slight difference in phrasing is immaterial, because neither formulation provides any sort of 'inventive concept.'"

The court further found Endo’s argument that the '737 patent does not claim a law of a nature, but rather"a new and useful process," to be “thoroughly unconvincing.”  The district court found that Endo had essentially admitted in their briefing that the '737 patent claims a natural law as its invention based on the following statement by Endo: “[I]t is true that the claimed inventions relate to the unexpected discovery that the bioavailability of oxymorphone is increased in patients with renal impairment.”
This is troubling, because while the patent statute explicitly states that a “discovery” can be patented, this court apparently construes a patent owner’s use of the term “discovery” as an admission that the “discovery” is a natural phenomenon.  If anything that can be discovered is a natural phenomenon, the availability of patent protection for innovation in the life sciences would appear to be extremely limited post-Mayo.

Endo made the policy argument “that the reasoning employed by the Magistrate Judge's Report and Recommendation would in effect invalidate all pharmaceutical method-of treatment patents using an existing, well-known compound.”  The district court responded that “this case is hardly the poster child for [such] a policy argument,” and speculated that patent protection would still be available for method of use claims are directed towards an invention embodying “creative steps or inventive leaps aside from the discovery of a natural law.”

But if the discovery that a chemical compound has therapeutic effect on a patient is to be considered a “natural law,” which appears to be the case under the rationale of this decision, how successful will a pharmaceutical company be in arguing that use of that chemical compound for its therapeutic effect constitutes a sufficient “inventive leap” to satisfy the new post-Mayo patent eligibility standard?

Tuesday, November 17, 2015

The Medicines Company v. Hospira: Federal Circuit Will Reconsider "Suppliers Exception" to 102(b) On-Sale Bar

In a previous post I reported on the Federal Circuit’s July 2, 2015, decision in the The Medicines Company v. Hospira, wherein a panel of the Federal Circuit held that a patent owner’s use of a contract manufacturer to prepare three “validation batches” of a drug formulation embodying the claimed invention created an invalidating on-sale bar, even though the contract was for manufacturing service, not for the sale of product, and title to the drug always resided with the patent owner, and even though the batches were produced for the purpose of demonstrating to FDA that the invention resulted in a formulation that satisfied FDA specifications.  In the post I pointed out that the decision illustrates the risk of using a contract manufacturer prior to filing a patent application, particularly now that the AIA has called into question the availability of the one year grace period previously available under pre-AIA 102(b).

On November 13, 2015, the Federal Circuit granted The Medicine Company’s petition for rehearing en banc and vacated the panel’s decision.  The court requested that the parties file new briefs addressing the following issues:

(a)    Do the circumstances presented here constitute a commercial sale under the on-sale bar of 35 USC 102(b)?

(i)                 Was the resale for the purpose of 102(b) despite the absence of a transfer of title?

(ii)               Was the sale commercial in nature for the purpose of 102(b) or an experiment to use?

(b)   Should this court overrule or revise the principle in Special Devices, Inc. v. OEA, Inc., 270 F.3d 1353 (Fed. Cir. 2001), that there is no “supplier exception” to the on-sale bar of 35 USC 102(b)?

In Special Devices the court rejected the patent owner’s policy-based argument urging the Federal Circuit to create a “supplier exception” to the 102(b) on-sale bar, concluding that the text of section 102(b) itself “makes no room for” such an exception.
Of course, for that matter the experimental use exception likewise finds no support in the language of the statute, and there is nothing to prevent the court from creating another judge-made exception to the 102(b) on-sale bar. Such an exception would seem to be justified on policy grounds, given that without a "supplier exception" an inventor, faces a loss of patent rights based solely on a decision to contract out manufacturing rather than manufacture in-house. This could be particularly problematic for a small or underfunded inventor lacking the resources to manufacture its invention itself.

Wednesday, November 11, 2015

Court Dismisses “Disaffected” Professor’s Attempt to Change Inventorship on Johns Hopkins Patent

Peter Pedersen, a professor in the Department of Biological Chemistry at The Johns Hopkins University School of Medicine is one of three named inventors on US Patent Nos. 7,547,673 and 8,119,116.  The patents are directed towards chemotherapeutic uses of certain adenosine triphosphate (“ATP”) inhibitors, particularly 3-bromopyruvate.  The patents have been exclusively licensed to a company called PreScience Labs.  According to the company’s webpage, “PreScience Labs has successfully completed preclinical mechanistic, in–vitro and animal testing using the intro–arterial delivery of its proprietary drug 3–bromopyruvate ( “3–BrPA” or “PSL-001” ), and FDA has authorized Phase I testing.

One of the other named inventors on the patent is Young Hee Ko.  According to court documents, Ko and Pedersen “have a lengthy professional history:  Ko joined Plaintiff’s laboratory in 1991 and the two worked together until Ko’s resignation from JHU in 2006.  The two also appear to have had some sort of domestic arrangement: Ko acknowledged in a 2006 deposition that she sometimes stayed overnight at Plaintiff’s house and that she co-owned a vehicle with plaintiff.”

The third named inventor on the patents is Jean-Francois Geschwind, a former member of The Johns Hopkins University School of Medicine Department of Radiology.  He is currently identified on the PreScience Labs website as Founder and CEO.

On June 11, 2015, Pedersen filed a lawsuit in the District of Maryland seeking a (1) declaration under 35 USC 256 that Ko is the sole inventor of both patents and (2) an order directing the United States Patent and Trademark Office (USPTO) to issue a Certificate of Correction accordingly.
Even though Pedersen initiated the patenting process in 2001 by executing an invention disclosure with the Johns Hopkins Office of Technology Licensing identifying all three of them as inventors of the subject matter, he claims that at the time did not understand the distinction between inventorship and authorship.  He now claims that Geschwind’s sole contribution during the experimentation phase of the invention was to “guide the catheter into the hepatic arteries” of laboratory animals and “push the plunger,” and that Geschwind “did not even know what 3-BrPA was before Ko educated him.”

On October 27, 2015, the court issued an order granting Defendants’ (Johns Hopkins and Geschwind) motion to dismiss.  The court found that Pedersen lacked standing under Article III of the Constitution because he had failed to identify a “cognizable injury redressable by the section 256 relief that he seeks.” 
In particular, the court rejected his argument that his status as “named inventor” was enough to allow him to sue the University for change inventorship.  According to the court, “Plaintiff cannot seriously contend that he has standing to sue in federal court simply because he is unhappy with the manner in which a bona fide assignee of a patent chooses to deploy or license its interest.  Such a theory would confer near-limitless standing on disaffected scientists, well beyond the bounds of the particularized injury that Article III mandates.”

The court also rejected Pedersen’s argument that he had financial interest in the matter sufficient to establish standing, pointing out that Pedersen currently enjoyed a financial interest equal to one-third of the 35% “inventors’ personal share” provided by the Johns Hopkins IP Policy, which he would lose if he succeeded in removing himself as an inventor on the patents.
Pedersen also argued for standing based purely on “reputational interest,” asserting that his status as a “fair and honest academician is and will be adversely affected by the inclusion of himself and Geschwind as co-inventors.”  The court acknowledged the fact that a recent Federal Circuit decision held that “concrete and particularized reputational injury can give rise to Article III standing” (citing Shukh v. Seagate Technologies (decided October 2, 2015)).  However, Shukh involved a plaintiff who argued he has been wrongfully omitted as an inventor.  In contrast, the District Court characterized as “conclusory and speculative” Pedersen’s allegation that his reputation has been harmed by being wrongly included as a named inventor on the patents.


Tuesday, October 27, 2015

PTAB Upholds Validity of Herceptin Patent

Today the Patent Trial and Appeal Board issued a unanimous decision in Phigenix, Inc. v. ImmunoGen, Inc., upholding the validity of Immunogen’s US Patent Number 8,337,856.  The petition for inter partes review (IPR) was filed by Phigenix, Inc..  Genentech is a real party-in-interest in the proceedings.

 The ’856 patent claims “[a]n immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, wherein the antibody is [HERCEPTIN].”  Herceptin is a biologic developed by Genentech for the treatment of some forms of breast cancer and gastric cancer.

Phigenix cited several prior art references which allegedly rendered the claims obvious and thus invalid under 35 USC 103.  One of the primary references, Chari 1992, describes immunoconjugates comprising an anti-ErbB2 mouse monoclonal antibody chemically coupled to a maytansinoid toxin (DMI).  The other primary reference was the HERCEPTIN label itself.  A Phigenix expert (Rosenblum) submitted a declaration which, according to Phigenix, established that it would have been obvious to substitute HERCEPTIN for the mouse antibody described in Chari 1192 “based on the teachings of Chari 1992 and HERCEPTIN label, as well as the general knowledge in the art at the time.”

The PTAB rejected petitioner’s argument, however, finding that the patent owner had provided persuasive evidence that at the time the patent was filed “prior art indicated that HERCEPTIN®-maytansinoid immunoconjugates would have been expected to exhibit unacceptable levels of antigen-dependent toxicity in normal human liver tissue in patients.”  The PTAB went on to find persuasive evidence in support of patent owner’s argument that ordinary artisans would not have had a reasonable expectation that any immunoconjugate, much less the claimed Herceptin®-maytansinoid immunoconjugate in particular, would be useful to treat solid tumors in humans,” given that “[r]esearchers had targeted tumors with immunoconjugates for about 40 years before the ’856 patent” without success and in view of evidence “indicating that preparing any antibody-toxin immunoconjugate for use in the treatment of human tumors was difficult and unpredictable.”

Previously, the PTAB declined to Institute review in a separate case involving a related patent, US Patent Number 7,575,748.  Phigenix, Inc. v. Genentech, Inc. and ImmunoGen, Inc., Case IPR2014-00842 (PTAB Dec. 9, 2014) (Paper 10).


Monday, October 5, 2015

Apotex Dances the BPCIA Patent Dance with Amgen, But Claims It Does Not Need to Provide 180-Day Notice of Commercial Marketing

The Federal Circuit held in Amgen v. Sandoz that the so-called “patent dance” is optional for applicants  seeking approval of a biosimilar product under the abbreviated BPCIA pathway, as discussed here.  Indeed, biosimilar applicants have in a number of cases chosen not to participate in the “patent dance.”  This occurred, for example, in a recent lawsuit filed by Amgen against Hospira in connection with Hospira’s plan to bring a biosimilar version of Epogen to market, as described in an earlier post.  In fact, until today I was personally unaware of any case in which a biosimilar applicant actually did participate in the patent dance with a reference sponsor, but that has changed with Amgen’s filing of a lawsuit against Apotex on October 2, 2015.

Amgen v. Apotex was filed in the Southern District of Florida, and alleges that Apotex has infringed, or will infringe, US Patent Numbers 8,952,138 and 6,162,427 by seeking approval under the abbreviated BPCIA pathway for a biosimilar version of filgrastim (which is sold by Amgen under the trade name Neupogen).  The complaint is available here.

According to the complaint, Apotex participated in the exchange of information set forth in the BPCIA, i.e., the patent dance, which included providing Amgen with a copy of its abbreviated Biologic License Application (aBLA), and as a result of these exchanges the parties agreed to the inclusion of these two US patents in the lawsuit.  The ‘138 patent “covers improved redox chemistry-based methodologies for efficiently refolding cysteine -containing proteins expressed in non-mammalian cells at high protein frustrations.”  Presumably Amgen believes the patent will be infringed by the processes Apotex will use to manufacture the biosimilar filgrastim.  

The ‘427 patent is directed towards a method that “employs a combination of G-CSF and a chemotherapeutic agent to mobilize stem cells more efficiently from the bone marrow to peripheral blood in a patient in need of a peripheral stem cell transplant.”  Amgen alleges that if FDA approves the Apotex product for the same indications as Amgen’s Neupogen product (which is what FDA did with respect to Zarxio, Sandoz’s biosimilar version of Neupogen), or if FDA requires Apotex’s label to contain the same information as Amgen’s Neupogen, then this will induce infringement of the ‘427 patent.  According to Amgen, “absent a legally cognizable and enforceable commitment by Apotex preventing Apotex from marketing its filgrastim product with a label that includes the same information regarding clinical trials, dosage and standard of care as Neupogen label… an actual controversy exists between the parties.”

The BPCIA also requires that biosimilar applicants “shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the” biosimilar product.  In Amgen v. Sandoz, the Federal Circuit interpreted this language as requiring that a biosimilar applicant “only give effective notice of commercial marketing after FDA has licensed its product.”  According to the complaint, Apotex sent Amgen a letter purporting to be Apotex’s Notice of Commercial Marketing on April 17, 2015.  Amgen seeks a declaratory judgment that the notice provided by Apotex on April 17, 2015 is invalid because at that time Apotex’s product had not been approved for licensure by FDA.
For its part, Apotex has reportedly taken the position, in a letter to Amgen dated August 24, 2015, that “because Apotex followed the pathway and provided Amgen with its application and manufacturing information, providing a notice of commercial marketing is not mandatory.”  Significantly, the Federal Circuit decided Amgen v. Sandoz on July 21, 2015, i.e., prior to Apotex’s letter, and held that notice of commercial marketing after licensure is mandatory.  I do not understand the basis for Apotex’s argument that notice of commercial marketing is not mandatory if the biosimilar applicant has participated in the patent dance, but it will likely be interesting to see how this plays out in the courts.





Monday, September 28, 2015

Magistrate Judge Finds Drug Method of Treatment Claim Patent Ineligible in Endo Pharmaceuticals v. Actavis

In 2009, I filed an amici brief on behalf of myself and several other law professors in Prometheus v.  Mayo, which was the first time the Federal Circuit heard the case.  In the decision below, the district court held that the interaction of a synthetic, non-naturally occurring pharmaceutical compound with the human body is a “natural phenomenon.”  In our brief, we basically argued that the interaction of a synthetic compound with the human body is not a natural phenomenon, but that if the definition of “natural phenomena” is interpreted so broadly as to encompass the interaction of human-made drugs with the human body, then by implication drug method of treatment claims seemed vulnerable to invalidation under 101 for encompassing patent ineligible subject matter.

Nonetheless, the Federal Circuit and the Supreme Court invalidated the Prometheus claims based on an assumption that the interaction of the pharmaceutical agent (the metabolic breakdown product of a drug) with the human body is a natural phenomenon.  In the Supreme Court’s decision, Mayo v. Prometheus, Justice Breyer seemed cognizant of this concern, and affirmatively stated that drug method of treatment claims should not be threatened by the holding in Mayo.  Still, I have continued to wonder how secure drug method of use claims are post-Mayo, particularly given the expansive interpretation of the Mayo/Alice by the district court’s and the Federal Circuit in decisions such as Ariosa (discussed in a previous post).

Thus, it came as no surprise when I saw a September 23, 2015 Report and Recommendation from a magistrate judge in the District of Delaware recommending invalidation of a drug method of treatment patent for patent ineligibility on a motion to dismiss under Rule 12(b)(6).  The case, Endo Pharmaceuticals v.  Actavis, is an ANDA litigation brought by Endo Pharmaceuticals against Actavis in connection with a Generic Oxymorphone ER Tablets.   The Report and Recommendation is available here.
The patent is US Patent Number 8,871,779, and representatives of claim one recites:

1. A method of treating pain in a renally impaired patient, comprising the steps of:

a. providing a solid oral controlled release dosage form, comprising: i. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and ii. a controlled release matrix;

b. measuring a creatinine clearance rate of the patient and determining it to be (a) less than about 30 ml/min, (b) about 30 mL/min to about 50 mL/min, (c) about 51 mL/min to about 80 mL/min, or (d) above about 80 mL/min; and

c. orally administering to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief;

wherein after said administration to said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21 nghr/mL.

The magistrate judge applied the Mayo/Alice two-part test for patent eligibility.  The first step is to determine whether the claims at issue are “directed to a patent-eligible concept,” in this case a natural law.  The magistrate judge notes that the “Mayo court provided a broad definition for a law of nature: ‘[a] patent that… describes a relationship that is the consequence of entirely natural processes sets forth a natural law.’”  The judge went on to conclude that “the connection between the severity of renal impairment and the bioavailability of oxymorphone” was the relevant natural law to which the claims are directed.

The second step is to determine whether the claims “add enough” to the “natural law” to render the claim patent eligible.  The magistrate judge essentially determined that the “providing,” “measuring,” and “administering” steps were analogous to the steps in the claims held to be patent ineligible in Mayo, and thus did not provide “enough” extra. 

The claims at issue in Mayo essentially recited a method of performing a diagnostic test and determining the optimal dosage of drug for a patient.  The claim did not recite a step of actually administering the optimized dosage to a patient, and many have held out the hope that in the future a claim that included this additional step of actually applying the information derived from the diagnostic test would be found patent eligible.

But note that Endo’s claim does expressly recite administering a lower dosage of drug to a patient based on the results of the diagnostic test, i.e., the claim does include the extra step that many thought would have rendered the claims in Mayo patent ineligible.  But, at least in the view of this magistrate judge, the inclusion of this extra step was not sufficient to render the claim patent eligible.  And given the sweeping language of Mayo, particularly as interpreted by the Federal Circuit in Ariosa, it is not hard to see how the magistrate judge came to this conclusion.

It is important to note that the Endo claim is not a straightforward method of treatment claim, i.e., “a method of treating disease X by administering drug Y,” and does not necessarily indicate that the magistrate judge would have ruled such a claim patent ineligible.  The decision does explicitly note that “oxymorphone is ‘widely used’ for acute and chronic pain relief, the showing that the utilization of oxymorphone is not the invention.”  Thus, the magistrate judge seemed to imply that in a case where the “invention” is the discovery of a new pharmaceutical agent for the treatment of some medical condition a method of treatment claim could still be patent eligible under Mayo. 

It seems inevitable that before long we will be seeing a decision involving an allegation that a more conventional method of treatment claim is patent ineligible.  It will be interesting to see how the courts handle that case, and also how the district court judge in Endo v. Actavis (and perhaps the Federal Circuit eventually) responds to the magistrate judge’s recommendation.